Combination therapies including MYT1 inhibitors and wee1 inhibitors

Abstract

This application relates the use of a combination of a membrane-associated tyrosine and threonine- specific CDC2-inhibitory kinase (Myt1) inhibitor with a Weel inhibitors in treating cancer or inducing cell death. The synergistic effect of the combination results in a subtherapeutic dose or a reduced dosing schedule of the Myt1 inhibitor, the Wee1 inhibitor, or both relative to a monotherapy of either the Myt1 inhibitor or the Wee1 inhibitor in isolation.

Description

[0001] COMBINATION THERAPIES INCLUDING MYT1 INHIBITORS AND WEE1 INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to therapies using inhibitors of membrane associated tyrosine and threonine specific CDC2 inhibitory kinase (Myt1) (gene name PKMYT1) inhibitors in combination with inhibitors of Wee1 (gene name WEE1), e.g., at a subtherapeutic dose or a reduced dosing schedule.

[0004] BACKGROUND

[0005] DNA is continuously subjected to both endogenous insults (e.g., stalled replication forks, reactive oxygen species) and exogenous insults (e.g., UV, ionizing radiation, chemical) that can lead to DNA damage. As a result, cells have established sophisticated mechanisms to counteract these deleterious events that would otherwise compromise genomic integrity and lead to genomic instability diseases such as cancer. These mechanisms are collectively referred to as the DNA damage response (DDR). One component of the overall DDR is the activation of various checkpoint pathways that modulate specific DNA-repair mechanisms throughout the various phases of the cell cycle, which includes the G1 , S, G2 and Mitosis checkpoints. A majority of cancer cells have lost their G1 checkpoint owing to p53 mutations and as such, rely on the G2 checkpoint to make the necessary DNA damage corrections prior to committing to enter mitosis and divide into two daughter cells.

[0006] There is a need for new anti-cancer therapeutic approaches, e.g., those utilizing small molecules, especially therapies allowing for targeted cancer treatment.

[0007] SUMMARY OF THE INVENTION

[0008] The disclosure provides methods of using membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1) inhibitors in combination with a Wee1 inhibitor. Advantageously, the combination of a Myt1 inhibitor and the Wee1 inhibitor may act synergistically in treating cancer or inducing cell death. The synergistic effect may result in effective treatment using a lower dose (e.g., a subtherapeutic dose) of the Myt1 inhibitor, the Wee1 inhibitor, or both relative to a monotherapy of either the Myt1 inhibitor or the Wee1 inhibitor in isolation.

[0009] In a first aspect, the disclosure provides a method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and (I) the dose of Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of Myt1 inhibitor is subtherapeutic; (iii) the dose of the Wee1 inhibitor is subtherapeutic; (iv) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or (v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[0010] In a second aspect, the disclosure provides a method of inducing cell death in a cancer cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and (I) the dose of Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of Myt1 inhibitor is subtherapeutic; (iii) the dose of the Wee1 inhibitor is subtherapeutic; (iv) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or (v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule. In some embodiments, the cell is in a subject. In some embodiments of the first or second aspect, the cancer is 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. In some embodiments, the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV. In some embodiments the cancer comprises a cancer previously identified as having a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0011] In some embodiments, the cancer comprises CCNE1 overexpression. In some embodiments, the cancer comprises 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.

[0012] In some embodiments, the cancer comprises a FBXI / l / 7mutation. In some embodiments, the cancer comprises uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0013] In some embodiments, the cancer comprises a KRAS mutation. In some embodiments, the cancer comprises KRAS overexpression. In some embodiments, the cancer comprises colorectal cancer, pancreatic cancer, lung cancer uterine cancers, ovarian cancers, cervical cancers or gastro-esophageal cancer. In some embodiments, the cancer comprises an HRAS mutation. In some embodiments, the cancer comprises kidney cancer, a bladder cancer, head and neck cancer, or a thyroid cancer. In some embodiments, the cancer comprises a NRAS mutation. In some embodiments, the cancer comprises colorectal cancer, thyroid cancer, or melanoma.

[0014] In some embodiments, the replication stress biomarker is a PPP2R1A mutation. In some embodiments, the cancer comprises endometrial cancer, ovarian cancer, and uterine cancer.

[0015] In a third aspect, the disclosure provides a method of increasing CDK1 activity in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and (i) the dose of Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of Myt1 inhibitor is subtherapeutic; (iii) the dose of the Wee1 inhibitor is subtherapeutic; (iv) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or (v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[0016] In a fourth aspect, the disclosure provides a method of causing premature mitosis in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and (i) the dose of Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of Myt1 inhibitor is subtherapeutic; (iii) the dose of the Wee1 inhibitor is subtherapeutic; (iv) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or (v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule. In some embodiments of the third or fourth aspect the cell is in a subject.

[0017] In some embodiments, the dose of the Myt1 inhibitor is at most 500 mg. In some embodiments, the dose of the Myt1 inhibitor is at most 250 mg. In some embodiments, the dose of the Myt1 inhibitor is at most 100 mg. In specific embodiments, 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 reduced dosing schedule of the Myt1 inhibitor comprises administering a dose once a day. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises administering a dose twice a day. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 1 / 6 dosing schedule. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 2 / 5 dosing schedule. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 3 / 4 dosing schedule. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 5 / 2 dosing schedule. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 1 week on / 1 week off dosing schedule. In some embodiments, the reduced dosing schedule of the Myt1 inhibitor comprises a 2 weeks on / 1 week off dosing schedule.

[0018] In some embodiments, the dose of the Wee1 inhibitor is at most 520 mg. In some embodiments, the dose of the Wee1 inhibitor is at most 400 mg. In some embodiments, the dose of the Wee1 inhibitor is at most 200 mg. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose once a day. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose twice a day. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 1 / 6 dosing schedule. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 2 / 5 dosing schedule. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 3 / 4 dosing schedule. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 5 / 2 dosing schedule. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 1 week on / 1 week off dosing schedule. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor comprises a 2 weeks on / 1 week off dosing schedule.

[0019] In some embodiments, the dose of the Myt1 inhibitor is subtherapeutic and the dose of the Wee1 inhibitor is subtherapeutic. In some embodiments, the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule and the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[0020] In some embodiments, the dose of the Myt1 inhibitor is a therapeutically effective dose and the dose of the Wee1 inhibitor is subtherapeutic. In some embodiments, the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule and the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[0021] In some embodiments, the Wee1 inhibitor is administered as a pharmaceutical composition. In some embodiments, the Wee1 inhibitor is one of:

[0022] or a pharmaceutically acceptable salt thereof. In some embodiments, the Wee1 inhibitor is selected from the group consisting of compounds W1 to W3052. In specific embodiments, 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 a PROTAC. In some embodiments, the Wee1 inhibitor is a molecular glue. In some embodiments, the Myt1 inhibitor is administered as a pharmaceutical composition.

[0023] In some embodiments, the Myt1 inhibitor is a compound of formula (I):

[0024] (I), or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2;

[0025] R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;

[0026] R5is H or -N(R7)2;

[0027] R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SO2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and each Q is independently optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted Ce-w arylene, optionally substituted C2-9 heterocyclylene, or optionally substituted C1-9 heteroarylene.

[0028] In some embodiments, the compound is enriched for the atropisomer of formula (IA):

[0029] (IA), or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, X is CR2.

[0031] In some embodiments, the compound is of formula (II): or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound is enriched for the atropisomer of formula (HA):

[0033] (HA), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of formula (III): wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound is enriched for the atropisomer of formula (IIIA):

[0035] (IHA); or a pharmaceutically acceptable salt thereof. In some embodiments, R2Ais hydrogen, optionally substituted C1-6 alkyl, or halogen.

[0036] In some embodiments, R3is optionally substituted C1-6 alkyl. In some embodiments, R3is halogen. In some embodiments, R4is optionally substituted C1-6 alkyl. In some embodiments, R4is halogen. In some embodiments, the halogen is chlorine.

[0037] In some embodiments, R2is hydrogen. In some embodiments, R2is optionally substituted C1-6 alkyl. In some embodiments, R2is optionally substituted methyl or optionally substituted isopropyl. In some embodiments, R2is halogen.

[0038] In some embodiments, R1is hydrogen. R1is halogen. In some embodiments, R1is chlorine or bromine. In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl. In some embodiments, R1is optionally substituted C1-9 heteroaryl. In some embodiments, R1is 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 R1is optionally substituted with substituents as defined for optionally substituted C1-9 heteroaryl. In some embodiments, R1is optionally substituted C3-8 cycloalkyl. In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C3-8 cycloalkyl. In some embodiments, R1is optionally substituted C2-9 heterocyclyl. In some embodiments, R1is 1 ,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3.3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9 heterocyclyl. In some embodiments, R1is optionally substituted C3-8 cycloalkenyl. In some embodiments, R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl. In some embodiments, R1is optionally substituted C6-10 aryl. In some embodiments, R1is optionally substituted phenyl. In some embodiments, R1is -Q- R7B. In some embodiments, Q is optionally substituted C2-6 alkynylene. In some embodiments, Q is optionally substituted C1-6 alkylene. In some embodiments, Q is optionally substituted Ce-w arylene. In some embodiments, R7Bis optionally substituted C2-9 heterocyclyl. In some embodiments, R7Bis optionally substituted Ce-w aryl. In some embodiments, R1is optionally substituted with one, two, or three groups independently selected 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, wherein n is 0 or 1. In some embodiments, R1is -N(R7)2. In some embodiments, R1is diethylamino.

[0039] In some embodiments, R5is hydrogen. In some embodiments, R5is -N(R7)2. In some embodiments, R5is -NH2. In some embodiments, R6is -C(O)NH(R8). In some embodiments, R6is - C(O)NH2. In some embodiments, R6is -C(O)NH(Me). In some embodiments, R6is -SO2R7A. In some embodiments, R6is -SCkMe.

[0040] In some embodiments, the Myt1 inhibitor is a compound selected from the group consisting of compounds 1 to 328 and pharmaceutically acceptable salts thereof. In specific embodiments, the Myt1 inhibitor is lunresertib or a pharmaceutically acceptable salt thereof.

[0041] In particular embodiments, the Myt1 inhibitor is lunresertib or a pharmaceutically acceptable salt thereof and the Wee1 inhibitor is Debio-0123 or a pharmaceutically acceptable salt thereof.

[0042] Definitions

[0043] The term "aberrant," as used herein, refers to different from normal. When used to describe activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, where returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0044] The term “acyl,” as used herein, represents a group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0045] The term “adenocarcinoma,” as used herein, represents a malignancy of the arising from the glandular cells that line organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0046] The term “alkanoyl,” as used herein, represents a hydrogen or an alkyl group that is attached to the parent molecular group through a carbonyl group and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain from 1 to 7 carbons. The alkanoyl group may be unsubstituted of substituted (e.g., optionally substituted Ci-7 alkanoyl) as described herein for alkyl group. The ending “-oyl” may be added to another group defined herein, e.g., aryl, cycloalkyl, and heterocyclyl, to define “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl.” These groups represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl” may be optionally substituted as defined for “aryl,” “cycloalkyl,” or “heterocyclyl,” respectively.

[0047] The term “alkenyl,” as used herein, represents acyclic monovalent straight or branched chain hydrocarbon groups of containing one, two, or three carbon-carbon double bonds. Non-limiting examples of the alkenyl groups include ethenyl, prop-1 -enyl, prop-2-enyl, 1 -methylethenyl, but-1 -enyl, but-2-enyl, but-3-enyl, 1 -methylprop-1 -enyl, 2-methylprop-1 -enyl, and 1 -methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl.

[0048] The term “alkenylene,” as used herein, refers to a divalent alkenyl group. An optionally substituted alkenylene is an alkenylene that is optionally substituted as described herein for alkenyl.

[0049] The term “alkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C1-6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group can be further substituted as defined herein. The term “alkoxy” can be combined with other terms defined herein, e.g., aryl, cycloalkyl, or heterocyclyl, to define an “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” groups. These groups represent an alkoxy that is substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” may optionally substituted as defined herein for each individual portion.

[0050] The term “alkoxyalkyl,” as used herein, represents a chemical substituent of formula -L-O-R, where L is C1-6 alkylene, and R is C1-6 alkyl. An optionally substituted alkoxyalkyl is an alkoxyalkyl that is optionally substituted as described herein for alkyl.

[0051] The term “alkyl,” as used herein, refers to an acyclic straight or branched chain saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has from 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from the group consisting of: amino; alkoxy; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =0; =S; -C(O)R or -SO2R, where R is amino; and =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0052] The term “alkylene,” as used herein, refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.

[0053] The term “alkylamino,” as used herein, refers to a group having the formula -N(RN1)2 or -NHRN1, in which RN1is alkyl, as defined herein. The alkyl portion of alkylamino can be optionally substituted as defined for alkyl. Each optional substituent on the substituted alkylamino may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0054] The term “alkylsulfenyl,” as used herein, represents a group of formula —S— (alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl. The term “alkylsulfinyl,” as used herein, represents a group of formula -S(O)-(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

[0055] The term “alkylsulfonyl,” as used herein, represents a group of formula -S(O)2-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

[0056] The term “alkynyl,” as used herein, represents monovalent straight or branched chain hydrocarbon groups of from two to six carbon atoms containing at least one carbon-carbon triple bond and is exemplified by ethynyl, 1 -propynyl, and the like. The alkynyl groups may be unsubstituted or substituted (e.g., optionally substituted alkynyl) as defined for alkyl.

[0057] The term “alkynylene,” as used herein, refers to a divalent alkynyl group. An optionally substituted alkynylene is an alkynylene that is optionally substituted as described herein for alkynyl.

[0058] The term “amino,” as used herein, represents -N(RN1)2, where, if amino is unsubstituted, both RN1are H; or, if amino is substituted, each RN1is independently H, -OH, -NO2, -N(RN2)2, -SO2ORN2, -SO2RN2, - SORN2, -C(O)ORN2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one RN1is not H, and where each RN2is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., -NHRN1), where RN1is independently -OH, SO2ORN2, -SO2RN2, -SORN2, -COORN2, optionally substituted alkyl, or optionally substituted aryl, and each RN2can be optionally substituted alkyl or optionally substituted aryl. In some embodiments, substituted amino may be alkylamino, in which the alkyl groups are optionally substituted as described herein for alkyl. In some embodiments, an amino group is -NHRN1, in which RN1is optionally substituted alkyl.

[0059] The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. Aryl group may include from 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, indanyl, indenyl, etc. The 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; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; -(CHzJn- C(O)ORA; -C(O)R; and -SO2R, where R is amino or alkyl, RAis H or alkyl, and n is 0 or 1 . Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0060] The term “aryl alkyl,” as used herein, represents an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as the individual groups as described herein.

[0061] The term “arylene,” as used herein, refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

[0062] The term “aryloxy,” as used herein, represents a chemical substituent of formula -OR, where R is an aryl group, unless otherwise specified. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0063] The term “azido,” as used herein, represents an -N3 group. The term "cancer," as used herein, refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans).

[0064] The term “carbocyclic,” as used herein, represents an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0065] The term “carbonyl,” as used herein, represents a -C(O)- group.

[0066] The term "carcinoma," as used herein, refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.

[0067] The term “cyano,” as used herein, represents -CN group.

[0068] The terms “CCNE1” and “cyclin E1 ,” as used interchangeably herein, refer to G1 / S specific cyclin E1 (Gene name: CCNET). A cell overexpressing CCNE1 (alternatively referred to herein as a CCNE1- high cell) is one that exhibits a higher activity of CCNE1 than a cell normally expressing CCNE1. For example, a CC / VET-overexpressing cell is a cell that exhibits a copy number of at least 3 compared to a diploid normal cell with 2 copies. Thus, a cell exhibiting a copy number greater than 3 of CCNE1 is a cell overexpressing CCNE1. The CCNE1 overexpression may be measured by identifying the expression level of the gene product in a cell (e.g., CCNE1 mRNA transcript count or CCNE1 protein level).

[0069] The terms “CDC25” and “CDC25 phosphatase,” used interchangeably herein, refer to the CDC25 family of cell division control phosphatase proteins. The family of CDC25 phosphatases remove phosphorylation events on CDK proteins, e.g., those caused by Myt1 and Wee1 . CDC25 and CDK1 participate in a positive feedback loop, wherein the activation of one promotes the activation of the other. CDC25 phosphatases act participate in regulating cell division, participating in controlling the transition from G1 phase to S phase, and the transition from G2 phase to M phase. The family of CDC25 phosphatases include CDC25A (encoded by the CDC25A gene), CDC25B (encoded by the CDC25B gene), and CDC25C (encoded by the CDC25C gene).

[0070] The term “CDK,” as used herein, refers to the family of cyclin-dependent kinases, e.g., cyclin- dependent kinase 4 (CDK4; encoded for by the CDK4 gene), cyclin-dependent kinase 6 (CDK6, encoded for by the CDK6 gene), or cyclin-dependent kinase 12 (CDK12; encoded for by the CDK12 gene). CDK proteins interact with a variety of regulatory proteins via phosphorylation of prescribed sites of the protein, either activating or inhibiting the protein. Though they are most commonly associated with cyclin proteins (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 several other cell-signaling proteins. A CDK gene with a loss-of-function mutation is one that fails to produce a functional CDK protein or produces reduced quantities of CDK protein in a cell.

[0071] The term “CDK regulatory protein” as used herein, refers to any polypeptide molecule which may function as a regulator (e.g., an inhibitor or an activator) of a CDK protein. CDK regulatory proteins include proteins which inhibit a CDK protein (e.g., p16 and p14arf; both encoded for by the CDKN2A gene; p16 and p14arf both inhibit CDK proteins such as CDK4 and CDK6) and proteins which prevent the inhibition of CDK proteins (e.g., CDC25A; encoded for by the CDC25A gene. CDC25A prevents the inhibition of CDK proteins by removing phosphorylation events on the CDK protein). A mutation to a CDK regulatory protein refers to a gain-of-function mutation or a loss-of-function mutation to a gene which encodes a CDK regulatory protein.

[0072] The term “cycloalkenyl,” as used herein, refers to a non-aromatic carbocyclic group having at least one double bond in the ring and from three to ten carbons (e.g., a C3-10 cycloalkenyl), unless otherwise specified. Non-limiting examples of cycloalkenyl include cycloprop-1 -enyl, cycloprop-2-enyl, cyclobut-1 -enyl, cyclobut-1 -enyl, cyclobut-2-enyl, cyclopent-1 -enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1 -yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. The cycloalkenyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl) as described for cycloalkyl.

[0073] The term “cycloalkenyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be substituted as the individual groups defined herein.

[0074] The term “cycloalkenylene,” as used herein, represents a divalent cycloalkenyl group. An optionally substituted cycloalkenylene is a cycloalkenylene that is optionally substituted as described herein for cycloalkyl.

[0075] The term “cycloalkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0076] The term “cycloalkyl,” as used herein, refers to a cyclic alkyl group having from three to ten carbons (e.g., a C3-C10 cycloalkyl), unless otherwise specified. Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of bicyclo[p.q.O]alkyl type, in which each of p and q is, 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 may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1 , 2, or 3, each of p and q is, 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. The cycloalkyl group may be a spirocyclic group, e.g., spiro[p.q]alkyl, in which each of p and q is, 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 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1 - bicyclo[2.2.1 Jheptyl, 2-bicyclo[2.2.1 Jheptyl, 5-bicyclo[2.2.1 Jheptyl, 7-bicyclo[2.2.1 Jheptyl, and decalinyl. The cycloalkyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkyl) with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =0; =S; -SO2R, where R is optionally substituted amino; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl; and -C0N(RA)2, where each RAis independently H or alkyl, or both RA, together with the atom to which they are attached, combine to form heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0077] The term “cycloalkyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally substituted as the individual groups described herein. The term “cycloalkylene,” as used herein, represents a divalent cycloalkyl group. An optionally substituted cycloalkylene is a cycloalkylene that is optionally substituted as described herein for cycloalkyl.

[0078] The term “cycloalkynyl,” as used herein, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having from eight to twelve carbons, unless otherwise specified. Cycloalkynyl may include one transannular bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. The cycloalkynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkynyl) as defined for cycloalkyl.

[0079] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.

[0080] The term “dosing schedule” or a “dosing regime,” as used herein, refers to the frequency at which a pharmaceutical composition is administered to a subject. For example, a pharmaceutical composition can be administered once per day, twice per day, three times per day, once per week, once per month, etc. A dosing schedule may include a system of administering treatment for a length of time, followed by a period of reduced or no dosing (e.g., an “on-off dosing schedule). For example, a pharmaceutical composition may be administered on a “3 days on, 4 days off’ dosing schedule (3 / 4 dosing); a 5 days on, 2 days off dosing schedule (5 / 2 dosing schedule), a “1 day on, 6 days off’ dosing schedule (1 / 6 dosing), a “2 days on, 5 days off’ dosing schedule (2 / 5 dosing), a “4 days on, 3 days off’ (4 / 3 dosing), a “1 week on, 1 week off’ dosing schedule, a “2 weeks on, 1 week off’ dosing schedule, or a “3 weeks on, 2 weeks off’ dosing schedule. Each day of an on-off dosing schedule including the dosing of an active pharmaceutical ingredient may include multiple administrations (e.g., an active pharmaceutical ingredient may be administered twice daily on a 3 / 4 dosing schedule). In a combination therapy, one or more of the active pharmaceutical ingredients may be dosed on different dosing schedules (e.g., a first active pharmaceutical ingredient is administered once daily, and a second active ingredient is administered twice daily).

[0081] The term “EGFR,” as used herein, refers to the epidermal growth factor receptor protein (encoded for by the EGFR gene). EGFR is a transmembrane glycoprotein with an extracellular domain and an intracellular domain. The extracellular domain receives signals (e.g., in the form of a signal peptide such as epidermal growth factor), resulting in a confirmational or chemical change in the intracellular domain. The intracellular domain may then interact with a variety of cell signaling pathways (e.g., the RAS / MAPK pathway). An EGFR gene with a loss-of-function mutation is one that fails to produce a functional EGFR protein or produces reduced quantities of EGFR protein in a cell.

[0082] The term “FBXW7,” as used herein, refers to F-box / WD Repeat-Containing Protein 7 transcript (gene name: FBXW7). An FBXW7 gene having an inactivating mutation is one that fails to produce a functional FBXW7 protein or produces reduced quantities of FBXW7 protein in a cell.

[0083] The term “gamma-H2AX" or “yH2AX,” as used herein, refers to the phosphorylated form of histone H2AX. The phosphorylation of H2AX is a marker known in the art to be indicative of the presence of double-strand breaks (DSBs) in the DNA. Further, the term “pan-yH2AX,” as used herein, refers to the broad presence of phosphorylated H2AX within a cell. The induction of pan-yH2AX may be used herein as an indicator that a cell may be more likely to undergo premature mitosis. The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, and fluorine.

[0084] The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. Each heteroatom is, independently, O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups includes two contiguous oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When heteroalkyl is substituted and the substituent is bonded to the heteroatom, the substituent is selected according to the nature and valency of the heteroatom. Thus, the substituent bonded to the heteroatom, valency permitting, is selected from the group consisting of =0, -N(RN2)2, -SO2ORN3, -SO2RN2, -SORN3, - COORN3, an N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, where each RN2is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each RN3is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. When heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I. It is understood that carbon atoms are found at the termini of a heteroalkyl group.

[0085] The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0086] The term “heteroarylene,” as used herein, represents a divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl.

[0087] The term “heteroaryloxy,” as used herein, refers to a structure -OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl.

[0088] The term “heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl can be aromatic or non-aromatic. Nonaromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups include from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may include up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. If the heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heterocyclyls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3- dihydrobenzothiophene. The heterocyclyl 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; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; 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 heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0089] The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0090] The term “heterocyclylene,” as used herein, represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl.

[0091] The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula -OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl.

[0092] The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group. The term “HRAS” (or alternatively “Hras,” “H-RAS,” or “H-ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the HRAS (alternatively referred to as “Hras," “H-RAS," or “H-ras") gene. “HRAS mutation,” as used herein, refers to a mutation in the HRAS gene which results in the alteration of the amino acid sequence of an HRAS protein. HRAS mutations are commonly observed in thyroid cancer, bladder cancer, head and neck cancer, and kidney cancer.

[0093] The term “KRAS” (or alternatively “Kras,” “K-RAS,” or “K-ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the KRAS (alternatively referred to as Kras, K-RAS, or K-ras”) gene. Two common isoforms of the KRAS protein are known, isoform a (KRAS4A) and isoform b (KRAS4B), which arise from alternative gene splicing. Unless otherwise specified, KRAS should be understood to refer to both isoforms. “KRAS mutation,” as used herein, refers to a mutation in the KRAS gene which results in the alteration of the amino acid sequence of a KRAS protein. KRAS mutations are commonly observed in colorectal cancer, lung cancer, pancreatic cancer, gynecological cancer (e.g., uterine cancer, ovarian cancer, cervical cancer, etc.) and gastro-esophageal cancer.

[0094] The term "leukemia," as used herein, refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).

[0095] The term “lymphoma,” as used herein, refers to a cancer arising from cells of immune origin.

[0096] The term "melanoma," as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs.

[0097] The term “molecular glue” as used herein, refers to a molecular species configured to force the association between a first protein and a second protein, e.g., by binding to the first protein, thereby affecting a chemical or confirmational change in the first protein and promoting an interaction between the first protein and the second protein. Critically, a molecular glue promotes association between two proteins which normally have minimal-to-no interaction in the absence of a molecular glue. A molecular glue may be specifically configured to induce binding between the first protein and the second protein.

[0098] The term “MYC” as used herein, refers to the MYC family of cell signaling proteins. The MYC family includes c-MYC, l-MYC, and n-MYC (encoded for by the c-MYC, l-MYC, and n-MYC genes respectively; collectively referred to as MYC genes). The MYC proteins perform several regulatory processes across cellular functions, many of which are associated with cell division, cell proliferation, and DNA replication. A MYC gene with a gain-of-function mutation is one that produces a MYC protein with enhanced activity (e.g., a MYC protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a MYC protein in a cell. A cell overexpressing MYC is one that exhibits a higher activity of a MYC gene than a cell normally expressing MYC. For example, a / WYC-overexpressing cell is a cell that exhibits a copy number of at least 3 compared to a diploid normal cell with 2 copies. Thus, a cell exhibiting a copy number greater than 3 of MYC is a cell overexpressing MYC. The MYC overexpression may be measured by identifying the expression level of the gene product in a cell (e.g., MYC mRNA transcript count or MYC protein level).

[0099] The term “Myt1 ,” as used herein, refers to membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1) (Gene name PKMYT1).

[0100] The term “Myt1 inhibitor,” as used herein, represents a compound that upon contacting the enzyme Myt1 , whether in vitro, in cell culture, or in an animal, reduces the activity of Myt1 , such that the measured Myt1 ICso is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Myt1 inhibitors, the Myt1 ICso may be 100 nM or less (e.g., 10 nM or less, or 3 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Myt1 IC50 is 1 nM to 1 pM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Even more preferably, the Myt1 ICso is less than 20 nm (e.g., 1 nM to 20 nM).

[0101] The term “nitro,” as used herein, represents an -NO2 group.

[0102] The term “NRAS” (or alternatively “Nras,” “N-RAS,” or “N-ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the NRAS (alternatively referred to as “Nras," “N-RAS," or ’’N-ras") gene. “NRAS mutation,” as used herein, refers to a change to the NRAS gene which results in the alteration of the amino acid sequence of an NRAS protein. NRAS mutations are commonly found in colorectal cancer, thyroid cancer and melanoma.

[0103] The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =0).

[0104] The term “Ph,” as used herein, represents phenyl.

[0105] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

[0106] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier,” as used interchangeably herein, refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0107] The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with 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 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can 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, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0108] The term “PIK3CA,” as used herein, refers to phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (alternatively referred to as P110a; encoded for by the PIK3CA gene); the catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). PI3K plays an important role in cell signaling, e.g., the PI3K / AKT / mTOR pathway. A PIKC3A gene with a gain-of-function mutation is one that produces a PIK3CA protein with enhanced activity (e.g., a PIK3CA protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a PIK3CA protein in a cell.

[0109] The term “PPP2R1 A,” as used herein, refers to the Serine / threonine-protein phosphatase 2A 65kDa regulatory subunit A alpha isoform (encoded by the PPP2R1A gene). PPP2R1 A is a regulatory subunit of protein phosphatase 2 (PP2A), one of the four major Ser / Thr phosphatases. Wild type PP2A is implicated for its role in regulating tumor production by controlling phosphorylation events in cell signaling pathways. A PPP2R1A gene with a loss-of-function mutation is one that fails to produce a functional PPP2R1A protein or produces reduced quantities of PPP2R1 A protein in a cell.

[0110] The term “PTEN,” as used herein, refers to the phosphatase and tensin homolog protein (encoded for by the PTEN gene). PTEN is a cell-cycle regulating phosphatase that plays a role in the regulation of several cell signaling pathways, e.g., the Akt / PKB signaling pathway. A PTEN gene with a loss-of-function mutation is one that fails to produce a functional PTEN protein or produces reduced quantities of PTEN protein in a cell.

[0111] The term “pre-malignant” or “pre-cancerous,” as used herein, refers to a condition that is not malignant but is poised to become malignant.

[0112] The term “proteolysis targeting chimera,” or alternatively PROTAC, as used herein refers to a molecule including two covalently linked protein binding moieties (e.g., at opposite ends of the molecule). One protein binding moiety is configured to bind to a E3 ubiquitin ligase and a target protein of interest (e.g., a replication associated protein described herein, e.g., Wee1) forming a ternary complex including the E3 ligase, the protein of interest, and the PROTAC. The forced association between the ligase and a target protein then triggers the degradation of the target protein. For example, a PROTAC may encourage the ubiquitination of the target protein by the E3 ubiquitin ligase. The ubiquitinated target protein is then recognized and degraded by a proteosome. Unlike traditional protein inhibitors, PROTAC molecules operate catalytically, and are not consumed by the degradation mechanism. Therefore, they may be administered at significantly lower dosages than traditional protein inhibitors. Further, the binding moieties may be designed to allow for targeted formation of specific ternary complexes, allowing for highly targeted drug administration. The term “protecting group,” as used herein, represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The term “O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term “N-protecting group,” as used herein, represents a group intended to protect a nitrogen containing (e.g., an amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- 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- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'- dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4- nitrobenzoyl.

[0113] Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1 ,3-dithianes, 1 ,3-dioxanes, 1 ,3-dioxolanes, and 1 ,3-dithiolanes.

[0114] Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p- methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl) ; carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2- trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

[0115] 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, and the like; sulfonyl- containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1 -(p-bipheny ly I)- 1 -methylethoxycarbonyl, a,a-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, p- methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like, silylalkylacetal groups such as [2-(trimethylsilyl)ethoxy]methyl and silyl groups such as trimethylsilyl, and the like. Useful N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0116] The term “RAS” (or alternatively, “Ras,” “RAS GTPase,” or “Ras GTPase”), as used herein, refers to the RAS family of cell signaling proteins. The RAS family includes KRAS, HRAS, and NRAS (encoded for by the KRAS, HRAS, and NRAS genes; collectively referred to as RAS genes). About 25% of human cancers are observed to involve a mutation to a RAS gene. A RAS gene with a gain-of-function mutation is one that produces a RAS protein with enhanced activity (e.g., a RAS protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a RAS protein in a cell. Some cancers of the present disclosure may include or be characterized by increased expression of a RAS gene. A cell overexpressing a RAS gene is one that exhibits a higher activity of a RAS gene than a cell normally expressing a RAS gene. For example, a RAS-overexpressing cell is a cell that exhibits a copy number of at least 3 compared to a diploid normal cell with 2 copies. Thus, a cell exhibiting a copy number greater than 3 of a RAS gene is a cell overexpressing RAS. The RAS gene overexpression may be measured by identifying the expression level of the gene product in a cell (e.g., RAS mRNA transcript count or RAS protein level). In some embodiments, the RAS gene overexpression may be a KRAS gene overexpression.

[0117] The term “replication stress” as used herein, refers to a cell undergoing more rapid and / or uncontrolled cell division. Many cancers can be characterized as including a biomarker for replication stress, e.g., a mutation (e.g., a loss-of-function mutation or a gain-of-function mutation) of a gene or the overexpression of a gene which results in shortening the time a cell spends in the G1 , S, or G2 phases of the cell cycle). Additionally, a therapeutic (e.g., chemotherapeutic) drug may also be a driver of replication stress. Methods of the present disclosure may include administration of one or more therapeutic agents which cause replication stress (e.g., a Myt inhibitor) to a cancer with a replication stress mutation.

[0118] The term “reduced dosing schedule” as used herein, refers to a dosing schedule of an active pharmaceutical composition that results in a less frequent dosing relative to a second dosing schedule. For example, a dosing schedule may be “reduced” in a combination therapy relative to the monotherapy. A “reduced” schedule may refer to a reduction in the number of administration events per day (e.g., once daily as opposed to twice daily), an increase in the number of off days (e.g., a 3 / 4 schedule as opposed to a 5 / 2 schedule). A compound (e.g., a MYT1 inhibitor, e.g., any of compounds 1 to 328; or a Wee1 inhibitor, e.g., any of compounds W1 to W3052) administered in a combination therapy may be provided on a reduced dosing schedule relative to the dosing schedule of a monotherapy. A reduced dosing schedule may further include a reduced dose (e.g., a subtherapeutic dose), of the compound.

[0119] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.

[0120] The term “subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having the symptom of cell hyperproliferation, e.g., a cancer. As used herein, the term “subtherapeutic dose” refers to a dose of an active pharmaceutical ingredient, either as an administered dose of pharmacologically active agent in a subject, that functionally is insufficient to elicit the intended pharmacological effect in itself, or that quantitatively is less than the established therapeutic dose for that active pharmaceutical ingredient (e.g., as published in a reference consulted by a person of skill in the art, as recommended by a manufacturer, etc.). In the context of combination therapy, “subtherapeutic dose” is used to refer to a dose of an active pharmaceutical ingredient which is less than the dose intended to elicit the intended pharmaceutical effect when the active pharmaceutical ingredient is administered as a monotherapy A subtherapeutic dose may be defined relative to the amount of the active pharmaceutical ingredient conventionally administered (i.e. , 75% less, 50% less, 40% less, 30% less, 20% less, 10% less, etc.).

[0121] The term “tautomer” refers to structural isomers that readily interconvert, often by relocation of a proton. Tautomers are distinct chemical species that can be identified by differing spectroscopic characteristics, but generally cannot be isolated individually. Non-limiting examples of tautomers include ketone - enol, enamine - imine, amide - imidic acid, nitroso - oxime, ketene - ynol, and amino acid - ammonium carboxylate.

[0122] “Treatment” and "treating," as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent, or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy).

[0123] The term “Wee1 ,” as used herein, refers to a nuclear kinase that is a tyrosine kinase belonging to the Ser / Thr family of protein kinases. This protein is encoded by the WEE1 gene. This protein catalyzes the inhibitory tyrosine phosphorylation of CDC2 / cyclin B kinase and appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from cytoplasmically activated CDC2 kinase, aiding in controlling when a cell enters mitosis. Inhibition of Wee1 (e.g., via a Wee1 inhibitor) causes a reduction in size of the daughter cells.

[0124] The term “Wee1 inhibitor,” as used herein, represents a compound that upon contacting the enzyme Wee1 , whether in vitro, in cell culture, or in an animal, reduces the activity of Wee1 , such that the measured Wee1 ICso is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Wee1 inhibitors, the Wee1 ICso may be 100 nM or less (e.g., 10 nM or less, or 3 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Wee1 IC50 is 1 nM to 1 pM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Even more preferably, the Wee1 ICso is less than 20 nm (e.g., 1 nM to 20 nM). As used herein, Wee1 inhibitor includes compounds which reduce the activity of Wee1 upon administration of the compound (e.g., by preventing Wee1 from binding to a substrate (e.g., Cdk1) without degradation Wee1), as well as compounds which cause the degradation of Wee1 upon administration of the compound. For example, a Wee1 inhibitor may be a compound which induces intracellular proteolysis (e.g., proteolysis targeting chimera (PROTAC) molecules) or molecular glues (e.g., bifunctional molecules, each half of which interact with a biomaterial). BRIEF DESCRIPTION OF THE DRAWINGS

[0125] FIG. 1 A is a plot showing the viability of FT282 wild type (WT) cells exposed to a monotherapy with lunresertib (compound 182; 37 nM), a monotherapy with Debio-0123 (123 nM), and a combination therapy with lunresertib (37 nM) and Debio-0123 (123 nM).

[0126] FIG. 1B is a plot showing the viability of CCA / ET-High cells exposed to a monotherapy with lunresertib (37 nM), a monotherapy with Debio-0123 (123 nM), and a combination therapy with lunresertib (37 nM) and Debio-0123 (123 nM).

[0127] FIG. 1C is a plot showing the viability of OVCAR3 cells exposed to a monotherapy with lunresertib (37 nM), a monotherapy with Debio-0123 (123 nM), and a combination therapy with lunresertib (37 nM) and Debio-0123 (123 nM).

[0128] FIG. 2A is a scatter plot showing the percent of FT282 WT cells with phosphorylation of histone H2AX after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM), at varying concentrations of lunresertib.

[0129] FIG. 2B is a scatter plot showing the percent of CCA / ET-high cells with phosphorylation of histone H2AX after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM), at varying concentrations of lunresertib.

[0130] FIG. 2C is a scatter plot showing the percent of OVCAR3 cells with phosphorylation of histone H2AX after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM), at varying concentrations of lunresertib.

[0131] FIG. 3A shows the percent phosphorylation of Th r 14 of CDK1 after treatment with 1000 nM of Debio-0123, 250 nM of lunresertib, and the combination therapy.

[0132] FIG. 3B shows the percent phosphorylation of Tyr15 of CDK1 after treatment with 1000 nM of Debio-0123, 250 nM of lunresertib, and the combination therapy.

[0133] FIG. 3C shows the band of a gel electrophoresis experiment corresponding with CDK1 -pT14 and CDK1-pY15, and unphosphorylated CDK1. Actinin is shown as a control.

[0134] FIG. 4A shows the percent phosphorylation of Ser151 of CDC25B after treatment with 1000 nM of Debio-0123, 250 nM of lunresertib and the combination therapy.

[0135] FIG. 4B shows the band of a gel electrophoresis experiment corresponding with CDC25B-pS151 and unphosphorylated CDC25B. Actinin is shown as a control.

[0136] FIG. 5A is a plot showing the treatments in a pancreatic xenograft model. The treatments include monotherapy with lunresertib (15 mg / kg twice a day (BID), 3-days-on / 4-days-off), monotherapy with Debio-0123 (15 mg / kg BID, 3-days-on / 4-days-off), and combination therapy with lunresertib (15 mg / kg BID, 3-days-on / 4-days-off) plus Debio-0123 (15 mg / kg BID, 3-days-on / 4-days-off). Both drugs were administered by oral gavage. The data show the change in tumor volume over the duration of 24 treatment days. Treatment started on Day 1 for both compounds. Results are expressed as mean ± SEM, N=6 / group in female NOD SCID mice.

[0137] FIG. 5B is a plot showing change in body weight in mice bearing pancreatic subcutaneous tumors treated with lunresertib and / or Debio-0123 for 24 days. The data show the percent body weight change over the duration of 24 treatment days. Treatment started on Day 1 for both compounds. Results are expressed as mean ± SEM, N=6 / group in female NOD SCID mice. FIG. 5C is a plot showing the treatments in a pancreatic xenograft model. The treatments include monotherapy with lunresertib (15 mg / kg BID, 3-days-on / 4-days-off), monotherapy with Debio-0123 (15 mg / kg BID, 3-days-on / 4-days-off), and combination therapy with lunresertib (15 mg / kg BID, 3-days-on / 4- days-off) plus Debio-0123 (15 mg / kg BID, 3-days-on / 4-days-off). Both drugs were administered by oral gavage. The data shows the tumor volume on day 22 of treatment. Results are expressed as mean ± SEM, N=6 / group in female NOD SCID mice. Statistical significance was established by One-Way ANOVA (Brown-Forsythe and Welch’s ANOVA tests in GraphPad Prism v10); ns not indicated, *p<0.05; **p<0.01 ; *** p<0.001.

[0138] FIG. 6A is a plot showing the treatments in an ovarian xenograft model. The treatments include monotherapy with lunresertib (5 mg / kg BID, 3-days-on / 4-days-off), monotherapy with Debio-0123 (30 mg / kg BID, 3-days-on / 4-days-off), and combination therapy with 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 by oral gavage. The data shows the change in tumor volume over the duration of 45 treatment days. Treatment started on Day 1 for both compounds. Results are expressed as mean ± SEM, N=8 / group in female SCID beige mice. Statistical significance was established by One-Way ANOVA (Brown-Forsythe and Welch’s ANOVA tests in GraphPad Prism v10).

[0139] FIG. 6B is a plot showing the change in body weight in mice bearing ovarian subcutaneous tumors treated with lunresertib and / or Debio-0123 for 45 days as described for Fig 6A. Both drugs were administered by oral gavage. The data show the percent body weight change over the duration of 45 treatment days. Treatment started on Day 1 for both compounds. Results are expressed as mean ± SEM, N=8 / group in female SCID beige mice. Statistical significance was established by One-Way ANOVA (Brown-Forsythe and Welch’s ANOVA tests in GraphPad Prism v10).

[0140] FIG. 6C is a plot showing the tumor volume on day 31 of mice in an ovarian xenograft model. The treatments include monotherapy with lunresertib (5 mg / kg BID, 3-days-on / 4-days-off), monotherapy with Debio-0123 (30 mg / kg BID, 3-days-on / 4-days-off), and combination therapy with 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 by oral gavage. Results are expressed as mean ± SEM, N=8 / group in female SCID beige mice. Statistical significance was established by One-Way ANOVA (Brown-Forsythe and Welch’s ANOVA tests in GraphPad Prism v10); ns not indicated, *p<0.05; **p<0.01 ; *** p<0.001.

[0141] DETAILED DESCRIPTION

[0142] In general, the invention provides methods of using Myt1 inhibitors in combination with a Wee1 inhibitor. Advantageously, the combination of a MYT1 inhibitor and the Wee1 inhibitor may act synergistically in treating cancer or inducing cell death.

[0143] Myt1 inhibitors may be used to inhibit Myt1 in a cell, e.g., a cell in a subject (e.g., a cell overexpressing CCNE1 or having an inactivating mutation in the FHXW7 gene). The subject may be in need of a treatment for a disease or condition, e.g., a disease or condition having a symptom of cell hyperproliferation, e.g., a cancer. The Myt1 inhibitory activity is useful for treating a subject in need of a treatment for cancer.

[0144] Myt1 is a cell cycle regulating kinase localized predominantly in the endoplasmic reticulum and golgi complex. It is part of the Wee family of kinases that includes Wee1 and Wee1 b. Myt1 and Wee1 are involved in the negative regulation of the CDK1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle. During DNA damage, Myt1 drives the phosphorylation on Thr14 of CDKlwhich maintains the kinase complex in an inactive state in G2 as part of the G2 checkpoint response along with Wee1 (which mediates only Tyr15 phosphorylation) and prevents entry into mitosis until the damage has been repaired. Additionally, it has been proposed that Myt1 directly interacts with CDK1-Cyclin B complexes in the cytoplasm and prevents their nuclear translocation thus inhibiting cell cycle progression.

[0145] Myt1 has been implicated as a potentially important cancer target as it is essential in many cancer cells. Overexpression of Myt1 has been observed in various cancers including hepatocellular carcinoma as well as clear-cell renal-cell carcinoma. Myt1 downregulation has a minor role in unperturbed cells but has a more prominent role in cells exposed to DNA damage. Additionally, cells that exhibit high levels of replication stress in addition to defective G1 checkpoint regulation may be particularly sensitive to loss of Myt1 function, as these cells will be prone to entering mitosis prematurely with compromised genomic material leading to mitotic catastrophe.

[0146] Inhibitors of Myt1 , a regulator of G2-M transition, may be particularly useful in the treatment of tumors harboring a replication stress biomarker a mutation (e.g., a gain-of-function mutation or a loss-of- function mutation) or gene amplification of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, l-MYC, n-MYC, PIK3CA, PPP2R1A, PTEN, RB1 , BRAF, a prior or current infection with the human papillomavirus (HPV), or a combination thereof.

[0147] Replication Stress Biomarkers

[0148] A cancer to be treated by a method of the present disclosure may include, be characterized by, or be identified by a replication stress biomarker. In some embodiments, the replication stress biomarker is a mutation to a replication stress associated 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 associated gene. In some embodiments, the replication stress biomarker is reduced expression of a replication stress associated gene. In some embodiments, the cancer is characterized by a resistance to an inhibitor of a replication associated protein. In some embodiments, the replication stress biomarker is a mutation or gene amplification to a gene encoding a cell-division-signaling protein. In some embodiments, the replication stress biomarker is a mutation (e.g., a gain-of-function mutation or a loss-of-function mutation) or gene amplification of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, l-MYC, n-MYC, PIK3CA, PPP2R1A, PTEN, RB1 , BRAF, or a prior or current infection with HPV.

[0149] RAS Biomarkers

[0150] RAS proteins (e.g., Kras (encoded by the KRAS gene), Hras (encoded by the HRAS gene), and Nras (encoded by the NRAS gene)) are members of the protein superfamily of small guanidine triphosphatases (GTPases, e.g., Ras, Rho, Ran, Rab, and Arf GTPases). RAS proteins bind to GTP molecules, converting the Ras protein into an “activated state” (Ras-GTP). The activated Ras-GTP complex may then be dephosphorylated, converting the Ras protein into a “deactivated state” (Ras-GDP). Many cancers are highly associated with mutations to a R4S 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 over-expression. Mutations to RAS genes (e.g., gain-of-function mutations) or RAS over-expression result in a breakdown of cellular signaling and either prevent the cell from transducing certain signals to the nucleus, stimulate the cell as if an absent signal were present, or amplify the cellular response to a stimuli. This results in the prolonged activation of the RAS protein, and therefore prolonged signaling (e.g., signaling to continue cell division).

[0151] TP53 Biomarkers

[0152] Transformation-related protein 53 (alternatively referred to as p53, Tumor Protein P53, cellular tumor antigen p53, or Tp53; encoded by the TP53 gene) is a regulatory protein associated with ensuring healthy cell division by preventing genomic mutation. Tp53 plays a role in activating DNA repair, preventing the transition to the mitotic stage of cell division, and the initiation of apoptosis, in cells with sufficiently damaged DNA. Due to its role in actively repairing DNA, Tp53 is classified as a “tumor suppressor gene,” and is commonly mutated in cancer cells. TP53 mutations are found in from about 30% to about 50% of ovarian cancers, esophageal cancers, colorectal cancers, head and neck cancers, and lung cancers. As a result, mutations to TP53 may be replication stress mutations. Accordingly, cancers harboring a TP53 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the cancer to be treated by the methods of the present disclosure include a TP53 mutation. In some embodiments, the TP53 mutation encodes for Tp53 / _.

[0153] CCNE1 Biomarkers

[0154] Cyclin E1 (encoded by the CCNE1 gene) is involved in the G1 to S phase cell cycle transition. In late G1 phase of the cell cycle, it complexes with cyclin-dependent kinase 2 (Cdk2) to promote E2F transcription factor activation and entry into S-phase. Cyclin E1 levels are tightly regulated during normal cell cycles, accumulating at the G1 / S transition and being completely degraded by the end of S phase. The cell cycle-dependent proteasomal degradation of Cyclin E1 is mediated by the SCFFBW7ubiquitin ligase complex. Once activated in late G1 , the Cyclin E1 / Cdk2 complex promotes the transition into S phase through phosphorylation and inactivation of pRB and subsequent release of E2F transcription factors. S phase is promoted by E2F-mediated transcription of numerous genes involved in DNA replication including the pre-replication complex subunits Orel , Cdc6, Cdt1 , and the Mem helicase factors. CCNE1 is frequently amplified and / or over-expressed in human cancers. CCNE1 amplification has been reported in several cancer types including ovarian cancer, breast cancer, uterine cancer, pancreatic cancer, bladder cancer, gastric cancer, esophageal cancers, and sarcomas.

[0155] CCNE1 over-expression is thought to drive tumorigenesis by inducing genome instability (e.g., increased origin firing, defective nucleotide pools, transcription-replication conflicts, and / or fork instability). Over-expression of CCNE1 has been shown to induce replication stress characterized by slowed or stalled replication forks and loss-of-heterozygosity at fragile sites. The primary mechanism by which CCNE1 over-expression causes replication stress is increased origin firing in early S-phase followed by depletion of replication factors including nucleotide pools. The decrease in overall replication proteins and nucleotides decreases fork progression and causes stalling and subsequent collapse or reversal. As a result, CCNE1 amplification is a replication stress biomarker. Accordingly, cancers harboring a CCNE1 mutation, or characterized by CCNE1 over-expression may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0156] In some embodiments, the cancer may include a CCNE1 mutation, overexpression, or amplification. In some embodiments, the cancer includes at least one other replication stress biomarker (e.g., a replication stress biomarker described herein) and a CCNE1 mutation, overexpression, or amplification.

[0157] CDK12 Biomarkers

[0158] Cyclin dependent kinase 12 (Cdk12; encoded for by the CDK12 gene) is a member of the cyclin dependent kinase (Cdk) family of cell-cycle serine-threonine kinases. Cdk family kinases interact with a variety of regulatory proteins via phosphorylation of prescribed sites of the protein, either activating or inhibiting the protein. Cdk proteins play regulatory roles at numerous phases of the cell cycle and the transitions therebetween. The entire family is considered important for maintaining healthy cell division across the cell cycle. Cdk12 belongs to the subclass of Cdk proteins which are particularly effective in the regulation of gene transcription. Cdk12 is further implicated in RNA splicing, translation, and the DNA damage response. Accordingly, cancers harboring a mutated Cdk12 protein, or cancers characterized by a reduced expression of a Cdk protein, may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0159] In some embodiments, the replication stress biomarker is a CDK12 mutation. In some embodiments, the cancer to be treated by a method of the present disclosure includes a CDK12 mutation. In some embodiments, the CDK12 mutation is a loss-of-function mutation.

[0160] CDK4 and CDK6 Biomarkers

[0161] Cyclin-dependent kinase 4 (Cdk4; encoded for by the CDK4 gene) and cyclin-dependent kinase 6 (Cdk6; encoded for by the CDK6 gene) are both members of the cyclin dependent kinase (Cdk) family of cell-cycle serine-threonine kinases. Cdk4 and Cdk6 both belong to a subclass of Cdk proteins which regulate progression through the cell cycle. Cdk4 and Cdk6 are both highly implicated in regulating the cellular transition between G1 phase and S phase of the cell cycle. As such, CDK4 and CDK6 are common drug targets in cancer treatment, as inhibition of Cdk4 or Cdk6 arrests cellular development in the G1 phase, and thereby prevents or slow mitosis. Some cancers (e.g., cancers including a CDK4 mutation or a CDK6 mutation) have been found to be resistant to chemotherapeutic treatment with a Cdk4 or Cdk6 inhibitor. Accordingly, cancers which are include a CDK4 mutation or a CDK6 mutation (or are resistant to chemotherapeutic treatment with an inhibitor of Cdk4 or Cdk6) are under a high degree of replication stress and therefore may be particularly susceptible to treatment with a drug causing 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 to be treated by the methods of the present disclosure includes a CDK4 mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a CDK6 mutation. In some embodiments, the cancer to be treated is resistant to treatment with a Cdk4 inhibitor a Cdk6 inhibitor, or a CDK 4 / 6 inhibitor (e.g., palbociclib, ribociclib, and abemaciclib).

[0162] CDKN2A Biomarkers p16 (alternatively known as p16INK4a) and p14arf (both encoded for by the CDKN2A gene) are naturally produced Cdk4 and Cdk6 inhibitors. A mutation to CDKN2A (particularly loss-of-function mutation) may result in non-functional or reduced-function may serve to increase the expression of Cdk4 and Cdk6, thereby serving as a replication stress mutation. Accordingly, cancers harboring a CDKN2A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one 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, the cancer to be treated by the methods of the present disclosure includes a CDKN2A mutation. In some embodiments, the CDKN2A mutation is a loss-of-function mutation.

[0163] CDC25A Biomarkers

[0164] M-phase inducer phosphatase 1 (Cdc25A; encoded by the CDC25A gene). Cdc25A is a regulatory protein phosphatase which serves to remove inhibitory phosphorylation events from Cdk proteins (in particular, Cdk2, Cdk4, and Cdk6). Accordingly, mutations to CDC25A (particularly gain-of- function mutation) may decrease phosphorylation of a Cdk protein, thereby increasing the activity of the Cdk protein and placing the cell in replicative stress. Accordingly, cancers harboring a CDC25A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one 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, the cancer to be treated by the methods of the present disclosure includes a gain-of-function CDC25A mutation.

[0165] EGFR Biomarkers

[0166] The epidermal growth factor receptor (Egfr, alternatively referred to as Herl or ErbB1 ; encoded for by the EGER gene) and is a transmembrane glycoproteins including an extracellular domain capable of binding to extracellular growth factors (e.g., epidermal growth factor (Egf), heparin binding Efg-like growth factor (Hbegf), betacellulin (Btc), amphiregulin (Areg), epiregulin (Ereg), epigen (Epgn), etc.) and an intracellular domain including a tyrosine-kinase domain. Binding of extracellular growth factor proteins to the extracellular domain promotes a confirmational 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 serves to transduce extracellular signals (e.g., those from extracellular polypeptide growth factor), into intracellular signals (e.g., as a part of the Ras / Mapk pathway) to promote cell division. Mutations to EGFR may result in a confirmational change to the tyrosine-kinase domain, independent of any interaction with an extracellular growth factor peptide, causing a perpetual activation of cell signals to undergo cell division. Egfr mutations are commonly observed in many cancers and are particularly common in lung cancer. Accordingly, cancers harboring a EGFR mutation (e.g., a gain-of-function mutation) may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0167] In some embodiments, the replication stress biomarker is an EGFR mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes an EGFR mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function EGFR mutation.

[0168] FBXW7 Biomarkers

[0169] Proteins containing at least one F-box domain (referred to as F-box proteins; e.g., the Fbxw7 protein encoded for by the gene FBXW7), in particular FBXW7, is frequently mutated in several cancer types including endometrial, colorectal, and gastric, ranging in frequency from 5-35%. FBXW7 driver mutations are observed in the more aggressive subtypes of endometrial cancer including UCS (-35%) and USC (-25%). FBXW7has a diverse spectrum of loss-of-function mutations in cancer including truncating mutations peppered across the gene and missense mutations within the Cyclin E1 recognizing WD40 repeats. Fbxw7 functions as a homodimer within the SCF complex and many deleterious missense mutations within the WD40 repeats are mostly heterozygous and dominant negative. Remarkably, several recurring hotspot missense mutations are found in the WD40 repeats including R465, R479, and R505 - all of which disrupt Cyclin E1 binding and ubiquitylation. Accordingly, cancers harboring a FBXW7 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0170] In some embodiments, the cancer may include a FBXW7 mutation (e.g., a loss of function mutation). In some embodiments, the cancer includes at least one other replication stress biomarker (e.g., a replication stress biomarker described herein) and a FBXW7 mutation. c-MYC Biomarkers

[0171] The Myc family of cell signaling proteins includes c-Myc, l-Myc, and n-Myc. c-Myc, l-Myc, and n- Myc are encoded for by the c-MYC, l-MYC, and n-MYC genes respectively. The MYC genes perform several regulatory processes across cellular functions, many of which are associated with cell division, cell proliferation, and DNA replication. Myc proteins aid in the regulation of almost 15% of all genes. Mutations in MYC genes, in particular mutations in c-MYC, are commonly found in cancer, wherein the mutation results in, e.g., uncontrolled cell division. Many c-MYC associated cancers are commonly considered undruggable, precluding conventional chemotherapeutic approaches. However, cancers harboring a mutation to a gene encoding a Myc protein (e.g., a mutation to c-MYC) mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0172] In some embodiments, the replication stress biomarker is a c-MYC mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of- function c-MYC mutation. In some embodiments, the cancer to be treated includes gene amplification of a c-MYC gene. PIK3CA Biomarkers

[0173] Phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (Pik3ca, alternatively referred to as P110a; encoded for by the PIK3CA gene) is the catalytic subunit of phosphatidylinositol- 4,5-bisphosphate 3-kinase (PI3k). Pik3ca uses ATP to phosphorylate phosphatidylinositols (Ptdlns) such as Ptdlns4P, Ptdlns(3,4)P2, Ptdlns(3,4,5)P3, and Ptdlns(4,5)P2. Ptdlns may then bind to protein kinase B (PKB or alternatively 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 critical inducer tissue growth in cells. As a result, mutations to PI3k, in particular gain-of-function mutations to the Pik3ca subunit, are implicated in many cancers. For example, nearly one-third of breast and cervical cancers include a PIK3CA mutation. Further, PIKC3A mutations may result in a number of genetic disorders resulting in the overgrowth of body parts in a subject, collectively referred to as Pik3ca-overgrowth spectrum (PROS). Accordingly, cancers harboring a mutation in a PI3k gene (e.g., a mutation to the Pik3ca subunit) may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the replication stress biomarker is a mutation in a PI3K protein. In some embodiments, the replication stress biomarker is a PIK3CA mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function PIK3CA mutation.

[0174] PPP2R1A Biomarkers

[0175] Serine / threonine-protein phosphatase 2A 65kDa regulatory subunit A alpha isoform (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 phosphorylating several cell division signaling pathways. Pp2a is implicated for its role in regulating tumor production by controlling phosphorylation events in cell signaling pathways. Mutation to PPP2R1A (e.g., loss-of-function mutations), result in the loss of Pp2a’s ability to regulate phosphorylation events, removing a critical biological response to cancer-causing mutations. PPP2R1A mutations are commonly observed in endometrial cancer, ovarian cancer, and uterine cancer. Accordingly, cancers harboring a PPP2R1A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the replication stress biomarker is a PPP2R1A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes PPP2R1A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of- function PPP2R1A mutation.

[0176] PTEN Biomarkers

[0177] Phosphatase and tensin homolog (Pten; encoded for by the PTEN gene) is a cell-cycle regulating phosphatase. Unlike many other protein tyrosine phosphatases, Pten preferentially dephosphorylates phosphoinositide substrates. Pten plays a role in the regulation of several cell signaling pathways, including the Akt / Pkb signaling pathway. PTEN is commonly observed to be mutated (e.g., a loss-of- function mutation) in tumor cells. PTEN mutations are commonly observed in breast cancer, prostate cancer, bladder cancer, lung cancer, endometrial cancer, lung cancer, melanoma, and head and neck cancer. Accordingly, cancers harboring a PTEN mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0178] In some embodiments, the replication stress biomarker is a PTEN mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a PTEN mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function PTEN mutation.

[0179] RB1 Biomarkers

[0180] The retinoblastoma protein (RB, or alternatively pRB; encoded for by the RB1 gene) is a cell cycle protein which serves to suppress cell cycle progression in cells by binding to transcription factor proteins (e.g., E2 promoter binding protein dimerization partner (E2F-DP) dimers), preventing the transduction of signals therefrom. Once the cell has sufficiently grown and / or received a signal to begin cell division, pRB is phosphorylated by CDK proteins, thereby inactivating pRB, allowing cell division to progress. Cancers associated with RB1 mutations include brain cancer, bone cancer, muscle cancer, prostate cancer, uterine cancer, breast cancer, lung cancer, and melanoma. Mutations to RB1 (e.g., loss of function mutations) may result in permanently inactive pRB, thereby causing uncontrolled cell division. Accordingly, cancers harboring a RB1 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0181] In some embodiments, the replication stress biomarker is a RB1 mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function RB1 mutation.

[0182] BRAF Biomarkers

[0183] The Braf protein BRAF (encoded for by the BRAFgene) is a member of the Raf family of proteins. The Raf family of proteins also includes Araf (encoded for by the ARAFgene) and Craf (encoded for by the CRAF gene), which play a critical role in several cell signaling pathways, including the Ras / Mapk pathway. Raf proteins are the second step in the Ras / Mapk pathway, and therefore wild type Raf proteins require interaction with a Ras protein to transduce a cellular signal. Similar to mutated Ras proteins (e.g., as described above), mutations to Raf proteins commonly prevent dephosphorylation of the phosphorylated Raf complex, resulting in a continuous cellular signal to undergo cell division processes, which may result in the development of tumors. Cancers associated with a BRAF mutations include melanoma, leukemia, lymphoma, and lung cancer. Cancer harboring a BRAF mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0184] In some embodiments, the replication stress biomarker is a BRAF mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a BRAF mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of- function BRAF mutation. HPV Biomarkers

[0185] The human papillomavirus (HPV) is a DNA virus commonly associated with the development of cancers in subjects previously suffering therefrom. HPV is commonly observed to cause DNA damage (e.g., mutations, e.g., replication stress mutations) to subjects. Even after the subject is cured of HPV (e.g., by removal of viral particles from the subject or relief of a symptom associated therewith), the DNA damage may result in tumor growth or the development of a cancer in the subject. HPV infections are known to result in cervical cancer, penile cancer, vaginal cancer, vulvar cancer, colorectal cancer, and throat cancer. In particular, some reports demonstrate that more than 90% of cervical cancers are associated with a prior or current HPV infection. Accordingly, cancers associated with or resulting from infection with HPV may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0186] In some embodiments, the replication stress biomarker is an HPV infection. In some embodiments, the cancer is treated by a method of the present disclosure developed in a patient previously infected with HPV. In some embodiments, the prior infection with HPV resulted in DNA damage. In some embodiments, the DNA damage causes a replication stress mutation. In some embodiments, the replication stress mutation is a CDKN2A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function CDKN2A mutation.

[0187] Myt1 Inhibitors

[0188] A compound used in the methods of the invention may be, e.g., a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2;

[0189] R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;

[0190] R5is H or -N(R7)2;

[0191] R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SO2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and each Q is independently optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted Ce-w arylene, optionally substituted C2-9 heterocyclylene, or optionally substituted C1-9 heteroarylene.

[0192] Preferably, the compound of formula (I) is enriched for the atropisomer of formula (IA):

[0193] (IA), where all variables are as described herein.

[0194] The compound used in the methods of the invention may be, e.g., a compound of formula (II):

[0195] (II), where all variables are as described herein.

[0196] Preferably, the compound of formula (II) is enriched for the atropisomer of formula (I I A):

[0197] (HA), where all variables are as described herein.

[0198] The compound used in the methods of the invention may be, e.g., a compound of formula (III): where R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B

[0199] Preferably, the compound of formula (III) is enriched for the atropisomer of formula (IIIA):

[0200] The compound used in the methods of the invention may be, e.g., a compound listed in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1

[0201]

[0202] Further examples of Myt1 inhibitors include those described in International Patent Publication No.: WO 2023 / 174397, WO 2023 / 155871 , WO 2023 / 155892, WO 2023 / 155870, WO 2023 / 174397, WO 2023 / 174329, and WO 2023 / 177356; and US Patent Application Nos.: 17 / 937,977 and 17 / 961 ,103; the inhibitors of which are incorporated herein by reference.

[0203] The methods of the disclosure include (where possible) individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of diastereomers and / or enantiomers thereof including racemic mixtures. Although the specific stereochemistries disclosed herein are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures of these may also have utility in treating Myt1 -mediated diseases. Inactive or less active diastereoisomers and enantiomers may be useful, e.g., for scientific studies relating to the receptor and the mechanism of activation.

[0204] It is understood that certain molecules can exist in multiple tautomeric forms. This invention includes all tautomers even though only one tautomer may be indicated in the examples.

[0205] The invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier. The compounds are especially useful, e.g., in certain kinds of cancer and for slowing the progression of cancer once it has developed in a patient.

[0206] The compounds disclosed herein may be used in pharmaceutical compositions including (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.

[0207] In one preferred example, the Myt1 inhibitor is lunresertib (compound 182).

[0208] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

[0209] Compounds disclosed herein may contain, e.g., one or more stereogenic centers and can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The invention includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures and as pure or partially purified compounds are included within the scope of this invention (i.e., all possible combinations of the stereogenic centers as pure compounds or in mixtures).

[0210] Some of the compounds described herein may contain bonds with hindered rotation such that two separate rotomers, or atropisomers, may be separated and found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this invention.

[0211] Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0212] Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the invention.

[0213] Compounds disclosed herein having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

[0214] Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0215] Metabolites - Prodrugs

[0216] The invention includes therapeutically active metabolites, where the metabolites themselves fall within the scope of the claims. The invention also includes prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient. The claimed chemical structures of this application in some cases may themselves be prodrugs.

[0217] Isotopically Enriched Derivatives

[0218] The invention includes molecules which have been isotopically enriched at one or more position within the molecule. Thus, compounds enriched for deuterium fall within the scope of the claims.

[0219] Methods of Preparing Myt1 inhibitors

[0220] Methods of preparing Myt1 inhibitors are known in the art (see, e.g., International Patent Publication No. WO 2022 / 213204, the entirety of which is incorporated herein by reference). Wee1 Inhibitors

[0221] Wee1 inhibitors may be compounds that upon contacting Wee1 , whether in vitro, in cell culture, or in an animal, reduce the activity of Wee1 , such that the measured Wee1 ICso is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Wee1 inhibitors, Wee1 ICso may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, Wee1 ICso is 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 degrader (e.g., a proteolysis targeting chimera (PROTAC) or molecular glue). A Wee1 inhibitor for use in the present invention may be, e.g., a compound listed in Table 2a-2g below or a pharmaceutically acceptable salt thereof.

[0222] Table 2a

[0223]

[0224] Table 2b d0pU L J

[0225] KX W

[0226] 0 < / C)

[0227] (068M) (688M) (888M) Z6 £01 TOI SOI

[0228] Table 2c

[0229] Table 2d Table 2e Table 2g

[0230] or a pharmaceutically acceptable salt thereof.

[0231] Further examples of Wee1 inhibitors include:

[0232] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1 -yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidine-5(6H)-one (W2217);

[0233] 2-anilino-6-(2-chlorophenyl)imidazo[1 ,2-a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2218);

[0234] 6-(2-chlorophenyl)-2-(pyridin-4-ylamino)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2219);

[0235] 6-(2-chlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1 'H- spiro[cyclopropane-1 ,4'-isoqu I n ol I n]-7'- yl)amino] imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2220);

[0236] 6-(2-chloropheny1 )-2-(5,6,7,8-tetrahydronaphthalen- 2-ylamino)imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin- 5(6H)-one (W2221 );

[0237] 6-(2-chlorophenyl)-2-{[3-(4-methylpiperazin-1 -yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2222);

[0238] 6-(2-chlorophenyl)-2-[(4-cyclohexylphenyl)amino]imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)- one (W2223);

[0239] 6-(2-chlorophenyl)-2-{[4-(piperidin-1 -yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2224);

[0240] 6-(2-chlorophenyl)-2-{[4-(pyrrolidin-1 -ylmethyl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2225);

[0241] 6-(2-chlorophenyl)-2-{[4-(morpholin-4-yl)phenyl]amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2226);

[0242] 6-(2-chlorophenyl)-2-{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2227);

[0243] 2-[(1 -acetyl-2,3-dihydro-l H-indol-6-yl)amino]-6-(2- chlorophenyl)imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2228);

[0244] 2-{[4-(4-acetylpiperazin-1 -yl)phenyl]amino}-6-(2- chlorophenyl)imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2229); 6-(2-methy Ipheny l)-2-{[4-(4-methy Ipiperazi n- 1 -yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2230);

[0245] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-[2- (trifluoromethyl)phenyl]imidazo[l,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2231);

[0246] 6-(2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1 -yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2232);

[0247] 6-(2-chloropheny1 )-2-{[2-methoxy-4-(4-methylpip- erazin-1 -yl)phenyl]amino}imidazo[1 ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2233);

[0248] 6-(2-chlorophenyl)-2-[(1-methyl-1 ,2,3,4-tetrahydro- quinolin-7-yl)amino]imidazo[l,2-a]pyrimido[5,4- e] pyrimidin-5(6H)-one (W2234);

[0249] 6-(2-chlorophenyl)-2-[(3-oxo-3,4-dihydro-2H-1 ,4- benzoxazin-6-yl)amino]imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin-5(6H)-one (W2235); tert-butyl 7-{[6-(2-chlorophenyl)-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-2-yl] amino}-3,4-dihydroisoquinoline-2(1 H)-carboxylate (W2236);

[0250] 6-(2-chlorophenyl)-2-(1 ,2,3,4-tetrahydroisoquinolin-7-ylamino)imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin-5(6H)-one (W2237);

[0251] 6-(2-chlorophenyl)-2-{[3-methyl-4-(4-methylpiper- azin-1 -yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2238);

[0252] 6-allyl-2-{[4-(4-methylpiperazin-1 -yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)- one (W2239);

[0253] 6-cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2240);

[0254] 6-(2-chlorophenyl)-9-methyl-2-{[4-(4-methylpiper- azin-1 -yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2241);

[0255] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1 -yl) phenyl]amino }pyrimido[5,4-e][1 ,2 ,4]triazolo[4,3- a]pyrimidin-5(6H)-one (W2242);

[0256] 4-(2-Chloro-phenyl)-1-methyl-8-methylsulfanyl-4H- 2,3,4,7,9,9b-hexaaza- cyclopenta[a]naphthalen-5-one (W2243);

[0257] 4-(2-chlorophenyl)-8-{[4-(4-methylpiperazin-1 -yl) phenyl]amino }pyrimido[5,4-e]tetrazolo[1 ,5- a]pyri- midin-5(4H)-one (W2244);

[0258] 6-(2-chlorophenyl)-2-({4-[4-(propan-2-yl)piperazin- l-yl]phenyl}amino)imidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2245);

[0259] 6-(2-chlorophenyl)-2-({4-[4-(cyclohexylmethyl) piperazin-1 -yl]phenyl}amino)imidazo[l, 2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2246);

[0260] 3-{[4-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)piperazin-1-yl]methyl}benzonitrile (W2247);

[0261] 2-{[3-chloro-4-( 4-methylpiperazin-1-yl)phenyl]amino}-6-(2-chlorophenyl)imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2248);

[0262] 6-(2-chlorophenyl)-2-({3-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]phenyl}amino)imidazo[l,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2249); 6-(2-chlorophenyl)-2-[(2-methyl-1 ,2,3,4-tetrahy- droisoquinolin-7-yl)amino]imidazo[ I ,2-a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2250);

[0263] 6-(2-chlorophenyl)-2-({4-[2-(dimethylamino) ethoxy]phenyl}amino)imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2251);

[0264] 6-(2-chlorophenyl)-2-({4-[2-(morpholin-4-yl) ethoxy]phenyl}amino)imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2252);

[0265] 6-(2-chlorophenyl)-2-{[3-methyl-4-(4-methyl-1 ,4- diazepan- l-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2253);

[0266] 6-(2-chlorophenyl)-2-{[4-(1 -methy Ipiperidi n-4-y I) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2254);

[0267] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6- phenylimidazo[l,2-a]pyrimido[ 5,4-e]pyrimidin-5 (6H)-one (W2255);

[0268] 6-(2-chloro-4-methylphenyl)-2-{[4-(4-methylpiper- azin-1 -yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2256);

[0269] 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[l, 2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}-N- cyclo- hexylbenzamide (W2257);

[0270] 6-(2-chlorophenyl)-2-({4-[(4-methylpiperazin-1-yl) carbonyl]phenyl}amino)imidazo[l,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2258);

[0271] 6-(2-chlorophenyl)-2-{[4-(IH-pyrazol-4-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-

[0272] 5(6H)-one (W2259);

[0273] 6-(2-chlorophenyl)-2-({4-[2-(diethylamino)ethoxy] phenyl}amino)imidazo[l,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2260);

[0274] 6-(2-chlorophenyl)-2-{[4-(pyridin-3-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)- one (W2261);

[0275] 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[l,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}-N-

[0276] (trans- 4-hydroxycyclohexyl)benzamide (W2262);

[0277] 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[l,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}-N- ethyl- benzamide (W2263);

[0278] 6-(2-chlorophenyl)-2-({4-[(4-hydroxypiperidin-1-yl) carbonyl]phenyl}amino)imidazo[l,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2264);

[0279] 4-{[6-(2-chloropheny1)-5-oxo-5, 6-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}-N- (pyri- din-4-yl)benzamide (W2265);

[0280] 6-(2-chlorophenyl)-2-({4-[3-(diethylamino)pro- poxy]-3-fluorophenyl}amino)imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2266);

[0281] 6-(2-chlorophenyl)-2-({3-fluoro-4-[2-(4-methylpip- erazin-1-yl)ethoxy]phenyl}amino)imidazo[l,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2267);

[0282] 6-(2-chlorophenyl)-2-{[2-(2-methoxyethyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[l,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2268);

[0283] 6-(2-chlorophenyl)-2-[(2,4,4-trimethyl-1 ,2,3,4-tet- rahydroisoquinolin-7-yl)amino]imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2269); 6-(3-hydroxy-2-methylphenyl)-2-(phenylamino) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2270);

[0284] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1 - yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2271);

[0285] 2-[(4-aminophenyl)amino]-6-(2-chlorophenyl)imi- dazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2272);

[0286] N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2- yl]amino}phenyl)acetamide (W2273);

[0287] N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)cyclopentanecarboxamide (W2274);

[0288] N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}pheny1)-4-hydroxycyclohexanecarboxamide (W2275);

[0289] N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)-1-methylpiperidine-4-carboxamide (W2276);

[0290] N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)pyridine-4-carboxamide (W2277);

[0291] 6-(2,6-dimethylphenyl)-2-[(2'-methyl-2',3'-dihydro- 1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl) amino]imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2278);

[0292] 2-({4-[4-(3-chlorobenzyl)piperazin-1-yl] phenyl}amino)-6-(2-chlorophenyl)imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2279);

[0293] 6-(2-chlorophenyl)-2-({4-[4-(2-methoxyethyl)piper- azin-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2280);

[0294] 6-(2-chloropheny1 )-2-{[3-methoxy-4-(4-methylpip- erazin-1 -yl)phenyl]amino}imidazo[1 ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2281);

[0295] 6-(2-chlorophenyl)-2-({3-methoxy-4-[4-(propan-2- y l)piperazi n- 1 -yl]phenyl}amino)imidazo[l ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2282);

[0296] 6-(2-chlorophenyl)-2-({3-methoxy-4-[2-(4-meth- y Ipiperazi n- 1 - yl)ethoxy]phenyl}amino)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2283);

[0297] 6-(3-hydroxyphenyl)-2-(phenylamino)imidazo[1 ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2284);

[0298] 6-(2-chlorophenyl)-2-[(4-methylphenyl)amino]imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2285);

[0299] 6-(2-chlorophenyl)-2-{[4-(piperidin-2-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2286);

[0300] 6-(2-chlorophenyl)-2-{[4-(pyrrolidin-2-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2287);

[0301] 6-(2-chlorophenyl)-2-{[4-(pyrrolidin-3-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2288);

[0302] 6-(2,6-dichlorophenyl)-2-[(2'-methyl-2',3'-dihydro- 1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl) amino]imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2289);

[0303] 6-(2,6-dichlorophenyl)-2-{[3-methyl-4-( 4-methyl-1 , 4-diazepan-1-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2290); 6-(2-chlorophenyl)-2-{[4-(piperazin- l-yl)-3-(trifluo- romethyl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2291 );

[0304] 6-(2-chlorophenyl)-2-({4-[(2S)-pyrrolidin-2-yl-methoxy]phenyl}amino)imidazo[l ,2-a]pyrimido[5, 4- e]pyrimidin-5(6H)-one (W2292);

[0305] 6-(2-chlorophenyl)-2-({2-methyl-4-[3-(4-methylpip- erazin-1 -yl)propoxy]phenyl}amino)imidazo[l ,2- a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2293);

[0306] 6-(2-chlorophenyl)-2-{[4-(morpholin-4-ylmethyl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2294);

[0307] 6-(2-chlorophenyl)-2-{[4-(1 H-imidazol-1 -ylmethyl)phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2295);

[0308] 6-(2-chlorophenyl)-2-{[4-(1 H-imidazol-1 -yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2296);

[0309] 6-(2-chlorophenyl)-2-{[6-(piperazin-1 -yl)pyridin-3- yl]amino}imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin-5 (6H)-one (W2297);

[0310] 6-(2-chlorophenyl)-2-({3-[3-(4-methylpiperazin-1 - yl)propoxy]phenyl}amino)imidazo[l ,2-a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2298);

[0311] 6-(2-chlorophenyl)-2-({3-[3-(piperidin-1 -yl)pro- poxy]phenyl}amino)imidazo[ I ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2299);

[0312] 6-(2,6-dichlorophenyl) 2-(phenylamino)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2300);

[0313] 6-(2-chlorophenyl)-2-({3-methoxy-4-[2-(propan-2- ylamino)ethoxy]phenyl}amino)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2301 );

[0314] 6-(2-chlorophenyl)-2-({3-chloro-4-[2-(propan-2- ylamino)ethoxy]phenyl}amino)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2302);

[0315] 6-(2-chlorophenyl)-2-{[4-(hydroxymethyl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2303);

[0316] 6-(2-chlorophenyl)-2-{[4-(IH-pyrazol-1 -ylmethyl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2304);

[0317] 6-(2-chlorophenyl)-2-{[4-(IH-pyrazol-1 -yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin- 5(6H)-one (W2305);

[0318] 6-(2-chlorophenyl)-2-(2',3'-dihydro-l 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-ylamino )imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2306);

[0319] 2-[(2'-acety I-2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 , 4'-isoquinolin]-7'-yl)amino]-6-(2- chlorophenyl)imi- dazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2307);

[0320] 6-(2-chlorophenyl)-2-[(1 -methyl-1 ,2,3,4-tetrahydro- quinolin-6-yl)amino]imidazo[ I ,2- a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2308);

[0321] 6-(2-chlorophenyl)-2-({1 -[2-(dimethylamino )ethy I]- 2,3-dihydro-IH-indol-5-yl}amino)imidazo[l ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2309);

[0322] 6-(2-chlorophenyl)-2-{[2-(dimethylamino )-2,3-dihy- dro-l H-inden-5-yl]amino}imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2310); 6-(2-chloro-6-fluorophenyl)-2-{[4-(4-methylpiper- azin-1 -yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2311 );

[0323] 6-(2-chloro-6-fluoropheny1 )-2-{[3-methy1 -4-(4-me- thy 1-1 ,4-diazepan-1 -yl)phenyl]amino}imidazo[l ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2312);

[0324] 6-(2-chloro-6-fluorophenyl)-2-[(2,4,4-trimethyl-1 ,2, 3,4-tetrahydroisoquinolin-7- yl)amino]imidazo[1 ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2313);

[0325] 6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazin-1 - yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2314);

[0326] 6-(2-chlorophenyl)-2-{[2-(2-hydroxyethyl)-1 ,2,3,4- tetrahydroisoquinolin-7-yl]amino}imidazo[l,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2315);

[0327] 6-(2-chlorophenyl)-2-{[3-(hydroxymethy1 )-4-(4- methyl-1 ,4-diazepan-1 -yl)phenyl]amino}imidazo[l, 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2316);

[0328] 6-(2-chlorophenyl)-2-{[4-(hexahydropyrrolo[1 ,2-a] pyrazin-2(1 H)-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2317);

[0329] 6-(2-chloropheny1 )-2-[(4-hydroxy-3-methylphenyl) amino]imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2318);

[0330] 6-(2-chlorophenyl)-2-({4-[3-(diethylamino)pro- poxy]-3-methylphenyl}amino)imidazo[l,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2319);

[0331] 6-(2-chlorophenyl)-2-{[3-methyl-4-(piperazin-1 -yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2320);

[0332] 6-(2-chlorophenyl)-2-{[4-(1 ,4-diazepan-1 -yl)-3-me- thylphenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4- e] pyrimidin-5(6H)-one (W2321 );

[0333] 6-(2-chloropheny1 )-2-(2,3,4,5-tetrahydro-l H-2-ben- zazepin-7-ylamino)imidazo[l ,2- a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2322);

[0334] 6-(2-chlorophenyl)-2-[(3-methyl-2,3,4,5-tetrahydro- IH-3-benzazepin-7-yl)amino]imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2323);

[0335] 6-(2-chlorophenyl)-2-[(1 ,1 ,2-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[ I ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2324);

[0336] 6-(2,6-dichlorophenyl)-2-(2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-ylamino)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2325);

[0337] 6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazin-1-yl)phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2326);

[0338] 6-(2,6-dichlorophenyl)-2-(1 ,2,3,4-tetrahydroiso- quinolin-7-ylamino)imidazo[1 ,2-a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2327);

[0339] 6-(2-chloropheny1 )-2-{[3-ethy 1 -4-(4-methylpiper- azin-1 -yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2328);

[0340] 6-(2-chloropheny1 )-2-{[2-(cyclohexylmethy1 )-4,4-dimethyl-l ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2329);

[0341] 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino )-2,3- dihydro- 1 H-inden-5-yl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2330); 6-(2 , 6-dich loropheny l)-2-({4-[4-(propan-2-y l)pi per- azin-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2331 );

[0342] 6-(2,6-dichlorophenyl)-2-{[4-(hexahydropyrrolo[1 ,2- a]pyrazin-2(1 H)-yl)phenyl]amino}imidazo[l,2- a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2332);

[0343] 6-(2-chlorophenyl)-2-{[2-(2-ethylbutyl)-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7- yl]amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2333);

[0344] 6-(2,6-dichlorophenyl)-2-({4-[2-(4-methylpiperazin- 1 -yl)ethyl]phenyl}amino)imidazo[l ,2- a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2334);

[0345] 6-(2,6-dichlorophenyl)-2-({1 -[2-(dimethylamino)ethyl]-2,3-dihydro-IH-indol-5-yl}amino)imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2335);

[0346] 6-(2 , 6-dich loropheny l)-2-{[3-ethy 1 -4-(4-methylpip- erazin-1 -yl)phenyl]amino}imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2336);

[0347] 6-(2,6-dichlorophenyl)-2-{[3-(hydroxymethy1 )-4-(4- methyl-1 ,4-diazepan-1 - yl)phenyl]amino}imidazo[l, 2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2337);

[0348] 6-(2,6-dichlorophenyl)-2-(1 ,2,3,4-tetrahydroiso- quinolin-6-ylamino)imidazo[1 ,2-a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2338);

[0349] 6-(2,6-dichloro-4-fluorophenyl)-2-{[4-(4-methylpip- erazin-1 -yl)phenyl]amino}imidazo[1 ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2339);

[0350] 6-(2,6-dichloro-4-fluorophenyl)-2-{[3-methy1 -4-(4- methyl-1 ,4-diazepan-1 -yl)phenyl]amino} imidazo[l, 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2340);

[0351] 6-(2,6-dichloro-4-fluorophenyl)-2-[(2'-methyl-2',3'-dihydro-l 'H-spiro[cyclopropane-1 ,4'-isoquinolin]- 7'- yl)amino]imidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2341 );

[0352] 6-(2,6-dichloro-4-fluorophenyl )-2-{[2-(dimethy-lamino)-2,3-dihydro-l H-inden-5- yl]amino}imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2342);

[0353] 6-(2,6-dichlorophenyl)-2-({4-[(4-rnethylpiperazin-1 -yl)methyl]phenyl}amino)imidazo[l,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2343);

[0354] 6-(2,6-dichlorophenyl)-2-({4-[(3R,5S)-3,5-dimeth- ylpiperazin-1 -yl]-3- fluorophenyl}amino)imidazo[l, 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2344);

[0355] 6-(2,6-dichloropheny1 )-2-{[3 , 5-dif I uoro-4-(piper-azi n- 1 -yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5, 4-e]pyrimidin-5(6H)-one (W2345);

[0356] 6-(2-chloropheny1 )-2-{[2-(cyclopropylmethyl)-4,4- dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl] arnino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2346);

[0357] 6-(2-chloropheny1 )-2-{[4,4-dimethyl-2-(pyridin-3- ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] arnino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2347);

[0358] 6-(2-chloropheny1 )-2-{[4,4-dimethyl-2-(thiophen-3- ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] arnino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2348);

[0359] 6-(2-chlorophenyl)-2-[(1 ,1 ,2-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino]imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2349);

[0360] 6-(2,6-dichloropheny1 )-2-{[4-(py rrol idi n-2-y l)phe- nyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin- 5(6H)-one (W2350); 6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2351);

[0361] 2-{[3-chloro-4-( 4-methylpiperazin-1-yl)phenyl] amino}-6-(2,6-dichlorophenyl)imidazo[l,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2352);

[0362] 6-(2,6-dichlorophenyl)-2-({3-methoxy-4-[4-(propan- 2-yl)piperazin-1-yl]phenyl}amino)imidazo[1 ,2- a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2353);

[0363] 6-(2-chlorophenyl)-2-{[4-(4-hydroxypiperidin-1-yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2354);

[0364] 6-(2-chloro-6-fluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-IH-inden-5-yl]amino}imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2355);

[0365] 6-(2-chloro-6-fluorophenyl)-2-[(2'-methyl-2',3'-dihy- dro-l 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- yl) amino]imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2356);

[0366] 6-(2-chloro-6-fluorophenyl)-2-{[4-(1 ,4-diazepan-l- yl)-3-methylphenyl]amino}imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2357);

[0367] 2-[(2'-methyl-2',3'-dihydro-l 'H-spiro[cyclopropane- 1 ,4'-isoquinolin]-7'-yl)amino]-6-(propan-2- yl)imi-dazo[l,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2358);

[0368] 6-(2,6-dichlorophenyl)-2-{[4-(3-oxopiperazin-1-yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2359);

[0369] 6-(2-chlorophenyl)-2-{[4,4-dimethy1 -2-(propan-2- yl)-1 ,2 ,3 ,4-tetrahydroisoqu i nol i n-7-y I] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2360);

[0370] 6-(2-chlorophenyl)-2-{[4,4-dimethyl-2-(4,4,4-trif- luorobutyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2361);

[0371] 6-(2-chlorophenyl)-2-[(1 ,1 ,2-trimethyl-2,3-dihydro- 1 H-isoindol-5-yl)amino]imidazo[ I ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2362);

[0372] 6-(2-chlorophenyl)-2-[(1 ,1 ,2,3,3-pentamethyl-2,3- dihydro- 1 H-isoindol-5-yl)amino]imidazo[l ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2363);

[0373] 6-(2,6-dichloropheny1 )-2-{[3-methoxy-4-(4-meth- y Ipiperazi n- 1 -yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2364);

[0374] 6-(2,6-dichlorophenyl)-2-({4-[3-(diethylamino )pro- poxy]-3-fluorophenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2365);

[0375] 6-(2,6-dichlorophenyl)-2-[(1 ,1 ,2-trimethyl-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2366);

[0376] 2-({4-[(1S,45)-2,5-diazabicyclo[2.2.1]hept-2-yl] phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2367);

[0377] 6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1 ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2368);

[0378] 6-(2,6-dichlorophenyl)-2-{[4-(4,4-difluoropiperidin- l-yl)phenyl]amino}imidazo[ I ,2-a]pyrimido[5,4- e] pyrimidin-5(6H)-one (W2369);

[0379] 6-(2,6-dichlorophenyl)-2-{[4-(3,3-difluoropiperidin- 1-yl)phenyl]amino}imidazo[1 ,2-a]pyrimido[5,4- e] pyrimidin-5(6H)-one (W2370); 6-(2 , 6-dich loropheny l)-2-({3-f I uoro-4-[ 4-(propan-2- y l)pi perazi n- 1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2371 );

[0380] 6-(2,6-dichlorophenyl)-2-{[4-(piperazin-l-yl)-3- (trifluoromethyl)phenyl]amino}imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2372);

[0381] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-l-yl)-3-(propan-2-yl)phenyl]amino}imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2373);

[0382] 2-{[4-(4-acetylpiperazin-1 -yl)phenyl]amino}-6-(2- chloro-6-fluorophenyl)imidazo[l ,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2374);

[0383] 6-(2-chloro-6-fluorophenyl)-2-[(4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[l,2- a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2375);

[0384] 6-(2,6-dichloro-4-fluoropheny1 )-2-(2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- ylamino) imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2376);

[0385] 6-(2-chlorophenyl)-2-[(2-ethyl-4,4-dimethyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)amino]imidazo[1 ,2- a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2377);

[0386] 6-(2-chloropheny1 )-2-{[4,4-dimethyl-2-(2,2,2-trif- luoroethyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2378);

[0387] 6-(2-chlorophenyl)-2-({2-[4-(IH-imidazol-1 -yl)benzyl]-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7- yl}amino)imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5 (6H)-one (W2379);

[0388] 2-({2-[(1 -benzylpiperidin-4-yl)methyl]-4,4-dim- ethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl}amino )-6- (2-chlorophenyl)imidazo[l ,2-a]pyrimido[ 5,4-e]pyri- midin-5(6H)-one (W2380);

[0389] 2-[(2'-acetyl-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)amino]-6-(2,6-dichloro-4- fluorophenyl)imidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2381 );

[0390] 6-(2,6-dichlorophenyl)-2-{[4-(4-hydroxypiperidin-1 - yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2382);

[0391] 2-[(4-cyclohexylphenyl)amino]-6-(2,6-dichlorophe- nyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin- 5(6H)-one (W2383);

[0392] 6-(2,6-dichloropheny1 )-2-{[4-(py rrol idi n-3-y l)phe- nyl]amino}imidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin- 5(6H)-one (W2384);

[0393] 6-(2,6-dichlorophenyl)-2-{[4-(morpholin-4-y l)phe- nyl]amino}imidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin- 5(6H)-one (W2385);

[0394] 6-(2,6-dichlorophenyl)-2-{[4,4-dimethy1 -2-(2,2,2- trifluoroethyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2386);

[0395] 2-{[2'-(cyclopropylcarbonyl)-2',3'-dihydro-l 'H-spiro [cyclopropane-1 , 4'-isoquinolin]-7'-yl]amino}-6- (2,6-dichloro-4-fluorophenyl)imidazo[1 ,2-a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2387);

[0396] 6-(2,6-dichloro-4-fluorophenyl)-2-{[2'-(methylsulfonyl)-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- iso- quinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2388);

[0397] 6-(2,6-dichloro-4-fluorophenyl)-2-{[6-(piperazin-1 - yl)pyridin-3-yl]amino}imidazo[l ,2-a]pyrimido[

[0398] 5,4- e]pyrimidin-5(6H)-one (W2389);

[0399] 6-(2,6-dichlorophenyl)-2-{[4-(2-oxopiperazin-1 -yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2390); 2-({4-[(1 R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl] phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2391);

[0400] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-l- yl)-3-(propan-2-yl)phenyl]amino}imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2392);

[0401] 6-(2,6-dichlorophenyl)-2-[(1 ,1 ,2,3,3-pentamethyl-2, 3-dihydro- 1 H-isoindol-5-yl)amino]imidazo[l ,2- a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2393);

[0402] 6-(2,6-dichlorophenyl)-2-[(1 , l,2-trimethyl-2,3-dihy- dro-l H-isoindol-5-yl)amino]imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2394);

[0403] (3aS,10aS)-8-{[6-(2,6-dichloropheny1)-5-oxo-5,6- dihydroimidazo[l ,2-a]pyrimido[5,4-e]pyrimidin- 2- yl]amino}-2,3,3a,5,10,10a-hexahydropyrrolo[3,4-c] [1]benzazepin-4(1 H)-one (W2395);

[0404] 6-(2,6-dichlorophenyl)-2-{[4-(6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2396);

[0405] 2-(1 ,2,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlo- rophenyl)imidazo[ 1 ,2-a]pyrimido[5,4- e]pyrimidin-5 (6H)-one (W2397);

[0406] 2-(1 ,3-benzothiazol-6-ylamino)-6-(2,6-dichlorophe- nyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin- 5(6H)-one (W2398);

[0407] 2-({4-[bis(2-methoxyethyl)amino]phenyl}amino )-6- (2-chlorophenyl)imidazo[1 ,2-a]pyrimido[ 5,4- e]pyri- midin-5(6H)-one (W2399);

[0408] 6-(2-chloropheny1 )-2-[(3-cyclopropy1 -2,3,4,5-tetrahydro- 1 H-3-benzazepin-7- yl)amino]imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2400);

[0409] 6-(2-chlorophenyl)-2-{[3-(2,2-difluoroethy1 )-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7- yl]amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2401);

[0410] 6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpip-erazin-1-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2402);

[0411] 6-(2-chloro-4,6-difluoropheny1 )-2-[(2,4,4-trimethy 1 - 1 ,2,3,4-tetrahydroisoquinolin-7- yl)amino]imidazo[1 , 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2403);

[0412] 6-(2-chloro-4,6-difluoropheny1)-2-{[2-(dimethy- lamino)-2,3-dihydro-l H-inden-5-yl]amino}imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2404);

[0413] 6-(2-chloropheny1 )-2-[(4-{[3-(morpholin-4-yl)pro- pyl]amino}phenyl)amino]imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2405);

[0414] 6-(2-ch loropheny l)-2-({4-[4-(py rrol idi n- 1 -yl)piperi- din-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2406);

[0415] 6-(2-chlorophenyl)-2-({4-[4-(dimethylamino )piperi- din-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2407);

[0416] 6-(2-chlorophenyl)-2-[(4-{[2-(l-methylpyrrolidin-2-yl)ethyl]amino}phenyl)amino]imidazo[l,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2408);

[0417] 4-(dimethylamino )cyclohexyl 4-{[6-(2,6-dichlo- ropheny1)-5-oxo-5,6-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-2-yl]amino}benzoate (W2409);

[0418] 6-(2,6-dichlorophenyl)-2-(1 H-indazol-5-ylamino) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)- one (W2410); 6-(2,6-dichlorophenyl)-2-({4-[(3S)-3-(propan-2-yl) piperazin-1 -yl]phenyl}amino)imidazo[l, 2- a]py-rimido[5,4-e]pyrimidin-5(6H)-one (W2411 );

[0419] 6-(2,6-dichlorophenyl)-2-[(4-{1 -[1 -dimethylamino)-3-methylbutyl]cyclobutyl}phenyl)amino]imidazo [1 , 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2412);

[0420] 6-(2,6-dichlorophenyl)-2-({4-[4-methyl-2-(methy- lamino)-1 ,3-thiazol-5-yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2413);

[0421] 6-(2,6-dichlorophenyl)-2-{[6-(piperazin-1 -yl)pyridin-3-yl]amino}imidazo[1 ,2-a]pyrimido[5,4-e]pyri- midin-5(6H)-one (W2414);

[0422] 6-(2,6-dichlorophenyl)-2-(1 H-indazol-6-ylamino)imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2415);

[0423] (1 R)-octahydro-2H-quinolizin-1 -yl 4-{[6-(2 , 6- dichlorophenyl)-5-oxo-5,6-dihydroimidazo[l,2-a] pyrimido[5,4-e]pyrimidin-2-yl]amino}benzoate (W2416);

[0424] 2-[cyclopropyl(methyl)amino]ethyl 4-{[6-(2,6- dichlorophenyl )-5-oxo-5,6-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-2-yl]amino}benzoate (W2417);

[0425] 6-(2,6-dichlorophenyl)-2-[(4-{[(1 R,5S)-7-ethyl-3,7- diazabicyclo[3.3.1]non-3-yl]carbonyl} phenyl)amino]imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2418);

[0426] 6-(2-chlorophenyl)-2-{[3,5-difluoro-4-(piperazin-1 - yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2419);

[0427] 6-(2-chlorophenyl)-2-({4-[(8aR)-hexahydropyrrolo [1 ,2-a]pyrazin-2(1 H)-yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2420);

[0428] 2-(2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 ,4'-iso- qu i nol i n]-7'-y lam i no )-6-(4-hydroxyphenyl)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2421 );

[0429] 6-(2,6-dichlorophenyl)-2-{[2'-(methylsulfonyl)-2',3'- dihydro-l 'H-spiro[cyclopropane-1 ,4'- isoquinolin]-7'- yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5 (6H)-one (W2422);

[0430] 2-[(2'-acety I-2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 , 4'-isoquinolin]-7'-yl)amino]-6-(2,6- dichlorophenyl) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2423);

[0431] 6-(2-chlorophenyl)-2-{[4-(octahydro-2H-pyrido[l ,2- a]pyrazin-2-yl)phenyl]amino}imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2424);

[0432] 6-(2-chloro-6-fluorophenyl)-2-[(1 ,1 ,2-trimethyl-2,3- dihydro- 1 H-isoindol-5-yl)amino]imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2425);

[0433] 6-(2-chloro-6-fluorophenyl)-2-[(1 ,1 ,2,3,3-pentam- ethyl-2,3-dihydro-l H-isoindol-5- yl)amino]imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2426);

[0434] 6-(2-chlorophenyl)-2-({4-[4-(oxetan-3-yl)piperazin- l-yl]phenyl}amino)imidazo[l,2-a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2427);

[0435] 6-(2,6-dichloro-4-fluorophenyl)-2-[(2,4,4-trimethyl- 1 ,2,3,4-tetrahydroisoquinolin-7- yl)amino]imidazo[l, 2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2428);

[0436] 6-(2,6-dichlorophenyl)-2-[(4-oxo-1 ,4-dihydrocinno- lin-6-yl)amino]imidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2429);

[0437] 2-{[4-(4-acetylpiperazin-1 -yl)phenyl]amino}-6-(2,6- dichlorophenyl)imidazo[1 ,2-a]pyrimido[5,4- e]pyri- midin-5(6H)-one (W2430); 6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino) piperidin-1 -yl]phenyl}amino)imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2431 ); methyl 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-2-yl] aminojbenzoate (W2432);

[0438] 6-(2-chlorophenyl)-2-{[3,5-dichloro-4-(piperazin-1 - yl)phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2433);

[0439] 6-(2-chlorophenyl)-2-{[4-(imidazo[1 ,2-a]pyridin-2- yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e] pyrimidin-5(6H)-one (W2434);

[0440] 6-(2-chlorophenyl)-2-({4-[4-oxo-3-(propan-2-yl)-1 , 3-thiazolidin-2-yl]phenyl}amino)imidazo[1 ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2435);

[0441] 6-(2-chlorophenyl)-2-{[4-(2,3-dihydroimidazo[2, I- b][1 ,3]thiazol-6-yl)phenyl]amino}imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2436);

[0442] 6-(2-chlorophenyl)-2-{[4-(5-methyl-4-oxo-1 ,3-thia- zolidin-2-yl)phenyl]amino}imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2437);

[0443] 6-(2-chlorophenyl)-2-{[4-(imidazo[2,l-b][1 ,3]thia- zol-6-yl)phenyl]amino}imidazo[l ,2-a]pyrimido[

[0444] 5,4- e]pyrimidin-5(6H)-one (W2438);

[0445] 6-(2-chlorophenyl)-2-{[4-(3-oxo-2,3-dihydro-IH-indazol-7-yl)phenyl]amino}imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2439);

[0446] 6-(2-chloro-6-fluoropheny1 )-2-{[2'-(2,2-dif luoroet- hyl)-2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 ,4'- iso- quinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2440);

[0447] 6-(2-chloro-6-fluoropheny1 )-2-{[2'-(2-f luoroethy 1 )- 2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 ,4'- isoquino- lin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2441 );

[0448] 6-(2-chloro-6-fluorophenyl)-2-{[2-(diethylamino)-2, 3-dihydro- IH-inden-5-yl]amino}imidazo[1 ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2442);

[0449] 6-(2-chloro-6-fluoropheny1 )-2-{[2-(cyclopropy- lamino)-2,3-dihydro-l H-inden-5-yl]amino}imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2443);

[0450] 6-(2-chloro-6-fluorophenyl)-2-(2',3'-dihydro-1 'H- spiro[cyclopropane-1 ,4'-isoquinolin]-7'-ylamino) imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2444);

[0451] 2-{[4-(1 ,4'-bipiperidi n- 1 '-yl)phenyl]amino}-6-(2- chlorophenyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2445);

[0452] 6-(2-chlorophenyl)-2-({4-[(3R)-3-(dimethylamino) pyrrolidin-1 -yl]phenyl}amino)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2446);

[0453] 6-(2-chlorophenyl)-2-({4-[3-(trifluoromethyl)piperi- din-1 -yl]phenyl}amino)imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin-5(6H)-one (W2447);

[0454] 3-[4-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)piperazin-1 -yl]propanenitrile (W2448);

[0455] 3-[(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-2-yl] amino}phenyl)(cyclopropyl)amino]propanenitrile (W2449);

[0456] 6-(2-chlorophenyl)-2-[(4-{[2-(dirnethylarnino)ethyl]amino}phenyl)amino]imidazo[l ,2- a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2450); 1 -(4-{[6-(2-ch loropheny l)-5-oxo-5, 6-di hydroi m idazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-2- yl]amino}phenyl) piperidine-4-carboxamide (W2451 );

[0457] 6-(2-chlorophenyl)-2-({4-[4-(morpholin-4-yl)piperi- din-1 -yl]phenyl}amino)imidazo[l ,2-a]pyrimido[

[0458] 5,4- e]pyrimidin-5(6H)-one (W2452);

[0459] 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);

[0460] 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimi- dazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}- N-[4-(dimethylamino )cyclohexyl]benzamide (W2454);

[0461] 4-{[6-(2,6-dichloropheny1 )-5-oxo-5, 6-di hydroi m i- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}- N-(l-methylpiperidin-4-yl)benzamide (W2455);

[0462] 6-(2 , 6-dich loropheny l)-2-({4-[4-(py rrol idi n- 1 -yl) piperidi n - 1 -yl]phenyl}amino)imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2456);

[0463] 2-[(2'-acetyl-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)amino]-6-(2-chloro-6-fluo- rophenyl)imidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2457);

[0464] 6-(2-chloro-6-fluoropheny1 )-2-{[2'-(cyclopropylcar- bonyl )-2' ,3'-di hydro- 1 'H-spiro[cyclopropane- 1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2458);

[0465] 6-(2-chloro-6-fluorophenyl)-2-{[2'-(methylsulfony1 )-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyri- midin-5(6H)-one (W2459);

[0466] 6-(2-chloro-6-fluorophenyl)-2-({4-[(SaR)-hexahy- dropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl]phenyl}amino) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2460);

[0467] 2-({4-[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino] phenyl}amino)-6-(2-chlorophenyl)imidazo[1 ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2461 );

[0468] 6-(2-chlorophenyl)-2-[(4-{[2-(pyrrolidin-1 -yl)ethyl] amino}phenyl)amino]imidazo[l ,2-a]pyrimido[5,4- e] pyrimidin-5(6H)-one (W2462);

[0469] 6-(2-chlorophenyl)-2-({4-[4-(pyridin-2-yl)piperazin- l-yl]phenyl}amino)imidazo[1 ,2-a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2463);

[0470] 6-(2-chlorophenyl)-2-[(4-{[2-(morpholin-4-yl)ethyl] amino}phenyl)amino]imidazo[l ,2- a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2464);

[0471] 6-(2-ch loropheny l)-2-({4-[(2S)-2-(py rrol idi n- 1 -ylm- ethy l)py rrol idi n- 1 -yl]phenyl}amino)imidazo[1 ,2- a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2465);

[0472] 6-(2-chlorophenyl)-2-[(4-{4-[3-(dimethylamino) propyl]piperazin-1 -yl}phenyl)amino ]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2466);

[0473] 6-(2-chlorophenyl)-2-({4-[(2R)-2-(methoxymethyl) pyrrolidin-1 -yl]phenyl}amino)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2467);

[0474] 1 -(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo [1 ,2-a]pyrimido[ 5,4-e]py ri m idi n-2-y I] amino}phenyl)-N,N-diethylpiperidine-3-carboxamide (W2468);

[0475] 6-(2-chlorophenyl)-2-[(4-{[3-(2-oxopyrrolidin-1 -yl) propyl]amino}phenyl)amino ]imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2469);

[0476] 6-(2-chlorophenyl)-2-({4-[4-(4-fluorophenyl)piper- azin-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2470); 6-(2-chloro-6-fluorophenyl)-2-({4-[4-(dimethy- lamino)piperidin-1 -yl]phenyl}amino)imidazo[1 ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2471 );

[0477] 6-(2-chloro-6-fluorophenyl)-2-({2-[(3S)-3-fluoropyr- rolidin-1 -yl]-2 ,3-di hydro- 1 H-inden-5- yl}amino)imi- dazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2472);

[0478] 6-(2-chloro-6-fluorophenyl)-2-({2-[(2-fluoroethyl) amino]-2,3-dihydro-IH-inden-5-yl}amino)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2473);

[0479] 6-(2-chloro-6-fluoropheny1 )-2-{[2-(propylamino)-2, 3-dihydro- IH-inden-5-yl]amino}imidazo[1 ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2474);

[0480] 6-(2-chloro-6-fluorophenyl)-2-{[2-(pyrrolidin-1 -yl)- 2, 3-dihydro- 1 H-inden-5-yl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2475);

[0481] 6-(2-chlorophenyl)-2-[(4-{4-[2-(dimethylamino) ethy l]piperazi n- 1 -yl}phenyl)amino ]imidazo[l ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2476);

[0482] 6-(2-chlorophenyl)-2-[(4-{[3-(dimethylamino )pro- pyl](methyl)amino}phenyl)amino]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2477);

[0483] 6-(2-chlorophenyl)-2-[(4-{[2-(dimethylamino )ethyl] (ethyl)amino }phenyl)amino]imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2478);

[0484] 6-(2-chlorophenyl)-2-[(4-{[2-(dimethylamino )ethyl] (methyl)amino }phenyl)amino]imidazo[l,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2479);

[0485] 6-(2-chlorophenyl)-2-({4-[(2S)-2-(methoxymethyl) pyrrolidin-1 -yl]phenyl}amino)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2480);

[0486] 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2-methylpro- panoyl)-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2481 );

[0487] 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2,2-dimethylpro- panoyl)-2',3'-dihydro-1 'H-spiro[cyclopropane- 1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2482);

[0488] 6-(2-chloro-6-fluoropheny1 )-2-{[2'-(cyclopentylcar- bonyl )-2' ,3’-di hydro- 1 'H-spiro[cyclopropane- 1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2483);

[0489] 6-(2-ch loropheny l)-2-[(4-{[2-( 1 H-imidazol-4-yl) ethyl]amino }phenyl)amino]imidazo[l ,2-a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2484);

[0490] 6-(2-chlorophenyl)-2-[(4-{[3-(1 H-imidazol-1 -yl) propyl]amino }phenyl)amino]imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2485);

[0491] 6-(2-chloropheny1 )-2-{[4-(thiomorpholin-4-yl)phe- nyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin- 5(6H)-one (W2486);

[0492] 6-(2-chlorophenyl)-2-[(4-{propan-2-y l[2-(propan-2- ylamino)ethyl]amino}phenyl)amino ]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2487);

[0493] 1 -(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-2- yl]amino}phenyl) piperidine-3-carboxamide (W2488);

[0494] 6-(2,6-dichlorophenyl)-2-[(4-{[2-(l-methylpyrroli- din-2-yl)ethyl]amino}phenyl)amino]imidazo[l ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2489);

[0495] 6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropanoyl)- 2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquino- lin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyri- midin-5(6H)-one (W2490); 6-(2-chloropheny1 )-2-{[4-(thiomorpholin-4-yl)phe- nyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimidin- 5(6H)-one (W2491 );

[0496] 6-(2-chlorophenyl)-2-[(4-{propan-2-y l[2-(propan-2- ylamino)ethyl]amino}phenyl)amino ]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2492);

[0497] 1 -(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-2- yl]amino}phenyl) piperidine-3-carboxamide (W2493);

[0498] 6-(2,6-dichlorophenyl)-2-[(4-{[2-(l-methylpyrroli- din-2-yl)ethyl]amino}phenyl)amino]imidazo[l ,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2494);

[0499] 6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropanoyl)- 2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquino- lin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyri- midin-5(6H)-one (W2495);

[0500] 2-{[2'-(cyclopropylcarbonyl)-2',3'-dihydro-l 'H-spiro [cyclopropane-1 ,4'-isoquinolin]-7'-yl]amino}-6- (2,6- dichlorophenyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2496);

[0501] 6-(2,6-dichlorophenyl)-2-{[2'-(2,2-dimethylpro- panoyl)-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquinolin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2497);

[0502] 6-(2-chloro-6-fluorophenyl)-2-(5,6,7,8-tetrahydro-l,6-naphthyridin-3-ylamino)imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2498);

[0503] 6-(2-chloro-3-hydroxyphenyl)-2-(2',3'-dihydro-1 'H- spiro[cyclopropane-1 ,4'-isoquinolin]-7'-ylamino) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2499);

[0504] 2-(2' ,3'-di hydro- 1 'H-spiro[cyclopropane-1 ,4'-iso- qu i nol i n]-7'-y lam i no )-6-(4-hydroxy-2- methylphenyl) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2500);

[0505] 6-(2-chloro-6-fluoropheny1 )-2-{[2-(2,2-difluoroet- hyl)-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin- 7- yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5 (6H)-one (W2501 );

[0506] 6-(2-chloro-6-fluorophenyl)-2-{[2-(2-fluoro ethyl)-4, 4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2502);

[0507] 2-{[4-(1 ,4'-bipiperidi n- 1 '-yl)phenyl]amino}-6-(2,6- dichlorophenyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyri- midin-5(6H)-one (W2503);

[0508] 6-(2,6-dichlorophenyl)-2-({4-[(3R)-3-(dimethy- lamino)pyrrolidin-1 -yl]phenyl}amino)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2504)

[0509] 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);

[0510] 2-{[2'-(cyclopropylsulfonyl)-2',3'-dihydro-l 'H-spiro [cyclopropane-1 ,4'-isoquinolin]-7'-yl]amino}-6- (2,6- dichlorophenyl)imidazo[1 ,2-a]pyrimido[5,4-e]pyri- midin-5(6H)-one (W2506);

[0511] 6-(2,6-dichlorophenyl)-2-{[2'-(propan-2-ylsulfonyl)- 2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'- isoquino- lin]-7'-yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2507);

[0512] 6-(2,6-dichlorophenyl)-2-{[4-(1 -methylpiperidin-4-yl)phenyl]amino}imidazo[l ,2-a]pyrimido[ 5,4- e]pyrimidin-5(6H)-one (W2508);

[0513] 2-{[4-(2,7-diazaspiro[3.5]non-7-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[l,2-a]pyrimido[

[0514] 5,4- e]pyrimidin-5(6H)-one (W2509);

[0515] 6-(2-chlorophenyl)-2-({4-[2-(trifluoromethyl)pyrro- lidin-1 -yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2510); 6-(2-chloropheny1 )-2-{[4-(piperidin-4-yloxy)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2511 );

[0516] 6-(2-chloropheny1 )-2-{[4-(piperidin-4-y!methyl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2512);

[0517] 6-(2-chloropheny1 )-2-{[4-(hexahydropyrrolo[3,4-c] py rrol-2( 1 H)-yl)phenyl]amino}imidazo[1 ,2- a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2513);

[0518] 1 -(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo [1 ,2-a]pyrimido[ 5,4-e]pyrimidin-2- yl]amino}pheny1 )-N-methylmethanesulfonamide (W2514);

[0519] 4-{[6-(2-chloropheny1 )-5-oxo-5, 6-dihydroimidazo[1 , 2-a]pyrimido[ 5,4-e]pyrimidin-2-yl]amino}- N,N- diethylbenzenesulfonamide (W2515);

[0520] 2-{[2-(cyclopropylamino)-2,3-dihydro-l H-inden-5- yl]amino}-6-(2,6-dichlorophenyl)imidazo[1 ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2516);

[0521] 6-(2,6-dichlorophenyl)-2-({2-[(2-fluoroethyl)amino]-2,3-dihydro-IH-inden-5-yl}amino)imidazo [1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2517);

[0522] 6-(2,6-dichloropheny1 )-2-{[2-(propy!amino)-2,3-dihydro- 1 H-inden-5-yl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2518);

[0523] 2-{[4-(2-acetyl-2,7-diazaspiro[3.5]non-7-yl)phenyl] amino}-6-(2,6-dichlorophenyl)imidazo[l,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2519);

[0524] 6-(2,6-dichlorophenyl)-2-({4-[2-(methylsulfonyl)-2,7-diazaspiro[3.5]non-7-yl]phenyl}amino) imidazo[l, 2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2520);

[0525] 7'-{[6-(2-chloro-6-fluoropheny1 )-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2- yl]amino}-N-methyl-1 'H-spiro[cyclopropane-1 ,4'-iso-quinoline]-2'(3'H)-carboxamide (W2521 );

[0526] 7'-{[6-(2-chloro-6-fluoropheny1 )-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-2- yl]amino}-N-(propan-2-yl)-1 'H-spiro[cyclopropane-1 ,4'-isoquinoline]-2'(3'H)-carboxamide (W2522);

[0527] 6-(2,6-dichlorophenyl)-2-{[2-(2-fluoroethy1 )-4,4- dimethyl-l ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2523);

[0528] 6-(2,6-dichlorophenyl)-2-({4-[6-(methylsulfonyl)-2, 6-diazaspiro[3.3]hept-2-yl]phenyl}amino) imidazo[1 ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2524);

[0529] 2-{[4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]amino}- 6-(2,6-dichlorophenyl)imidazo[1 ,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2525);

[0530] 6-(2,6-dichlorophenyl)-2-{[2-(pyrrolidin-1 -yl)-2,3- dihydro- 1 H-inden-5-yl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2526);

[0531] 6-(2 , 6-dich loropheny l)-2-({2-[(3S)-3-f I uoropy rrol i- din-1 -yl]-2 ,3-di hydro- 1 H-inden-5- yl}amino)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2527);

[0532] 6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)amino]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2528);

[0533] 6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-ylamino)phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2529);

[0534] 6-(2-chloro-6-fluorophenyl)-2-{[4-(1 -methylpiperi- din-4-yl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2530); 2-[(2-acetyl-4,4-dimethyl-1 ,2,3,4-tetrahydroiso- quinolin-7-yl)amino]-6-(2-chloro-6-fluorophenyl) imidazo[l,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2531 );

[0535] 6-(2-chloro-6-fluorophenyl)-2-{[2-(cyclopropylcar- bonyl)-4,4-dimethyl-1 ,2,3,4- tetrahydroisoquinolin-7- yl]amino}imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5 (6H)-one (W2532);

[0536] 6-(2-chloro-6-fluoropheny1 )-2-{[4,4-dimethyl-2- (methylsulfonyl)-l ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2533);

[0537] 2-{[4-(2,6-diazaspiro[3.4]oct-2-yl)phenyl]amino}-6- (2,6-dichlorophenyl)imidazo[1 ,2- a]pyrimido[5,4-e] pyrimidin-5(6H)-one (W2534);

[0538] 2-{[4-(2,7-diazaspiro[3.5]non-2-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[l,2-a]pyrimido[

[0539] 5,4- e]pyrimidin-5(6H)-one (W2535);

[0540] 6-(2,6-dichlorophenyl)-2-({4-[(3S)-3-(dimethy- lamino)pyrrolidin-1 -yl]phenyl}amino)imidazo[1 ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2536);

[0541] 6-(2-chloro-6-fluoropheny1 )-2-{[2-(hydroxyacety1 )- 4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7- yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2537);

[0542] 7-{[6-(2-chloro-6-fluorophenyl)-5-oxo-5,6-dihy- droimidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-2-yl] amino}-4,4-dimethyl-3,4-dihydroisoquinoline-2 (1 H)-sulfonamide (W2538);

[0543] 2-[(2-acetyl-4,4-dimethyl-1 ,2,3,4-tetrahydroiso- quinolin-7-yl)amino]-6-(2,6-dichlorophenyl)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2539);

[0544] 6-(2,6-dichloropheny1 )-2-{[4,4-dimethyl-2-(methyl-sulfonyl)-1 ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2540);

[0545] 6-(2,6-dichloropheny1 )-2-{[2-(ethylsulfony1 )-4,4-dimethyl-l ,2,3,4-tetrahydroisoquinolin-7-yl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2541 );

[0546] 2-({4-[(1 -acetylpiperidin-4-y!)amino] phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2542);

[0547] 6-(2 , 6-dich loropheny l)-2-[(4-{[1 -(methylsulfonyl) piperidin-4-yl]amino}phenyl)amino ]imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2543);

[0548] 6-(2,6-dichloropheny1 )-2-{[4-(9-methy1 -3,9-diaza- spiro[5.5]undec-3-yl )phenyl]amino}imidazo[l,2- a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2544);

[0549] 6-(2,6-dichlorophenyl)-2-({4-[6-(methylsulfonyl)-2,6-diazaspiro[3.4]oct-2-yl]phenyl}amino) imidazo[l, 2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2545);

[0550] 6-(2-chlorophenyl)-2-({4-[(8aS)-hexahydropyrrolo [1 ,2-a]pyrazin-2(1 H)-yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2546);

[0551] 6-(2,6-dichlorophenyl)-2-({4-[(3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1 (2H)- yl]phenyl}arnino)imidazo[l,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2547);

[0552] 6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino) ethyl](ethyl)amino }phenyl)amino]imidazo[l,2-a] pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2548);

[0553] 6-(2,6-dichloropheny1 )-2-[(4-{propan-2-yl[2-(pro-pan-2-ylamino)ethyl]amino}phenyl)amino] imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2549);

[0554] 2-[(2-acetyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl) amino]-6-(2,6-dichlorophenyl)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2550); 6-(2,6-dichlorophenyl)-2-{[2-(methylsulfonyl)-1 ,2,3, 4-tetrahydroisoquinolin-6-yl]amino}imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2551);

[0555] 2-[(2-acetyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl) amino]-6-(2,6-dichlorophenyl)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2552);

[0556] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1 -yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4- e]pyrimi- dine-5(6H)-thione (W2553);

[0557] 6-(2-chlorophenyl)-5-imino-N-[4-(4-methylpiper-azin-1-yl)phenyl]-5,6-dihydroimidazo[l,2-a]py- rimido[5,4-e]pyrimidin-2-amine (W2554);

[0558] 6-(2-chlorophenyl)-2-[(2,4,4-trimethyl-1 ,2,3,4-tet- rahydroisoquinolin-7-yl)amino]imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidine-5(6H)-thione (W2555);

[0559] 6-(2-chlorophenyl)-5-imino-N-(2,4,4-trimethyl-1 ,2, 3,4-tetrahydroisoquinolin-7-yl)-5,6- dihydroimidazo [1 ,2-a]pyrimido[ 5,4-e]pyrimidin-2-amine (W2556);

[0560] 6-(3-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2557);

[0561] 6-(3-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl) phenyl]amino}imidazo[l,2-a]pyrimido[5,4- e]pyrimi- din-5(6H)-one (W2558);

[0562] 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);

[0563] 6-[2-chloro-4-(trifluoromethyl)phenyl]-2-{[4-(4- methylpiperazin-1-yl)phenyl]amino}imidazo[l ,2-a] pyrimido[5,4-e]pyrimidin-5(6H)-one (W2560);

[0564] 2-{[4-(4-methylpiperazin-1 -yl)phenyl]amino}-6-[2- (trifluoromethoxy)phenyl]imidazo[1 ,2- a]pyrimido[5, 4-e]pyrimidin-5(6H)-one (W2561);

[0565] 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[l, 2-a]pyrimido[ 5,4-e]pyrimidin-2- yl]amino}benzoic acid (W2562);

[0566] 2-[(4-bromophenyl)amino]-6-(2-chlorophenyl)imi- dazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2563);

[0567] 6-(3-methoxy-2-methylphenyl)-2-(phenylamino) imidazo[l ,2-a]pyrimido[ 5,4-e]pyrimidin-5(6H)-one (W2564);

[0568] 2-{[4-(1 ,4-diazepan-1-yl)-3-methylphenyl]amino}- 6-(2,6-dichlorophenyl)imidazo[l,2-a]pyrimido[

[0569] 5,4- e]pyrimidin-5(6H)-one (W2565);

[0570] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6- (propan-2-yl)imidazo[l,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2566);

[0571] 6-(2-chloropheny1 )-2-{[3 , 5-dif I uoro-4-(4-methy Ipip- erazin-1 -yl)phenyl]amino}imidazo[l ,2- a]pyrimido [5,4-e]pyrimidin-5(6H)-one (W2567);

[0572] 6-(2-chlorophenyl)-2-{[4-(trifluoromethyl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2568);

[0573] 6-(2-chlorophenyl)-2-{[4-(1 ,3-thiazol-4-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2569);

[0574] 6-(2-chlorophenyl)-2-{[4-(1 ,3-thiazol-2-yl)phenyl] amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2570); 6-(2-chlorophenyl)-2-{[4-(1 ,8-naphthyridin-2-yl) phenyl]amino}imidazo[l ,2-a]pyrimido[5,4-e]pyrimi- din-5(6H)-one (W2571);

[0575] 6-(2-chlorophenyl)-2-({4-[(2S)-2-(trifluoromethyl) pyrrolidin-1-yl]phenyl}amino)imidazo[1 ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2572);

[0576] 2-{[3-chloro-4-(4-methylpiperazin-l-yl)-5-(trifluo- romethyl)phenyl]amino}-6-(2- chlorophenyl)imidazo [1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2573);

[0577] 6-(2-chlorophenyl)-2-{[3-chloro-4-(piperazin-1-yl)- 5-(trifluoromethyl)phenyl]amino}imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2574);

[0578] 6-(2-chlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1 'H- spiro[cyclopropane-1 ,4'-isoqu i n ol i n]-7'- y!)amino] imidazo[1 ,2-a]pyrimido[5,4-e]pyrimidine-5(6H)- thione (W2575);

[0579] 2-{[7-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimi- dazo[l ,2-a]pyrimido[5,4-e]pyrimidin-2-yl]amino}-

[0580] 4.4-dimethyl-3,4-dihydroisoquinolin-2(1 H)-yl]methyl}benzonitrile (W2576);

[0581] 6-(2-chlorophenyl)-2-{[4,4-dimethyl-2-(4-propoxy- benzyl)-1 ,2,3,4-tetrahydroisoquinolin-7- yl]amino}imidazo[l,2-a]pyrimido[5,4-e]pyrimidin-5 (6H)-one (W2577);

[0582] 6-(2-chlorophenyl)-2-({2-[3-fluoro-5-(trifluorom- ethyl)benzyl]-4,4-dimethy1-1 ,2,3,4-tetrahydroiso- quinolin-7-yl}amino)imidazo[l ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2578);

[0583] 6-(2-chlorophenyl)-2-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}phenyl)amino]imidazo[l ,2-a]py- rimido[5,4-e]pyrimidin-5(6H)-one (W2579);

[0584] 6-(2-chlorophenyl)-2-({4-[2-(morpholin-4-yl)-1 ,3- thiazol-4-yl]phenyl}amino)imidazo[l ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2580);

[0585] 6-(2-chlorophenyl)-2-({4-[2-(6-methylquinolin-2-yl) ethyl]phenyl}amino)imidazo[l,2-a]pyrimido[5,4- e] pyrimidin-5(6H)-one (W2581);

[0586] 6-allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2582);

[0587] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-[(1 E)-prop-1-en-1-yl]-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2583);

[0588] 6-allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2584);

[0589] 6-allyl-N-cyclohexyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2585);

[0590] 1-{6-[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]-2,3-dihydro-1 H-indol-1- yljethanone (W2586);

[0591] 6-[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]-2H-1 ,4-benzoxazin-3(4H)- one (W2587),

[0592] 6-allyl-N-[4-(pyridin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2588),

[0593] 6-allyl-N-(1 -methyl-1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine

[0594] 5.5-dioxide (W2589);

[0595] 6-allyl-N-[4-(4-methylpiperidin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2590);

[0596] 1-(4-{4-[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]phenyl}piperazin-1- yl)ethanone (W2591); 6-allyl-N-[4-(piperidin-1 -yl)phenyl]-6H-pyrimido[5,4-c][2,1 ]benzothiazin-2-amine 5,5-dioxide (W2592);

[0597] 6-allyl-N-[2-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2593);

[0598] 6-allyl-N-(4-cyclohexylphenyl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2594);

[0599] 6-allyl-N-[4-(1 H-imidazo[4,5-c]pyridin-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine

[0600] 5,5-dioxide (W2595);

[0601] 6-allyl-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2596);

[0602] 6-allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2597);

[0603] 6-allyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2598);

[0604] 6-allyl-N-[3-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2599);

[0605] 6-allyl-N-[4-(1-methylpiperidin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide(W2600);

[0606] 6-allyl-N-[4-(1 H-benzimidazol-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2601);

[0607] 6-allyl-N-[4-(1-methyl-1 H-benzimidazol-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine

[0608] 5,5-dioxide (W2602);

[0609] 6-allyl-N-(2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2603);

[0610] 6-allyl-N-[4-(pyrimidin-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2604);

[0611] 6-allyl-N-phenyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2605);

[0612] 6-allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2606);

[0613] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2607);

[0614] 6-allyl-N-(pyridin-4-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2608);

[0615] 6-allyl-N-(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2609);

[0616] 6-allyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2610);

[0617] 6-allyl-N-(1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2611);

[0618] 6-allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2612);

[0619] 6-allyl-N-phenyl-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2613);

[0620] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0621] 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);

[0622] 1 -{6-[(6-allyl-5,5-dioxido-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-yl)amino]-2,3-dihydro-1 H- indol-1 -yl}ethanone (W2616);

[0623] 6-allyl-N-[3-fluoro-4-(piperazin-1 -yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0624] 5,5-dioxide (W2617);

[0625] 6-allyl-N-[4-(piperidin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2618);

[0626] 6-allyl-N-(1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5- dioxide (W2619);

[0627] 6-allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0628] 5,5-dioxide (W2620);

[0629] 6-allyl-N-[4-(4-methylpiperazin-1 -yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0630] 5,5-dioxide (W2621 );

[0631] 6-allyl-N-[3-chloro-4-(4-methylpiperazin-1 -yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2- amine 5,5-dioxide (W2622);

[0632] 6-allyl-N-[3-methyl-4-(piperazin-1 -yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0633] 5,5-dioxide (W2623);

[0634] {4-[(6-allyl-5,5-dioxido-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-yl)amino]phenyl}(4- methylpiperazin-1 -yl)methanone (W2624);

[0635] 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 (W2625);

[0636] 6-allyl-N-[4-(pyrrolidin-3-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2626);

[0637] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-6-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0638] 5,5-dioxide (W2627);

[0639] 6-allyl-N-(2'-methyl-2',3'-dihydro-1 'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrido[2,3- c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2628);

[0640] 6-allyl-N-[4-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5- e][1 ,2]thiazin-2-amine 5,5-dioxide (W2629);

[0641] 6-allyl-N-(1 -methyl-1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2- amine 5,5-dioxide (W2630);

[0642] 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 (W2631 );

[0643] 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 (W2632);

[0644] 6-allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5- dioxide (W2633);

[0645] 6-allyl-N-[3-methyl-4-(4-methyl-1 ,4-diazepan-1 -yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5- e][1 ,2]thiazin-2-amine 5,5-dioxide (W2634); 6-allyl-N-(2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrido[2,3- c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2635);

[0646] 6-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[4,5-e]thieno[3,2-c][1 ,2]thiazin-2-amine 5,5-dioxide (W2636);

[0647] 6-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2637);

[0648] 6-methyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2638);

[0649] 6-methyl-N-[4-(pyrrolidin-1-ylmethyl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2639);

[0650] 6-allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-7- carboxylic acid 5,5-dioxide (W2640); methyl 6-allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-

[0651] 7-carboxylate 5,5-dioxide (W2641);

[0652] 6-allyl-N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2642);

[0653] 6-allyl-N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2643);

[0654] 6-allyl-8-bromo-N-phenyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2644);

[0655] 6-allyl-8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2645); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-8- carboxylate 5,5-dioxide (W2646);

[0656] 8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2647);

[0657] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2648);

[0658] N-[4-(4-methylpiperazin-1-yl)phenyl]-8-phenyl-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2649);

[0659] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-3-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2650);

[0660] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1 H-pyrazol-4-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2651);

[0661] 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)benzamide (W2652);

[0662] N-cyclopropyl-4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H- pyrimido[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2653);

[0663] 8-(2-aminopyrimidin-5-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2654);

[0664] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(3-thienyl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2655); 4-(2-{[4-(4-methylpiperazin-1 -yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)phenol (W2656);

[0665] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-4-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2657);

[0666] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2658); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2659);

[0667] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-8- carboxamide 5,5-dioxide (W2660);

[0668] 2-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)propan-2-ol (W2661);

[0669] N-cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2662);

[0670] N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2663);

[0671] 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);

[0672] N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2665);

[0673] N-(2-methoxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2666);

[0674] N-(trans-4-aminocyclohexyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H- pyrimido[5,4-c][2,1]benzothiazine-8-carboxamide-5,5-dioxide (W2667);

[0675] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-N-(pyridin-3-ylmethyl)-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2668); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2669); methyl 6-(3-methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2670); methyl 6-(3,5-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2671); methyl 6-[3,5-bis(trifluoromethyl)phenyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H- pyrimido[5,4-c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2672);

[0676] 8-(1 H-imidazol-1 -yl)-N-[4-(4-methylpiperazin-1 -yl)phenyl]-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2673);

[0677] N-[4-(4-methylpiperazin-1 -y l)pheny l]-6-propy l-8-( 1 H-pyrrol-1 -yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2674);

[0678] N-[4-(4-methylpiperazin-1 -y l)pheny l]-6-propy l-8-( 1 H-1 ,2 ,4-triazol- 1 -yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2675); methyl 6-(2,6-dichlorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2676);

[0679] 9-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2677);

[0680] N-[4-(4-methylpiperazin-1-yl)phenyl]-9-phenyl-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2678);

[0681] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-9-(pyridin-3-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2679);

[0682] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-9-(pyridin-4-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2680);

[0683] N-methyl-3-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-9-yl)benzamide (W2681);

[0684] 9-{2-[(dimethylamino)methyl]phenyl}-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H- pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2682);

[0685] 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);

[0686] 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);

[0687] 6-allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2685);

[0688] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-[(1 E)-prop-1-en-1-yl]-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2686);

[0689] 6-allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2687);

[0690] 6-allyl-N-cyclohexyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2688);

[0691] 1-{6[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]-2,3-dihydro-1 H-indol-1- yljethanone (W2689);

[0692] 6-[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]-2H-1 ,4-benzoxazin-3(4H)- one (W2690);

[0693] 6-allyl-N-(1 -methyl-1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2691);

[0694] 6-allyl-N-[4-(4-methylpiperidin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2692);

[0695] 1-(4-{4-[(6-allyl-5,5-dioxido-6H-pyrimido[5,4-c][2,1]benzothiazin-2-yl)amino]phenyl}piperazin-1- yl)ethanone (W2693);

[0696] 6-allyl-N-[4-(piperidin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2694);

[0697] 6-allyl-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2695);

[0698] 6-allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2696); 6-allyl-N-[3-(4-methylpiperazin-1 -yl)phenyl]-6H-pyrimido[5,4-c][2, 1 ]benzothiazin-2-amine 5,5- dioxide (W2697);

[0699] 6-allyl-N-[4-(1-methylpiperidin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2698);

[0700] 6-allyl-N-(2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2699);

[0701] 6-allyl-N-phenyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2700);

[0702] 6-allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2701);

[0703] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2702);

[0704] 6-allyl-N-(pyridin-4-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2703);

[0705] 6-allyl-N-(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2704);

[0706] 6-allyl-N-(1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2705);

[0707] 6-allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2706);

[0708] 6-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2707);

[0709] 6-methyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2708);

[0710] 6-methyl-N-[4-(pyrrolidin-1-ylmethyl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2709);

[0711] 6-allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-7- carboxylic acid 5,5-dioxide (W2710); methyl 6-allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-

[0712] 7-carboxylate 5,5-dioxide (W2711);

[0713] 6-allyl-N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1] benzothiazine-7-carboxamide 5,5-dioxide (W2712);

[0714] 6-allyl-N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2713);

[0715] 6-allyl-8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5-dioxide (W2714); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4-c][2,1]benzothiazine-8- carboxylate 5,5-dioxide (W2715);

[0716] 8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2716);

[0717] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-2-amine 5,5- dioxide (W2717); N-[4-(4-methylpiperazin-1 -yl)phenyl]-8-phenyl-6-propyl-6H-pyrimido[5,4-c][2, 1 ]benzothiazin-2- amine 5,5-dioxide (W2718);

[0718] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-3-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2719);

[0719] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1 H-pyrazol-4-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2720);

[0720] 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)benzamide (W2721);

[0721] N-cyclopropyl-4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H- pyrimido[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2722);

[0722] 8-(2-aminopyrimidin-5-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2723);

[0723] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(3-thienyl)-6H-pyrimido[5,4-c][2,1]benzothiazin-2- amine 5,5-dioxide (W2724);

[0724] 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)phenol (W2725);

[0725] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-4-yl)-6H-pyrimido[5,4-c][2,1]benzothiazin- 2-amine 5,5-dioxide (W2726);

[0726] N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2727); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2728);

[0727] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-8- carboxamide 5,5-dioxide (W2729);

[0728] 2-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxido-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-8-yl)propan-2-ol (W2730);

[0729] N-cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2731);

[0730] N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2732);

[0731] 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 (W2733);

[0732] N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2734);

[0733] N-(2-methoxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2735);

[0734] N-(trans-4-aminocyclohexyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H- pyrimido[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2736);

[0735] 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-N-(pyridin-3-ylmethyl)-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2737); methyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenyl-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2738); methyl 6-(3-methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimido[5,4- c][2,1]benzothiazine-8-carboxylate 5,5-dioxide (W2739);

[0736] 8-(1 H-imidazol-1 -yl)-N-[4-(4-methylpiperazin-1 -yl)phenyl]-6-propyl-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2740);

[0737] N-[4-(4-methylpiperazin-1 -y l)pheny l]-6-propy l-8-( 1 H-pyrrol-1 -yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide; (W2741)

[0738] N-[4-(4-methylpiperazin-1 -y l)pheny l]-6-propy l-8-( 1 H-1 ,2 ,4-triazol- 1 -yl)-6H-pyrimido[5,4- c][2,1]benzothiazin-2-amine 5,5-dioxide (W2742).

[0739] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0740] 5,5-dioxide (W2743);

[0741] 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);

[0742] 1-{6-[(6-allyl-5,5-dioxido-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-yl)amino]-2,3-dihydro-1 H- indol-1-yl}ethanone; (W2745)

[0743] 6-allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0744] 5,5-dioxide (W2746);

[0745] 6-allyl-N-[4-(piperidin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2747);

[0746] 6-allyl-N-(1 ,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5- dioxide (W2748);

[0747] 6-allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0748] 5,5-dioxide (W2749);

[0749] 6-allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0750] 5,5-dioxide (W2750);

[0751] 6-allyl-N-[3-methyl-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0752] 5,5-dioxide (W2751);

[0753] {4-[(6-allyl-5,5-dioxido-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-yl)amino]phenyl}(4- methylpiperazin-1-yl)methanone (W2752);

[0754] 6-allyl-N-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-

[0755] 2-amine 5,5-dioxide (W2753);

[0756] 6-allyl-N-[4-(pyrrolidin-3-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2754);

[0757] 6-allyl-N-(1 ,2,3,4-tetrahydroisoquinolin-6-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine

[0758] 5,5-dioxide (W2755);

[0759] 6-allyl-N-(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrido[2,3- c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2756);

[0760] 6-allyl-N-[4-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5- e][1 ,2]thiazin-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]thiazin-2- amine 5,5-dioxide (W2758);

[0761] 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);

[0762] 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);

[0763] 6-allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5- dioxide (W2761);

[0764] 6-allyl-N-[3-methyl-4-(4-methyl-1 ,4-diazepan-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5- e][1 ,2]thiazin-2-amine 5,5-dioxide (W2762);

[0765] 6-allyl-N-(2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)-6H-pyrido[2,3- c]pyrimido[4,5-e][1 ,2]thiazin-2-amine 5,5-dioxide (W2763);

[0766] 6-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[4,5-e]thieno[3,2-c][1 ,2]thiazin-2-amine 5,5-dioxide (W2764);

[0767] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin -5(8H)-one (W2765);

[0768] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[2,3-d]pyrimidin- 5(8H)-one (W2766);

[0769] 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-7-phenylpyrido[2,3-d]pyrimidin- 5(8H)-one (W2767);

[0770] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[2,3- d]pyrimidin-5(8H)-one (W2768);

[0771] 6-(2-chlorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin- 5(8H)-one (W2769);

[0772] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8,9-dihydropyrimido[4,5- e]indolizin-5(7H)-one (W2770);

[0773] 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);

[0774] 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2772);

[0775] 6-(2,6-dichlorophenyl)-8-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2773);

[0776] 8-cyclopropyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2774);

[0777] 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);

[0778] 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);

[0779] 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'- isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2778);

[0780] 8-cyclobutyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2779);

[0781] 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);

[0782] 8-cyclopropyl-6-(2,6-dichlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane -1 ,4'- isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2781);

[0783] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)- one (W2782);

[0784] 6-(2,6-dichlorophenyl)-8-methyl-2-{[3-methyl-4-(4-methyl-1 ,4-diazepan-1- yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2783);

[0785] 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);

[0786] 6-(2,6-dichlorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'-ylamino)-8- methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2785);

[0787] 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1 H-inden-5-yl]amino}-8- methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2786);

[0788] 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);

[0789] 8-cyclopropyl-6-(2,6-dichlorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2788);

[0790] 8-cyclopropyl-6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1 H-inden-5- yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2789);

[0791] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(propan-2-yl)pyrido[2,3- d]pyrimidin-5(8H)-one (W2790);

[0792] 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(oxetan-3-yl)pyrido[2,3- d]pyrimidin-5(8H)-one (W2791);

[0793] 8-tert-butyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2792);

[0794] 6-(2,6-dichlorophenyl)-8-(4-methoxybenzyl)-2-[(2'-methyl-2',3'-dihydro-1'H -spiro[cyclopropane- 1 ,4'-isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2793);

[0795] 6-(2,6-dichlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2794);

[0796] 6-(2,6-dichlorophenyl)-8-ethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin- 5(8H)-one (W2795);

[0797] 6-(2,6-dichlorophenyl)-8-ethyl-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]- 7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2796);

[0798] 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'- isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2798);

[0799] 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);

[0800] 6-(2-chloro-6-fluorophenyl)-8-(4-methoxybenzyl)-2-[(2'-methyl-2',3'-dihydro-1'H - spiro[cyclopropane-1 ,4'-isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2800);

[0801] 6-(2-chloro-6-fluorophenyl)-8-cyclopropyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2801);

[0802] 6-(2-chloro-6-fluorophenyl)-8-cyclopropyl-2-[(2'-methyl-2',3'-dihydro-1'H -spiro[cyclopropane-1 ,4'- isoquinolin]-7'-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2802);

[0803] 6-(2-chloro-6-fluorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2803);

[0804] 6-(2-chloro-6-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin- 5(8H)-one (W2804);

[0805] 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1 H-inden-5-yl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2805);

[0806] 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);

[0807] 6-(2,6-dichlorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-isoquinolin]-7'- ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2807);

[0808] 6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-methylpyrido[2,3- d]pyrimidin-5(8H)-one (W2808);

[0809] 6-(2,6-dichlorophenyl)-8-methyl-2-(1 ,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrido[2,3-d]pyrimidin- 5(8H)-one (W2809);

[0810] 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);

[0811] 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)- one (W2811);

[0812] 6-(2,6-dichlorophenyl)-2-(2,3-dihydro-1 H-isoindol-5-ylamino)-8-methylpyrido[2,3-d]pyrimidin- 5(8H)-one (W2812);

[0813] 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrido[2,3-d]pyrimidin- 5(8H)-one (W2813);

[0814] 6-(2,6-dichlorophenyl)-8-methyl-2-(1 ,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrido[2,3-d]pyrimidin- 5(8H)-one (W2814);

[0815] 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);

[0816] 6-(2,6-dichlorophenyl)-8-methyl-2-[(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)amino]pyrido[2,3- d]pyrimidin-5(8H)-one (W2816);

[0817] 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}-1 H- isoindole-1 ,3(2H)-dione (W2818);

[0818] 6-(2,6-dichlorophenyl)-8-methyl-2-{[2-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden-5- yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2819);

[0819] 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);

[0820] 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);

[0821] 6-(2,6-dichlorophenyl)-8-methyl-2-[(1 ,1 ,2-trimethyl-2,3dihydro-1 H-isoindol-5- yl)amino]pyrido[2,3d]pyrimidin-5(8H)-one (W2822);

[0822] 6-(2,6-dichlorophenyl)-8methyl-2-({4-[(1-methylpiperdin-4yl)amino]phenyl}amino) pyrido[2,3d]pyrimidin-5(8H)-one (W2823);

[0823] 6-(2,6-dichlorophenyl)-2-({2-[4-(dimethylamino)piperidin-1-yl]pyrimidin-5yl}amino)-8- methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2824);

[0824] 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(3R)-pyrrolidin-3-ylamino]phenyl}amino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2825);

[0825] 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(3S)-pyrrolidin-3-ylamino]phenyl}amino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2826);

[0826] 6-(2,6-dichlorophenyl)-2-[(1 ,1-dimethyl-2,3-dihydro-1 H-isoindol-5-yl)amino]-8-methylpyrido[2,3- d]pyrimidin-5(8H)-one (W2827);

[0827] 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(piperdin-4ylamino)phenyl]amino}pyrido [2,3-d]pyrimidin- 5(8H)-one (W2828);

[0828] 6-(2,6-dichlorophenyl)-8-methyl-2-({4[(1-methylpyrrolidin-3yl)amino]phenyl}amino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2829);

[0829] 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2830);

[0830] 6-(2-chloro-6fluorophenyl)-8-methyl-2-({4-[(1-methylpiperdin-4-yl)amino]phenyl}amino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2831);

[0831] 6-(2-chloro-6-fluorophenyl)-8-methyl-2-[(1 ,1 ,2-trimethyl-2,3-dihydro-1 H-isoindol-5- yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2832); methyl 5-{[6-(2,6-dichlorophenyl)-8-methyl-5-oxo-5,8-dihydropyrido[2,3-]pyrimidin-2-yl]amino}-2- (4-methylpiperazin-1-yl)benzoate (W2833);

[0832] 6-(2,6-dichlorophenyl)-2-({2-[4-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1 H-inden-5-yl}amino)-8- methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2834);

[0833] 6-(2-chloro-6-fluorophenyl)-8-methyl-2-{[4-(piperdin-4ylamino)phenyl]amino}pyrido[2,3- d]pyrimidin-5(8H)-one (W2835);

[0834] 6-(2-chloro-6-fluorophenyl)-8-methyl-2-(1 ,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrido[2,3- d]pyrimidin-5(8H)-one (W2836);

[0835] 6-(2-chloro-6-fluorophenyl)-8methyl-2-(1 ,2,3,4-tetrahydroisoquinolin-6ylamino)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);

[0836] 6-(2,6-dichlorophenyl)-2-[(4-{[cis-4-(dimethylamino)cyclohexyl]amino}phenyl)amino]-8- methylpyrido[2,3d]pyrimidin-5(8H)-one (W2839);

[0837] 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);

[0838] 6-(2,6-dichlorophenyl)-2-[(4-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}phenyl)amino]-

[0839] 8methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2841);

[0840] 6-(2-Chlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2842);

[0841] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2843);

[0842] 4-(2-Chlorophenyl)-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2,4-dihydroimidazo[1 ,2- a]pyrido[3,4-e]pyrimidin-5(1 H)-one (W2844);

[0843] 6-(2,6-Dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2845);

[0844] 6-(2-Chloro-6-methylphenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2846);

[0845] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2847);

[0846] 2-((4-(4-Acetylpiperazin-1-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2848);

[0847] 6-(2-Chloro-6-fluorophenyl)-2-((2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2849);

[0848] 6-(2-Chloro-6-fluorophenyl)-2-((2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2850);

[0849] 6-(2-Chloro-6-fluorophenyl)-2-((2'-methyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'-isoquinolin)-7'- yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2851);

[0850] 6-(2-Chloro-6-fluorophenyl)-2-((2'-acetyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'-isoquinolin)-7'- yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2852);

[0851] 6-(2,6-Dichlorophenyl)-2-((2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one 5(6H)-one (W2853);

[0852] 6-(2,6-Dichlorophenyl)-2-((2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2854);

[0853] 6-(2,6-Dichlorophenyl)-2-((2'-methyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'-isoquinolin)-7'- yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2855);

[0854] 6-(2,6-Dimethylphenyl)-2-((2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2856);

[0855] 6-(2,6-Dimethylphenyl)-2-((2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2857); 6-(2,6-Dimethylphenyl)-2-((2'-methyl-2',3'-dihydro-1 'H-spirocyclopropane-1 ,4'isoquinolin-7'- yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2858);

[0856] 6-lsopropyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2859);

[0857] 6-(Tert-butyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2860);

[0858] 6-Cyclopropyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2861);

[0859] 6-Cyclohexyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2862);

[0860] 6-Allyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2863);

[0861] 2-((4-(4-Methylpiperazin-1-yl)phenyl)amino)-6-(thiophen-2-yl)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(61)-one (W2864);

[0862] 6-(Furan-2-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2865);

[0863] 2-((4-(4-Methylpiperazin-1 -yl)phenyl)amino)-6-(1 H-pyrrol-2-yl)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2866);

[0864] 6-(1 H-lmidazol-5-yl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2867);

[0865] 6-(2-Chloro-6-fluorophenyl)-8,8-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2868);

[0866] 6-(2-Chloro-6-fluorophenyl)-9,9-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2869);

[0867] 6-(2-Chloro-6-fluorophenyl)-2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2870);

[0868] 6-(2-Chloro-6-fluorophenyl)-2-((4-(morpholinomethyl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2871);

[0869] 6-(2-Chloro-6-fluorophenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2872);

[0870] 6-(2-Chloro-6-fluorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)amino)-

[0871] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2873);

[0872] 6-(2-Chloro-6-fluorophenyl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2874);

[0873] 6-(2-Chloro-6-fluorophenyl)-2-((2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-

[0874] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2875);

[0875] 6-(2-Chloro-6-fluorophenyl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2876);

[0876] 6-(2-Chloro-6-fluorophenyl)-2-((2-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-

[0877] 8,9-dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2878);

[0878] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2879);

[0879] 6-(2-Chloro-6-fluorophenyl)-2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2880);

[0880] 6-(2-Chloro-6-fluorophenyl)-2-((2-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-

[0881] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2881);

[0882] 6-(2-Chloro-6-fluorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2882);

[0883] 6-(2-Chloro-6-fluorophenyl)-2-((3-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-

[0884] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2883);

[0885] 6-(2-Chloro-6-fluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2884);

[0886] 2-((3-Chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)-

[0887] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2885);

[0888] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2886);

[0889] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2887);

[0890] 6-(2-Chloro-6-fluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2888);

[0891] 6-(2-Chloro-6-fluorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-

[0892] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2889);

[0893] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)-3-methylphenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2890);

[0894] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2891);

[0895] 6-(2-Chloro-6-fluorophenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2892);

[0896] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2893);

[0897] 6-(2-Chloro-6-fluorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2894);

[0898] 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);

[0899] 6-(2-Chloro-6-fluorophenyl)-2-((2'-isopropyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'-isoquinolin)- 7'-yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2896);

[0900] 6-(2-Chloro-6-fluorophenyl)-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine-2-ylamino)-

[0901] 8,9-dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2898);

[0902] 6-(2-Fluoro-6-(trifluoromethyl)phenyl)-2-((3-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2899);

[0903] 6-(2-Fluoro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2900);

[0904] 6-(2,6-Dichlorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2901 );

[0905] 6-(2,6-Dichlorophenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2902);

[0906] 6-(2,6-Dichlorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2903);

[0907] 6-(2,6-Dichlorophenyl)-2-((2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2904);

[0908] 6-(2,6-Dichlorophenyl)-2-((2-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2905);

[0909] 6-(2,6-Dichlorophenyl)-2-((2-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1 - yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2906);

[0910] 6-(2,6-Dichlorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2907);

[0911] 6-(2,6-Dichlorophenyl)-2-((3-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2908);

[0912] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2909);

[0913] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2910);

[0914] 6-(2,6-Dichlorophenyl)-2-((4-(4-methylpiperazin-1 -yl)-3-(trifluoromethyl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2911 );

[0915] 6-(2,6-Dichlorophenyl)-2-((3-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1 - yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2912);

[0916] 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2913);

[0917] 6-(2,6-Dichlorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)-3-methylphenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2914);

[0918] 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2915);

[0919] 6-(2,6-Dichlorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1 -yl)-3- methylphenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2916);

[0920] 6-(2,6-Dichlorophenyl)-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine-2-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2918);

[0921] 6-(2-Chloro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2919);

[0922] 6-(2-Chloro-6-methoxyphenyl)-2-((3-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2920);

[0923] 6-(2,6-Dimethylphenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2921 );

[0924] 6-(4-Chlorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2922);

[0925] 6-(3-Chlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2923);

[0926] 6-(2,4-Dichlorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2924);

[0927] 6-(2-Chloro-4-fluorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2925);

[0928] 6-(2-Chloro-3-fluorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2926);

[0929] 6-(2,5-Dichlorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2927);

[0930] 6-(2,3-Dichlorophenyl)-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2928);

[0931] 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);

[0932] 2-((4-(4-Methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin- 5(6H)-one (W2930);

[0933] 6-Cyclobutyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2931 );

[0934] 6-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2932);

[0935] 6-Phenyl-2-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W2933);

[0936] 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);

[0937] 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);

[0938] 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);

[0939] 6-(2,6-Difluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1 -yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2938);

[0940] 6-(2-Chloro-6-fluorophenyl)-2-((4-(1 H-imidazol-1 -yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2939);

[0941] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-methyl-1 ,4-diazepan-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2940);

[0942] 6-(2-Chloro-6-fluorophenyl)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2941);

[0943] 6-(2-Chloro-6-fluorophenyl)-2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2942);

[0944] 6-(2-Chloro-6-fluorophenyl)-2-((4-(3-(dimethylamino)propoxy)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2943);

[0945] 6-(2-Chloro-6-fluorophenyl)-2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2944);

[0946] 6-(2-Chloro-6-fluorophenyl)-2-((4-((2-(dimethylamino)ethyl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2945);

[0947] 6-(2-Chloro-6-fluorophenyl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2946);

[0948] 6-(2-Chloro-6-fluorophenyl)-2-((4-((3-(dimethylamino)propyl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2947);

[0949] 6-(2-Chloro-6-fluorophenyl)-2-((4-((3-(dimethylamino)propyl)(methyl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2948);

[0950] 6-(2-Chloro-6-fluorophenyl)-2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2949);

[0951] 6-(2-Chloro-6-fluorophenyl)-2-((4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2950);

[0952] 6-(2-Chloro-6-fluorophenyl)-2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2951);

[0953] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2952);

[0954] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2953);

[0955] 6-(2-Chloro-6-fluorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2954);

[0956] 6-(2-Chloro-6-fluorophenyl)-2-((3-bromo-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2955);

[0957] 6-(2-Chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2956);

[0958] 6-(2-Chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-4-(4-(dimethylamino)piperidin-1- yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2958);

[0959] 6-(2-Chloro-6-fluorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2959);

[0960] 6-(2-Chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2960);

[0961] 6-(2-Chloro-6-fluorophenyl)-2-((3-fluoro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2961);

[0962] 6-(2-Chloro-6-fluorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2962);

[0963] 6-(2-Chloro-6-fluorophenyl)-2-((3-chloro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2963);

[0964] 6-(2-Chloro-6-fluorophenyl)-2-((3-bromo-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2964);

[0965] 6-(2-Chloro-6-fluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)-5-

[0966] (trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2965);

[0967] 6-(2-Chloro-6-fluorophenyl)-2-((3-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2966);

[0968] 6-(2,6-Dichlorophenyl)-2-((5-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2967);

[0969] 6-(2,6-Dichlorophenyl)-2-((2,5-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2968);

[0970] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2969);

[0971] 6-(2,6-Dichlorophenyl)-2-((2,4,4,5-tetramethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2970);

[0972] 6-(2,6-Dichlorophenyl)-2-((5'-chloro-2'-methyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'- isoquinolin)-7'-yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2971);

[0973] 6-(2,6-Dichlorophenyl)-2-((2',5'-dimethyl-2',3'-dihydro-1'H-spiro(cyclopropane-1 ,4'-isoquinolin)-7'- yl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2972);

[0974] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2973);

[0975] 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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2974);

[0976] 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2975);

[0977] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2976);

[0978] 6-(2,6-Dichlorophenyl)-2-((3-bromo-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2978);

[0979] 6-(2,6-Dichlorophenyl)-2-((3,5-dichloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2979);

[0980] 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5-methylphenyl)amino)-

[0981] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2980);

[0982] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)-5-methoxyphenyl)amino)-

[0983] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2981);

[0984] 6-(2,6-Dichlorophenyl)-2-((3-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2982);

[0985] 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2983);

[0986] 6-(2,6-Dichlorophenyl)-2-((3-chloro-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2984);

[0987] 6-(2,6-Dichlorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2985);

[0988] 6-(2,6-Dichlorophenyl)-2-((3-fluoro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2986);

[0989] 6-(2,6-Dichlorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2987);

[0990] 6-(2,6-Dichlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2988);

[0991] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)amino)-

[0992] 8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2989);

[0993] 6-(2,6-Dichlorophenyl)-2-((3-chloro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2990);

[0994] 6-(2,6-Dichlorophenyl)-2-((3-bromo-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2991);

[0995] 6-(2,6-Dichlorophenyl)-2-((3-bromo-5-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2992);

[0996] 6-(2,6-Dichlorophenyl)-2-((3-bromo-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2993);

[0997] 6-(2,6-Dichlorophenyl)-2-((3-bromo-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2994);

[0998] 6-(2,6-Dichlorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2995);

[0999] 6-(2,6-Dichlorophenyl)-2-((3-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2996);

[1000] 6-(2-Bromo-6-chlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5- methylphenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2998);

[1001] 6-(2-Bromo-6-chlorophenyl)-2-((3-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2999);

[1002] 6-(2-Bromo-6-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3000);

[1003] 6-(2-Bromo-6-chlorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3001);

[1004] 6-(2-Bromo-6-chlorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3002);

[1005] 6-(2-Bromo-6-chlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3003);

[1006] 6-(2-Bromo-6-chlorophenyl)-2-((3-bromo-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3004);

[1007] 6-(2-Fluoro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3005);

[1008] 6-(2-Fluoro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3006);

[1009] 6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5- methylphenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3007);

[1010] 6-(2-Chloro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3008);

[1011] 6-(2-Chloro-6-methylphenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3009);

[1012] 6-(2-Chloro-6-methylphenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3010);

[1013] 6-(2-Chloro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3011);

[1014] 6-(2,6-Dichlorophenyl)-2-((4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W3012);

[1015] 6-(2,6-Dichlorophenyl)-2-((3-chloro-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3013);

[1016] 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3014);

[1017] 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3015);

[1018] 6-(2-Chloro-6-fluorophenyl)-2-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3016);

[1019] 6-(2,6-Dichlorophenyl)-2-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[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]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3018);

[1020] 6-(2,6-Dichlorophenyl)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3019);

[1021] 6-(2,6-Dichlorophenyl)-2-((4-morpholinophenyl)amino)-8,9-dihydroimidazo[1 ,2-a]pyrimido[5,4- e]pyrimidin-5(6H)-one (W3020);

[1022] 6-(2,6-Dichlorophenyl)-2-((3-((methylamino)methyl)-4-morpholinophenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3021);

[1023] 6-(2-Bromo-6-chlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9- dihydroimidazo[1 ,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3022);

[1024] 6-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1 ,2- a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W3023);

[1025] 3-(2,6-Dichlorophenyl)-2-methyl-7-((4-(piperazin-1-yl)phenyl)amino)- 2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3024);

[1026] 3-(2-Chloro-6-methylphenyl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimido[5,4- e][1 ,3]oxazin-4-one (W3025);

[1027] 3-(2,6-Dichlorophenyl)-7-((3-(hydroxymethyl)-4-(piperazin-1- yl)phenyl)amino)-2-methyl-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]oxazin-4-one (W3026);

[1028] 3-(2,6-Dichlorophenyl)-2,2-dimethyl-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3027);

[1029] 3-(2-Chloro-6-fluorophenyl)-7-((3-(hydroxymethyl)-4-(piperazin-1- yl)phenyl)amino)-2-methyl-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]oxazin-4-,one (W3028);

[1030] 3-(2-Chloro-6-(hydroxymethyl)phenyl)-7-((4-(piperazin-1-,yl)phenyl)amino)-2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3029);

[1031] 3-(4-Chloro- IH-pyrazol-5-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-,dihydro-4H-pyrimido[5,4- e][1 ,3]oxazin-4-one (W3030);

[1032] 3-(2-Chloro-6-(hydroxymethyl)phenyl)-7-((1 ,2,3,4-tetrahydroisoquinolin-,7-yl)amino)-2,3-dihydro- 4H-pyrimido[5,4-e][1 ,3]oxazin-4-one (W3031);

[1033] 7-((IH-lndol-5-yl)amino)-3-(2-chloro-6-(hydroxymethyl)phenyl)-2,3-,dihydro-4H-pyrimido[5,4- e][1 ,3]oxazin-4-one (W3032);

[1034] 3-(2,6-Dichlorophenyl)-2-methyl-7-((2-(methylsulfonyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino)-

[1035] 2.3-dihydro-4H-pyrimido[5,4-,e][l,3]oxazin-4-one (W3033);

[1036] 7-((2-Acetyl-1 , 1 -dimethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino)-3-,(2,6-dichlorophenyl)-2- methyl-2,3-dihydro-4H-pyrimido[5,4- e][1 ,3]thiazin-4-one (W3034);

[1037] 3-(2,6-Dichlorophenyl)-2-methyl-7-((2-(methylsulfonyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino)-

[1038] 2.3-dihydro-4H-pyrimido[5,4-e][1 ,3]thiazin-4-one (W3035);

[1039] 3-(2,6-Dichlorophenyl)-2-methyl-7-((1 ,1 ,2-trimethyl-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino)-2,3- dihydro-4H-pyrimido[5,4-e][l,3]oxazin-4-one (W3036);

[1040] 3-(2,6-Dichlorophenyl)-7-((4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2-methyl-2,3- dihydro-4H-pyrimido[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-pyrimido[5 ,4- e][l,3]oxazin-4-one (W3038);

[1041] 3-(2-Chloro-6-methylphenyl)-7-((1 , l-dimethyl-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino)-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]thiazin-4-one (W3039);

[1042] 3-(2-Chloro-6-methylphenyl)-7-((1 ,1 ,2-trimethyl-1 ,2,3,4- tetrahydroisoquinolin-6-yl)amino)-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]thiazin-4-one (W3040);

[1043] 3-(2-Chloro-6-methylphenyl)-7-((4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3- dihydro-4H-pyrimido[5 ,4- e][1 ,3]thiazin-4-one (W3041);

[1044] 3-(2-Chloro-6-fluorophenyl)-7-((1 ,l -dimethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2-methyl-

[1045] 2.3-dihydro-4H-pyrimido[5,4- e][l,3]oxazin-4-one (W3042);

[1046] 6-((3-(2-Chloro-6-methylphenyl)-4-oxo-3,4-dihydro-2H-pyrimido[5,4- e][l ,3]oxazin-7-yl)amino)-l ,l ,2-trimethyl-1 ,2,3,4-tetrahydroisoquinoline-8-carbonitrile (W3043);

[1047] 6-((3-(2-Chloro-6-fluorophenyl )-2-methyl-4-oxo-3,4-dihydro-2H- pyrimido[5,4-e][l,3]oxazin-7- yl)amino)-1 ,1 ,2-trimethyl-1 ,2,3,4-tetrahydroisoquinoline-8-carbonitrile (W3044);

[1048] 3-(2-Chloro-6-methylphenyl)-7-((8-fluoro- 1, l-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2- methyl-2,3-dihydro-4H-pyrimido[5,4- e][l,3]oxazin-4-one (W3045);

[1049] 3-(2-Chloro-6-methylphenyl)-7-((2,4,4-trimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3- dihydro-4H-pyrimido[5 ,4- e][l,3]oxazin-4-one (W3046);

[1050] 3-(2-Chloro-6-methylphenyl)-7-((4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2-methyl-

[1051] 2.3-dihydro-4H-pyrimido[5,4-e][l,3]oxazin-4-one (W3047);

[1052] 2-Acetyl-7-((3-(2-chloro-6-methylphenyl)-4-oxo-3,4-dihydro-2H- pyrimido[5,4-e][l,3]oxazin-7- yl)amino)-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-5-carbonitrile (W3048);

[1053] 3-(2-Chloro-6-methylphenyl)-7-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-2,3-dihydro- 4H-pyrimido[5,4-e][1 ,3]oxazin-4-one (W3049);

[1054] 3-(2,6-Dichlorophenyl)-7-((4-(4-(dimethylamino)piperidin- 1 -yl)-3- methylphenyl)amino)-2-methyl-

[1055] 2.3-dihydro-4H-pyrimido[5,4-e][1 ,3]thiazin-4-one (W3050);

[1056] 3-(2-Chloro-6-fluorophenyl)-7-((4-(4-(dimethylamino )piperidin- 1 -yl)-3-methoxyphenyl)amino)-2- methyl-2,3-dihydro-4H-pyrimido[5,4- e][1 ,3]thiazin-4-one (W3051);

[1057] 3-(2-Chloro-6-fluorophenyl)-2-methyl-7-((4-((R)-2-methylpiperazin-1-yl)phenyl)amino)-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]oxazin-4-one (W3052);

[1058] 3-(2,6-Dichlorophenyl)-2-methyl-7-((4-((S)-2-methylpiperazin-1-yl)phenyl)amino)-2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3053);

[1059] 3-(3,5-Dichloropyridin-4-yl)-7-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3054);

[1060] 3-(3,5-Dichloropyridin-4-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimido[5,4- e][1 ,3]oxazin-4-one (W3055);

[1061] 3-(2-Oxo- l,2-dihydropyridin-4-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H- pyrimido[5,4-e][1 ,3]oxazin-4-one (W3056);

[1062] 7-((4,4-Dimethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)amino)-3-(2-oxo- 1 ,2-dihydropyridin-4-yl)-2,3- dihydro-4H-pyrimido[5,4-e][1 ,3]oxazin-4-one (W3057); or a pharmaceutically acceptable salt thereof. Further Examples of Wee1 inhibitors can be found in, e.g., US 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; the Wee1 inhibitors of which are all incorporated herein by reference in their entirety.

[1063] Methods Of Treatment

[1064] Methods disclosed herein may be used for the treatment of a disease or condition (e.g., a cancer overexpressing CCNE1, a cancer with an inactivating mutation in the FBXW7 gene, a cancer with an activating mutation in a RAS gene, a cancer overexpressing a RAS, or a cancer with an inactivating mutation in the PPP2R1A gene) which depend on the activity of membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1) (Gene name PKMYT1). Methods disclosed herein may include the step of administering to the subject in need thereof 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 the monotherapy.

[1065] The disease or condition may have the symptom of cell hyperproliferation. For example, the disease or condition may be a cancer (e.g., a cancer overexpressing CCNE1, a cancer with an inactivating mutation in the FBXW7 gene, a cancer with an activating mutation in a RAS gene, a cancer overexpressing a RAS, or a cancer with an inactivating mutation in the PPP2R1A gene).

[1066] Cancers which have or are associated with a high incidence of CCNE1 overexpression include, e.g., uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, and endometrial cancer. Preferably, the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[1067] Cancers which have or are associated with a deficiency in FBXW7 or loss-of-function in FBXW7 include, e.g., uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, gastric 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.

[1068] Cancers which have or are associated with RAS activation mutations or a high incidence of RAS overexpression include, 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. In embodiments wherein the mutation is a KRAS mutation, preferably the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[1069] Cancers which have or are associated with a deficiency in PPP2R1A or loss-of-function in PPP2R1A include, e.g., endometrial cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, head and neck cancer, gastric cancer, bladder cancer, throat cancer, and pancreatic cancer. Compounds disclosed herein may be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, intratumoral, and topical administration.

[1070] In some embodiments, the Myt1 inhibitor is administered before the Wee1 inhibitor (e.g., within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, or within 12 hours). In some embodiments, the Myt1 inhibitor is administered after the Wee1 inhibitor (e.g., within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, or within 12 hours). In some embodiments, the Myt1 inhibitor is co-administered with the Wee1 inhibitor. In some embodiments, the Myt1 inhibitor is administered continuously on a daily basis. 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 on a continuous daily basis. In some embodiments, the Wee1 inhibitor is administered intermittently (e.g., 1 day / week, 2 days / week, or 3 days / week).

[1071] Pharmaceutical Compositions

[1072] The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may include one or more additional pharmaceutically active agents described herein.

[1073] The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[1074] For human use, a compound of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate processing of a compound of the invention into preparations which can be used pharmaceutically.

[1075] This invention also includes methods of administering pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

[1076] The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[1077] These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[1078] Dosages

[1079] The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In some embodiments, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. In some embodiments, an effective dose is a subtherapeutic dose relative to the monotherapy. Such an effective dose will generally depend upon the factors described above.

[1080] A compound of the disclosure may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1 -24 hours, 1 -7 days, 1 -4 weeks, or 1 -12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day, every 2nd, 3rd, 4th, 5th, or 6th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[1081] A monotherapy of a MYT1 inhibitor described herein, a Wee1 inhibitor described herein, or both include a therapeutically effective dose (i.e., at least an amount required to elicit the intended pharmacological effect). The therapeutically effective amount of a MYT1 inhibitor or a Wee1 inhibitor may be, e.g., between 0.05 mg and 3000 mg (e.g., greater than 100 mg of the compound, greater than 150 mg of the compound, greater than 200 mg of the compound, greater than 250 mg of the compound, greater than 300 mg of the compound, etc.). In some embodiments, the dosage amount can be calculated using the body weight of the patient.

[1082] A monotherapy of a MYT1 inhibitor described herein or a Wee1 inhibitor described herein, or both may be provided on a dosing schedule. The dosing schedule may include providing a MYT1 inhibitor or a Wee1 inhibitor, e.g., once a day, twice a day, once every other day, etc. A dosing schedule may include a time period over which the dosing schedule is applied. In some embodiments, the dosing schedule may change over the time period. For example, in some embodiments, doses of the compounds of the invention are administered at a dosing schedule to a patient over a time period that is 1 -7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1-30 years. In some embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day.

[1083] Subtherapeutic Dosages

[1084] In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both may be administered in a subtherapeutic dose relative to the monotherapies. The compounds used in the methods described herein (e.g., an Myt1 inhibitor selected from compounds 1 to 328 in combination with a Wee1 inhibitor selected from compounds W1 to W3052) may be independently administered initially in a suitable monotherapy dosage (e.g., a therapeutically effective dose for the monotherapy). The dose may then be reduced (e.g., to a subtherapeutic dose) depending on the clinical response. Alternatively, the compounds used in the methods described herein may be administered initially in a subtherapeutic dose. A subtherapeutic dose of either the Myt1 inhibitor or the Wee1 inhibitor may be administered in combination with a therapeutically effective dose of the other. The extent to which a dose is reduced (i.e., the amount less than the therapeutically effective dose at which the subtherapeutic dose is administered at) will generally depend upon, e.g., synergy between the Myt1 inhibitor and the Wee1 inhibitor, in addition to the factors described herein.

[1085] In some embodiments, the subtherapeutic dose of the Myt1 inhibitor may be about half of the therapeutically effective dose of the Myt1 inhibitor. In some embodiments, the subtherapeutic dose of the Myt1 inhibitor may be, e.g., at most 500 mg (e.g., at most 400 mg, at most 350 mg, at most 300 mg, at most 250 mg, at most 240 mg, at most 230 mg, at most 220 mg, at most 210 mg, at most 200 mg, at most 190 mg, at most 180 mg, at most 170 mg, at most 160 mg, at most 150 mg, at most 140 mg, at most 130 mg, at most 120 mg, at most 110 mg, at most 100 mg, etc.).

[1086] In some embodiments, the subtherapeutic dose of the Wee1 inhibitor may be about half the therapeutically effective dose of the Wee1 inhibitor. In some embodiments, the subtherapeutic dose of the Wee1 inhibitor is, e.g., at most 600 mg (e.g., at most 550 mg, at most 500 mg, at most 450 mg, at most 400 mg, at most 350 mg, at most 300 mg, at most 250 mg, at most 200 mg, at most 175 mg, at most 150 mg, at most 125 mg, at most 100 mg, at most 75 mg, at most 50 mg, at most 40 mg, at most 30 mg, or at most 20 mg).

[1087] In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both are administered continuously at a subtherapeutic dose. In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both are administered on a reduced dosing schedule (e.g., a reduced dosing schedule described herein) at a subtherapeutic dose.

[1088] Reduced Dosing Schedule

[1089] In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both may be administered on a reduced dosing schedule relative to the Myt1 inhibitor or the Wee1 inhibitor as a monotherapy. Any dosing scheduled, as described herein, may therefore be a reduced dosing schedule if the Myt1 inhibitor or the Wee1 inhibitor are provided at a reduced frequency relative to a monotherapy dose. For example, a monotherapy of the Myt1 inhibitor may include a dose described herein (e.g., a therapeutic dose or a subtherapeutic dose) provided once per day, the monotherapy of the Wee1 inhibitor may include a dose described herein (e.g., a therapeutic dose or a subtherapeutic dose), provided once per day, or both. In a combination therapy of such an embodiment, the dosing schedule of the Myt1 inhibitor, the Wee1 inhibitor, or both, may be reduced e.g., to once every other day, once a week, or an on-off dosing schedule). As a further example, the monotherapy of the Myt1 inhibitor may include a dose described herein (e.g., a therapeutic dose or a subtherapeutic dose) provided twice a day, the monotherapy of the Wee1 inhibitor may include a dose described herein (e.g., a therapeutic dose or a subtherapeutic dose) provided twice a day, or both. In a combination therapy of such an embodiment, the Myt1 inhibitor, the Wee1 inhibitor, or both may be reduced, e.g., to once a day, once a week, or an on-off dosing schedule.

[1090] The compounds used in the methods described herein may be administered initially on any suitable dosing schedule (e.g., once per day, twice per day, etc.) that may be adjusted (e.g., reduced) (e.g., to once every other day, or to an on-off dosing schedule) depending on the clinical response. Alternatively, the compounds used in the methods described herein may be administered initially on a reduced dosing schedule. In some embodiments, only the Myt1 inhibitor dosing schedule is a reduced dosing schedule. In some embodiments, only the Wee1 inhibitor dosing schedule is a reduced dosing schedule. In some embodiments, both the Myt1 inhibitor dosing schedule and the Wee1 dosing schedule are reduced dosing schedules. In some embodiments, a single dosing schedule may be maintained for the duration of treatment. In some embodiments, treatment may include a change in dosing schedules. In some embodiments, the dosing schedule may include a reduced dosing schedule for the entire time period of treatment. In some embodiments the dosing schedule may include a reduced dosing schedule for only a portion of treatment.

[1091] In some embodiments, the dose administered of the Myt1 inhibitor or the Wee1 inhibitor on a reduced dosing schedule is a therapeutically effective dose. In some embodiments, the dose administered of the Myt1 inhibitor or the Wee1 inhibitor is a subtherapeutic dose. In some embodiments, the dose of the Myt1 inhibitor, the Wee1 inhibitor, or both administered on a reduced dosing schedule is a dose described herein.

[1092] In some embodiments, the reduced dosing schedule of the Myt1 inhibitor includes intermittent dosing of the Myt1 inhibitor (e.g., 1 day / week, 2 days / week, or 3 days / week). In some embodiments, the reduced dosing schedule of the Wee1 inhibitor includes intermittent dosing of the Wee1 inhibitor (e.g., 1 day / week, 2 days / week, or 3 days / week). In some embodiments, the reduced dosing schedule may be an on-off dosing schedule. In an on-off dosing schedule, the Myt1 inhibitor or the Wee1 inhibitor is administered for a number of consecutive days (e.g., administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks), followed by no-administration for a number of consecutive days (e.g., not administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks). Each day of an on-off dosing schedule including the dosing of an active pharmaceutical ingredient may include multiple administrations of an active pharmaceutical ingredient. For example, a reduced dosing schedule may be a “3 days on, 4 days off’ dosing schedule (3 / 4 dosing); a 5 days on, 2 days off dosing schedule (5 / 2 dosing schedule), a “1 day on, 6 days off’ dosing schedule (1 / 6 dosing), a “2 days on, 5 days off’ dosing schedule (2 / 5 dosing), a “4 days on, 3 days off’ (4 / 3 dosing), a “1 week on, 1 week off’ dosing schedule, a “2 weeks on, 1 week off’ dosing schedule, or a “3 weeks on, 2 weeks off’ dosing schedule. A reduced dosing schedule may include a time period over which the reduced dosing schedule is applied. In some embodiments, the time period during which can vary. For example, in some embodiments, doses of the compounds of the invention are administered at a dosing schedule to a patient over a time period that is 1-7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1 -30 years.

[1093] In some embodiments, the Myt1 inhibitor and the Wee1 inhibitor are co-administered on a reduced dosing schedule. In some embodiments, the Myt1 inhibitor and the Wee1 inhibitor are administered separately on a reduced dosing schedule.

[1094] In some embodiments, the reduced dosing schedule of the Myt1 inhibitor may be, e.g., once per day; twice per day, three times per day, four times per day, five times per day, once every other day, once every three days, once per week; once per month; on for three days and off for four days; on for five days and off for two days; on for two weeks and off for one week. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor may be, e.g., once per day; twice per day, three times per day, four times per day, five times per day, once every other day, once every three days, once per week; once per month; on for three days and off for four days; on for five days and off for two days; on for two weeks and off for one week. In some embodiments, the reduced dosing schedule of the Wee1 inhibitor may include administration of the Wee1 inhibitor at most 1 day per week.

[1095] In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both are administered at a therapeutic dose on a reduced dosing schedule. In some embodiments, the Myt1 inhibitor, the Wee1 inhibitor, or both are administered at a subtherapeutic dose on a reduced dosing schedule.

[1096] Formulations

[1097] A compound 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 with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a disease or condition. Administration may begin before the patient is symptomatic.

[1098] Exemplary routes of administration (e.g., of a compound described herein or a pharmaceutical composition thereof) in the methods of the present disclosure include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present invention. The pharmaceutical composition may both a Wee1 inhibitor and a Myt1 inhibitor at a fixed dosage.

[1099] Formulations for Oral Administration

[1100] The pharmaceutical compositions contemplated by the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[1101] Formulations for oral administration may also be presented as chewable tablets, as 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 as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus, or a spray drying equipment.

[1102] Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and / or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., 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, compositions include biodegradable, pH, and / or temperature-sensitive polymer coatings.

[1103] Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl- polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.

[1104] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[1105] Formulations for Parenteral Administration

[1106] The compounds described herein for use in the methods of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, nontoxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.

[1107] The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

[1108] (1) Drug Injection: a liquid preparation that is a drug substance (e.g., a compound of the invention), or a solution thereof;

[1109] (2) Drug for Injection: the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

[1110] (3) Drug Injectable Emulsion: a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium;

[1111] (4) Drug Injectable Suspension: a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and

[1112] (5) Drug for Injectable Suspension: the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[1113] Formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[1114] Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[1115] The parenteral formulation can be formulated for prompt release or for sustained / extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oilbased solutions, liposomes, microspheres, and polymeric gels.

[1116] EXAMPLES

[1117] The following examples were meant to illustrate the invention. They were not meant to limit the invention in any way.

[1118] Example 1 : Subtherapeutic Dosing in Myt1 Inhibitor / Wee1 Inhibitor Combination Therapies

[1119] 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 administered to (1) a wild type cell (FIG. 1 A), (2) a CCWET-high cell line (FIG. 1 B), and (3) an OVCAR3 cell line (FIG. 1 C). The cell viability of wild type cells does not significantly change with addition of lunresertib or Debio-0123, alone or in the combination therapy, (100%, 104%, 87%, and 84% for the vehicle without lunresertib or Debio-0123, lunresertib monotherapy, Debio-0123 monotherapy, and the combination therapy). The cell viability of CCWET-high cells and OVCAR3 cells is not significantly impacted with in the monotherapy (68% and 72% for lunresertib monotherapy and 98% and 99% of Debio-0123 monotherapy respectfully), demonstrating that the monotherapies are subtherapeutic at the current concentrations. However, the combination therapies demonstrate nearcomplete lethality in CCA / EEhigh and OVCAR3 cells (cell viability of 4% and 11% respectfully).

[1120] Next, the dependence of the combination therapy on the dose of lunresertib was investigated in wild type cells (FIG. 2A), CCWET-high cells (FIG. 2B), and OVCAR3 cells (FIG. 2C) at two concentrations of Debio-0123 (250 nM and 1000 nM). Efficacy of the therapy was measured as the percentage of cells with induced pan-y-H2AX. At low (<500 nM) concentrations of lunresertib, high synergy is observed. In CC / VET-high cells, greater than 80% of cells exhibit pan-y-H2AX. Unexpectedly, comparable, or greater exhibition of pan-y-H2AX is observed at both 250 nM of Debio-0123 and 1000 nM of Debio-0123, demonstrating very high synergy. Similar results are observed in OVCAR3 cells.

[1121] Example 2: Investigation into Biological Origin of Subtherapeutic Dosing in Myt1 Inhibitor / Wee1 Inhibitor Combination Therapies

[1122] To determine the origin of the observed synergy between lunresertib and Debio-0123, the phosphorylation of CDK1 was measured in the presence of lunresertib and Debio-0123. FIG. 3A, FIG. 3B, and FIG. 3C show the phosphorylation of the threonine at amino acid position 14 (CDK1 -pT 14) and the tyrosine at amino acid position 15 (CDK1-pY15) in cells exposed to lunresertib and Debio-0123 monotherapies, and the combination therapy. Alone, Debio-0123 decreases CDK1-pY15 and increases CDK1-pT14, and lunresertib decreases CDK1-pT14 and increases CDK1-pY15. Neither therapy alone is capable of complete reduction in of CDK1 phosphorylation. However, the combination therapy drives a deep reduction in phosphorylation on both sites.

[1123] Further studies were performed to investigate the effect of the combination therapy on the related family of CDC25 phosphatases. CDC25 family phosphatases remove phosphorylation events caused by Myt1 and Wee1 . Further, CDC25 and CDK1 also act in a positive feedback loop (i.e. , the activation of one results in the activation of the other), resulting in robust CDK1 activation. Incomplete dephosphorylation of CDK1 in monotherapy with a MYT1 inhibitor may lead to an incomplete activation of CDC25 phosphatase, and therefore result in the partial activation of CDK1 observed for the monotherapy. The results are summarized in FIG. 4A and FIG. 4B.

[1124] Treatment with lunresertib alone results in an increase in phosphorylation of CDC25B of the serine at amino acid position 151 (CDC25B-pS151), inhibiting phosphatase activity. Treatment with Debio-0123 alone also results in an increase of CDC25B-pS151 . However, the combination therapy of lunresertib and Debio-0123 results in a net decrease in CDC25B phosphorylation (and therefore increased activity) relative to either monotherapy, further suggesting the increased efficacy of the combination therapy (and therefore treatment with a sub-therapeutic dose) is related to the decreased phosphorylation of CDK1 (and therefore a decrease in phosphorylation and increased in activation of CDC25).

[1125] Increased activity of CDK1 drives a treated cell into early mitosis (shortening the time the cell is in the inactive G2 state during the G2 checkpoint response), resulting in the early death of tumor cells. Combination therapies of a Myt1 inhibitor (such as lunresertib or another compound disclosed herein) and a Wee1 inhibitor are therefore capable of treating cancer, even at subtherapeutic doses.

[1126] Example 3: Efficacy of Treatment Studies in Xenograft Models

[1127] The efficacy of treatment was investigated for: (i) a Myt1 inhibitor as a monotherapy, (ii) a Wee1 inhibitor as a monotherapy, and (iii) the combination therapy including a Myt1 inhibitor and a Wee1 inhibitor. Lunresertib (see Table 1) was the Myt1 inhibitor used in these experiments. Debio-0123 (see Table 2a) was the Wee1 inhibitor used in these experiments.

[1128] One in vivo efficacy of treatment study was performed in a pancreatic (PSN) xenograft model. The change in tumor volume (FIG. 5A and FIG. 5C) and the change in body weight (FIG. 5B) was analyzed over 24 treatment days. Treatment started on day 1 for both compounds. A comparative analysis shows that the efficacy of the low dose combination therapy including lunresertib and Debio- 0123 was superior to the lunresertib monotherapy and the Debio-0123 monotherapy. The combination of lunresertib and Debio-0123 resulted in 91% tumor growth inhibition (TGI) on treatment day 22, whereas lunresertib as a monotherapy provided 40% TGI and Debio-0123 as monotherapy provided a nonsignificant reduction in TGI of 3% (FIG. 5C).

[1129] Another in vivo efficacy of treatment study was performed in an ovarian (OVCAR3) xenograft model. The change in tumor volume (FIG. 6A and FIG. 6C) and the change in body weight (FIG. 6B) was analyzed over 45 treatment days. Treatment started on day 1 for both compounds. A comparative analysis shows that the efficacy of the low dose combination therapy including lunresertib and Debio- 0123 was superior to the lunresertib monotherapy and the Debio-0123 monotherapy. The combination of lunresertib and Debio-0123 resulted in 64% tumor regression (TR) on treatment day 31 , whereas lunresertib as a monotherapy provided 31% TGI and Debio-0123 as monotherapy provided a nonsignificant change in TGI of -5% (FIG. 6C). ENUMERATED EMBODIMENTS

[1130] E1 . A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a dose of a membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1) inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and

[1131] (I) the dose of Myt1 inhibitor is subtherapeutic;

[1132] (ii) the dose of the Wee1 inhibitor is subtherapeutic;

[1133] (iii) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or

[1134] (iv) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[1135] E2. A method of inducing cell death in a cancer cell, the method comprising contacting the cell with a dose of a MYT1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and

[1136] (I) the dose of Myt1 inhibitor is subtherapeutic;

[1137] (ii) the dose of the Wee1 inhibitor is subtherapeutic;

[1138] (iii) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or

[1139] (iv) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[1140] E3. The method of claim E2, wherein the cell is in a subject.

[1141] E4. The method of 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.

[1142] E5. The method of any one of claims E1 to E4, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, or BRAF, or a prior or current infection with HPV.

[1143] E6. The method of any one of claims E1 to E4, wherein the cancer comprises a cancer previously identified as a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, or BRAF, or a prior or current infection with HPV.

[1144] E7. The method of claim E5 or claim E6, wherein the cancer comprises CCNE1 overexpression.

[1145] E8. The method of claim E7, wherein the cancer comprises 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.

[1146] E9. The method of claim E5 or claim E6, wherein the cancer comprises a FBXW7 mutation.

[1147] E10. The method of claim E9, wherein the cancer comprises uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[1148] E11 . The method of claim E5 or claim E6, wherein the cancer comprises a KRAS mutation.

[1149] E12. The method of claim E5 or claim E6, wherein the cancer comprises KRAS overexpression.

[1150] E13. The method of claim E11 or claim E12, wherein the cancer comprises colorectal cancer, pancreatic cancer, lung cancer uterine cancers, ovarian cancers, cervical cancers or gastro-esophageal cancer.

[1151] E14. The method of claim E5 or claim E6, wherein the cancer comprises an HRAS mutation. E15. The method of claim E14, wherein the cancer comprises kidney cancer, a bladder cancer, head and neck cancer, or a thyroid cancer.

[1152] E16. The method of claim E5 or claim E6, wherein the cancer comprises a NRAS mutation.

[1153] E17. The method of claim E16, wherein the cancer comprises colorectal cancer, thyroid cancer, or melanoma.

[1154] E18. The method of claim E5 or claim E6, wherein the replication stress biomarker is a PPP2R1A mutation.

[1155] E19. The method of claim E18, wherein the cancer comprises endometrial cancer, ovarian cancer, and uterine cancer.

[1156] E20. A method of increasing CDK1 activity in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and

[1157] (I) the dose of Myt1 inhibitor is subtherapeutic;

[1158] (ii) the dose of the Wee1 inhibitor is subtherapeutic;

[1159] (iii) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or

[1160] (iv) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[1161] E21 . A method of causing premature mitosis in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and

[1162] (I) the dose of Myt1 inhibitor is subtherapeutic;

[1163] (ii) the dose of the Wee1 inhibitor is subtherapeutic;

[1164] (iii) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or

[1165] (iv) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

[1166] E22. The method of claim E20 or claim E21 , wherein the cell is in a subject.

[1167] E23. The method of any one of claims E1 to E22, wherein the dose of the Myt1 inhibitor is at most 500 mg.

[1168] E24. The method of any one of claims E1 to E23, wherein the dose of the Myt1 inhibitor is at most 240 mg.

[1169] E25. The method of any one of claims E1 to E24, wherein the dose of the Myt1 inhibitor is at most 100 mg.

[1170] E26. The method of any one of claims E1 to E25, wherein the reduced dosing schedule of the Myt1 inhibitor comprises administering a dose once a day.

[1171] E27. The method of any one of claims E1 to E25, wherein the reduced dosing schedule of the Myt1 inhibitor comprises administering a dose twice a day.

[1172] E28. The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 1 / 6 dosing schedule.

[1173] E29. The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 2 / 5 dosing schedule.

[1174] E30. The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 3 / 4 dosing schedule.

[1175] E31 . The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 5 / 2 dosing schedule.

[1176] E32. The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 1 week on / 1 week off dosing schedule. E33. The method of any one of claims E1 to E27, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 2 weeks on / 1 week off dosing schedule.

[1177] E34. The method of any one of claims E1 to E33, wherein the dose of the Wee1 inhibitor is at most 520 mg.

[1178] E35. The method of any one of claims E1 to E34, wherein the dose of the Wee1 inhibitor is at most 400 mg.

[1179] E36. The method of any one of claims E1 to E35, wherein the dose of the Wee1 inhibitor is at most

[1180] 200 mg.

[1181] E37. The method of any one of claims E1 to E36, wherein the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose once a day.

[1182] E38. The method of any one of claims E1 to E36, wherein the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose twice a day.

[1183] E39. The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 1 / 6 dosing schedule.

[1184] E40. The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 2 / 5 dosing schedule.

[1185] E41 . The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 3 / 4 dosing schedule.

[1186] E42. The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 5 / 2 dosing schedule.

[1187] E43. The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 1 week on / 1 week off dosing schedule.

[1188] E44. The method of any one of claims E1 to E38, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 1 week on / 2 weeks off dosing schedule.

[1189] E45. The method of any one of claims E1 to E44, wherein the dose of the Myt1 inhibitor is subtherapeutic and the dose of the Wee1 inhibitor is subtherapeutic.

[1190] E44. The method of any one of claims E1 to E43, wherein the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule and the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule. E45. The method of any one of claims E1 to E44, wherein the Wee1 inhibitor is administered as a pharmaceutical composition.

[1191] E46. The method of any one of claims E1 to E45, wherein the Wee1 inhibitor is one of: or a pharmaceutically acceptable salt thereof.

[1192] E47. The method of any one of claims E1 to E45, wherein the Wee1 inhibitor is selected from the group consisting of compounds W1 to W3052.

[1193] E48. The method of any one of claims E1 to E45, wherein the Wee1 inhibitor binds to Wee1 , thereby reducing the activity of Wee1 .

[1194] E49. The method of any one of claims E1 to E45, wherein the Wee1 inhibitor is a PROTAC.

[1195] E50. The method of any one of claims E1 to E45, wherein the Wee1 inhibitor is a molecular glue.

[1196] E51 . The method of any one of claims E1 to E50, wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

[1197] E52. The method of any one of claims E1 to E51 , wherein the Myt1 inhibitor is a compound of formula (I):

[1198] (I), or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2;

[1199] R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;

[1200] R5is H or -N(R7)2;

[1201] R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SO2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and each Q is independently optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted Ce-w arylene, optionally substituted C2-9 heterocyclylene, or optionally substituted C1-9 heteroarylene.

[1202] E53. The method of claim E52, wherein the compound is enriched for the atropisomer of formula (IA):

[1203] (IA), or a pharmaceutically acceptable salt thereof.

[1204] E54. The method of claim E52 or E53, wherein X is CR2.

[1205] E55. The method of claim E53, wherein the compound is of formula (II): or a pharmaceutically acceptable salt thereof.

[1206] E56. The method of claim E53, wherein the compound is enriched for the atropisomer of formula (HA):

[1207] (HA), or a pharmaceutically acceptable salt thereof.

[1208] E57. The method of claim E52, wherein the compound is of formula (III): wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or a pharmaceutically acceptable salt thereof.

[1209] E58. The method of claim E57, wherein the compound is enriched for the atropisomer of formula (IIIA):

[1210] (IHA); or a pharmaceutically acceptable salt thereof.

[1211] E59. The method of claim E57 or E58, wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, or halogen.

[1212] E60. The method of any one of claims E52 to E59, wherein R3is optionally substituted C1-6 alkyl.

[1213] E61 . The method of any one of claims E52 to E59, wherein R3is halogen.

[1214] E62. The method of any one of claims E52 to E61 , wherein R4is optionally substituted C1-6 alkyl.

[1215] E63. The method of any one of claims E52 to E61 , wherein R4is halogen.

[1216] E64. The method of claim 63, wherein the halogen is chlorine.

[1217] E65. The method of any one of claims E52 to E64, wherein R2is hydrogen.

[1218] E66. The method of any one of claims E52 to E64, wherein R2is optionally substituted C1-6 alkyl.

[1219] E67. The method of claim 66, wherein R2is optionally substituted methyl or optionally substituted isopropyl.

[1220] E68. The method of any one of claims E52 to E64, wherein R2is halogen.

[1221] E69. The method of any one of claims E52 to E68, wherein R1is hydrogen.

[1222] E70. The method of any one of claims E52 to E68, wherein R1is halogen.

[1223] E71 . The method of claim E70, wherein R1is chlorine or bromine.

[1224] E72. The method of any one of claims E52 to E67, wherein R1is optionally substituted C1-6 alkyl.

[1225] E73. The method of claim E72, wherein R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl.

[1226] E74. The method of any one of claims E52 to E68, wherein R1is optionally substituted C1-9 heteroaryl. E75. The method of claim E74, wherein R1is 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 R1is optionally substituted with substituents as defined for optionally substituted C1-9 heteroaryl.

[1227] E76. The method of any one of claims E52 to E68, wherein R1is optionally substituted C3-8 cycloalkyl.

[1228] E77. The method of claim E76, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C3-8 cycloalkyl. E78. The method of any one of claims E53 to E68, wherein R1is optionally substituted C2-9 heterocyclyl.

[1229] E79. The method of claim E78, wherein R1is 1 ,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3.3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9 heterocyclyl.

[1230] E80. The method of any one of claims E52 to E68, wherein R1is optionally substituted C3-8 cycloalkenyl.

[1231] E81 . The method of claim E80, wherein R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl.

[1232] E82. The method of any one of claims E52 to E68, wherein R1is optionally substituted Ce-w aryl.

[1233] E83. The method of claim E82, wherein R1is optionally substituted phenyl.

[1234] E84. The method of any one of claims E52 to E68, wherein R1is -Q-R7B.

[1235] E85. The method of claim 84, wherein Q is optionally substituted C2-6 alkynylene.

[1236] E86. The method of claim 84, wherein Q is optionally substituted C1-6 alkylene.

[1237] E87. The method of claim 84, wherein Q is optionally substituted Ce-w arylene.

[1238] E88. The method of any one of claims E84 to E87, wherein R7Bis optionally substituted C2-9 heterocyclyl.

[1239] E89. The method of any one of claims E84 to E87, wherein R7Bis optionally substituted Ce-w aryl.

[1240] E90. The method of any one of claims E52 to E89, wherein R1is optionally substituted with one, two, or three groups independently selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), -C(0)N(Me)2, -(CH2)n-C(O)OH, and -(CH2)n-C(O)Ot-Bu, wherein n is 0 or 1.

[1241] E91 . The method of any one of claims E52 to E68, wherein R1is -N(R7)2.

[1242] E92. The method of claim E91 , wherein R1is diethylamino.

[1243] E93. The method of any one of claims E52 to E92, wherein R5is hydrogen.

[1244] E94. The method of any one of claims E52 to E92, wherein R5is -N(R7)2.

[1245] E95. The method of claim E92, wherein R5is -NH2.

[1246] E96. The method of any one of claims E52 to E94, wherein R6is -C(O)NH(R8).

[1247] E97. The method of any one of claims E52 to E94, wherein R6is -C(O)NH2.

[1248] E98. The method of any one of claims E52 to E94, wherein R6is -C(O)NH(Me).

[1249] E99. The method of any one of claims E52 to E94, wherein R6is -SO2R7A.

[1250] E100. The method of claim E99, wherein R6is -SCkMe.

[1251] E101 . The method of any one of claims E1 to E52, wherein the Myt1 inhibitor is a compound selected from the group consisting of compounds 1 to 328 and pharmaceutically acceptable salts thereof. E102. The method of any one of claims E1 to E52, wherein the Myt1 inhibitor is a compound is lunresertib or a pharmaceutically acceptable salt thereof.

[1252] OTHER EMBODIMENTS Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

[1253] Other embodiments are in the claims.

Claims

What is claimed is:CLAIMS1 . A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a dose of a membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1 ) inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and(I) the dose of Myt1 inhibitor is a therapeutically effective dose;(ii) the dose of Myt1 inhibitor is subtherapeutic;(iii) the dose of the Wee1 inhibitor is subtherapeutic;(iv) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or(v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

2. A method of inducing cell death in a cancer cell, the method comprising contacting the cell with a dose of a MYT1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and(I) the dose of Myt1 inhibitor is a therapeutically effective dose;(ii) the dose of Myt1 inhibitor is subtherapeutic;(iii) the dose of the Wee1 inhibitor is subtherapeutic;(iv) the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule; or(v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

3. The method of claim 2, wherein the cell is in a subject.

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

6. The method of any one of claims 1 to 4, wherein the cancer comprises a cancer previously identified as a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, or BRAF, or a prior or current infection with HPV.

7. The method of claim 5 or claim 6, wherein the cancer comprises CCNE1 overexpression.

8. The method of claim 7, wherein the cancer comprises 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 of claim 5 or claim 6, wherein the cancer comprises a FBXI / l / 7mutation.

10. The method of claim 9, wherein the cancer comprises 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 of claim 5 or claim 6, wherein the cancer comprises a KRAS mutation.

12. The method of claim 5 or claim 6, wherein the cancer comprises KRAS overexpression.

13. The method of claim 11 or claim 12, wherein the cancer comprises colorectal cancer, pancreatic cancer, lung cancer uterine cancers, ovarian cancers, cervical cancers or gastro-esophageal cancer.

14. The method of claim 5 or claim 6, wherein the cancer comprises an HRAS mutation.

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

16. The method of claim 5 or claim 6, wherein the cancer comprises a NRAS mutation.

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

18. The method of claim 5 or claim 6, wherein the replication stress biomarker is a PPP2R1A mutation.

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

20. A method of increasing CDK1 activity in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and(I) the dose of Myt1 inhibitor is a therapeutically effective dose;(ii) the dose of Myt1 inhibitor is subtherapeutic;(iii) the dose of the Wee1 inhibitor is subtherapeutic;(iv) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or(v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.21 . A method of causing premature mitosis in a cell, the method comprising contacting the cell with a dose of a Myt1 inhibitor on a dosing schedule and a dose of a Wee1 inhibitor on a dosing schedule; and(I) the dose of Myt1 inhibitor is a therapeutically effective dose_ ,,36(ii) the dose of Myt1 inhibitor is subtherapeutic;(iii) the dose of the Wee1 inhibitor is subtherapeutic;(iv) the dosing schedule of the Myt1 inhibitor a reduced dosing schedule; or(v) the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

22. The method of claim 20 or claim 21 , wherein the cell is in a subject.

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

24. The method of any one of claims 1 to 23, wherein the Myt1 inhibitor is a compound of formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2;R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;R5is H or -N(R7)2;R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SO2R7A, or optionally substituted alkoxy;each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and each Q is independently optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted Ce-w arylene, optionally substituted C2-9 heterocyclylene, or optionally substituted C1-9 heteroarylene.

25. The method of claim 24, wherein the compound is enriched for the atropisomer of formula (IA):(IA), or a pharmaceutically acceptable salt thereof.

26. The method of claim 24 or 25, wherein X is CR2.

27. The method of claim 25, wherein the compound is of formula (II):or a pharmaceutically acceptable salt thereof.

28. The method of claim 25, wherein the compound is enriched for the atropisomer of formula (HA):(HA), or a pharmaceutically acceptable salt thereof.Z „o,„o3829. The method of claim 24, wherein the compound is of formula (III):wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the compound is enriched for the atropisomer of formula (I I IA) :(IHA); or a pharmaceutically acceptable salt thereof.31 . The method of claim 29 or 30, wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, or halogen.

32. The method of any one of claims 24 to 31 , wherein R3is optionally substituted C1-6 alkyl.

33. The method of any one of claims 24 to 31 , wherein R3is halogen.

34. The method of any one of claims 24 to 33, wherein R4is optionally substituted C1-6 alkyl.

35. The method of any one of claims 24 to 33, wherein R4is halogen.

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

37. The method of any one of claims 24 to 36, wherein R2is hydrogen.

38. The method of any one of claims 24 to 36, wherein R2is optionally substituted C1-6 alkyl.

39. The method of claim 38, wherein R2is optionally substituted methyl or optionally substituted isopropyl.

40. The method of any one of claims 24 to 36, wherein R2is halogen.41 . The method of any one of claims 24 to 40, wherein R1is hydrogen.

42. The method of any one of claims 24 to 40, wherein R1is halogen.

43. The method of claim 42, wherein R1is chlorine or bromine.

44. The method of any one of claims 24 to 39, wherein R1is optionally substituted C1-6 alkyl.

45. The method of claim 44, wherein R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl.

46. The method of any one of claims 24 to 40, wherein R1is optionally substituted C1-9 heteroaryl.

47. The method of claim 46, wherein R1is 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 R1is optionally substituted with substituents as defined for optionally substituted C1-9 heteroaryl.

48. The method of any one of claims 24 to 40, wherein R1is optionally substituted C3-8 cycloalkyl.

49. The method of claim 48, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, whereinR1is optionally substituted with substituents as defined for optionally substituted C3-8 cycloalkyl.

50. The method of any one of claims 25 to 40, wherein R1is optionally substituted C2-9 heterocyclyl.

51. The method of claim 50, wherein R1is 1 ,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3.3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9 heterocyclyl.

52. The method of any one of claims 24 to 40, wherein R1is optionally substituted C3-8 cycloalkenyl.

53. The method of claim 52, wherein R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl.

54. The method of any one of claims 24 to 40, wherein R1is optionally substituted Ce-w aryl.

55. The method of claim 54, wherein R1is optionally substituted phenyl.

56. The method of any one of claims 24 to 40, wherein R1is -Q-R7B.

57. The method of claim 56, wherein Q is optionally substituted C2-6 alkynylene.

58. The method of claim 56, wherein Q is optionally substituted C1-6 alkylene.

59. The method of claim 56, wherein Q is optionally substituted Ce-w arylene.

60. The method of any one of claims 56 to 59, wherein R7Bis optionally substituted C2-9 heterocyclyl.61 . The method of any one of claims 56 to 59, wherein R7Bis optionally substituted Ce-w aryl.

62. The method of any one of claims 24 to 61 , wherein R1is optionally substituted with one, two, or three groups independently selected 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, wherein n is 0 or 1.

63. The method of any one of claims 24 to 40, wherein R1is -N(R7)2.

64. The method of claim 63, wherein R1is diethylamino.

65. The method of any one of claims 24 to 64, wherein R5is hydrogen.

66. The method of any one of claims 24 to 64, wherein R5is -N(R7)2.

67. The method of claim 64, wherein R5is -NH2.

68. The method of any one of claims 24 to 66, wherein R6is -C(O)NH(R8).

69. The method of any one of claims 24 to 66, wherein R6is -C(O)NH2.

70. The method of any one of claims 24 to 66, wherein R6is -C(O)NH(Me).71 . The method of any one of claims 24 to 66, wherein R6is -SO2R7A.

72. The method of claim 71 , wherein R6is -SCkMe.

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

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

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

76. The method of any one of claims 1 to 75, wherein the Wee1 inhibitor is one of:or a pharmaceutically acceptable salt thereof.

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

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

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

80. The method of any one of claims 1 to 76, wherein the Wee1 inhibitor binds to Wee1 , thereby reducing the activity of Wee1 .81 . The method of any one of claims 1 to 75, wherein the Wee1 inhibitor is a PROTAC.

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

83. The method of any one of claims 1 to 82, wherein the reduced dosing schedule of the Myt1 inhibitor comprises administering a dose once a day.

84. The method of any one of claims 1 to 82, wherein the reduced dosing schedule of the Myt1 inhibitor comprises administering a dose twice a day.

85. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 1 / 6 dosing schedule.

86. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 2 / 5 dosing schedule.

87. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 3 / 4 dosing schedule.

88. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 5 / 2 dosing schedule.

89. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 1 week on / 1 week off dosing schedule.

90. The method of any one of claims 1 to 84, wherein the reduced dosing schedule of the Myt1 inhibitor comprises a 2 weeks on / 1 week off dosing schedule.91 . The method of any one of claims 1 to 90, wherein the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose once a day.

92. The method of any one of claims 1 to 90, wherein the reduced dosing schedule of the Wee1 inhibitor comprises administering a dose twice a day.

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

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

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

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

97. The method of any one of claims 1 to 92, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 1 week on / 1 week off dosing schedule.

98. The method of any one of claims 1 to 92, wherein the reduced dosing schedule of the Wee1 inhibitor comprises a 1 week on / 2 weeks off dosing schedule.

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

100. The method of 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 subtherapeutic.101 . The method of any one of claims 1 to 100, wherein the dosing schedule of the Myt1 inhibitor is a reduced dosing schedule and the dosing schedule of the Wee1 inhibitor is a reduced dosing schedule.

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