Wee1 inhibitors and methods for treating cancer

Abstract

Compounds of general Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including conditions characterized by excessive cellular proliferation, such as breast cancer.

Description

ZENO.187WO PATENT WEE1 INHIBITORS AND METHODS FOR TREATING CANCERINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby expressly incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U. S. Provisional Application No. 63 / 723,437, filedNovember 21, 2024, which is incorporated by reference in its entirety including any drawings.BACKGROUNDField

[0002] The present application relates generally to compounds that are WEE1 inhibitors and / or degraders thereof, and methods of using them to treat conditions characterized by excessive cellular proliferation, such as cancer.Description

[0003] DNA is constantly damaged from the environment. Light, chemicals, stress, and cellular replication lead to single- or double-stranded breakage along DNA’s backbone. Typically, organisms defend against DNA damage by repair proteins that either reconnect, or re-synthesize damaged DNA. The correct functioning of these proteins are essential for life. The incorrect replacement of nucleotides into DNA can cause mutations (and other genetic alterations including but not limited to insertions, deletions, and frameshifts), genetic disease, and loss of protein function. The altogether loss of DNA repair can cause cell death, tumor progression, and cancer.

[0004] Cell cycle checkpoints are important for proper DNA repair, ensuring that cells do not progress with cellular replication until their genomic integrity is restored. WEE1 is a nuclear kinase involved in the G2-M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest. Cancer cells often have a deficient Gl-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types.

[0005] Various inhibitors and / or degraders of WEE1 are known to those skilled in the art. See, e.g., International Patent Application Publication Nos. WO 2019 / 173082 and WO 2020 / 069105. However, there remains an urgent need for inhibitors and / or degraders of WEE1 that are useful for the treatment of conditions characterized by excessive cellular proliferation, such as cancer.SUMMARY

[0006] Various embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein the variables Ring A, Ring B, L, W, X, R1, R2, R3, m and n are as defined herein.

[0007] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from those of Compound Nos. 1 to 26 as described herein.

[0008] Another embodiment provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0009] Another embodiment provides a method of ameliorating or treating a cancer in a subject comprising administering to the subject an effective amount of a compound of Formula (I) as described herein, or a compound selected from Compound Nos. 1 to 26 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer, a stomach cancer, a gallbladder / bile duct cancer, a liver cancer,a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

[0010] Another embodiment provides a method of inhibiting replication of a malignant growth or a tumor in a subject comprising administering to the subject an effective amount of a compound of Formula (I) as described herein, or a compound selected from Compound Nos. 1 to 26 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the malignant growth or tumor is due to a cancer selected from the list of cancers described above.

[0011] Another embodiment provides a method of ameliorating or treating a malignant growth or a tumor in a subject comprising administering to the subject an effective amount of a compound of Formula (I) as described herein, or a compound selected from Compound Nos. 1 to 26 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the malignant growth or tumor is due to a cancer selected from the list of cancers described above.DETAILED DESCRIPTION

[0012] WEE1 is a tyrosine kinase that is a critical component of the ATR-mediated G2 cell cycle checkpoint control that prevents entry into mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1, leading to the selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyrl5, thereby stabilizing the CDKl-cyclin B complex and halting cell-cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA prior to entering mitosis. Inhibition of WEE1 abrogates the G2 checkpoint, promoting cancer cells with DNA damage to enter into unscheduled mitosis and undergo cell death via mitotic catastrophe. Therefore, WEE1 inhibition and / or degradation has the potential to sensitize tumors to DNA-damaging agents, such as cisplatin, and to induce tumor cell death.-J-Definitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] Whenever a group is described as being “substituted or unsubstituted” or “a substituted or an unsubstituted,” that group may be unsubstituted or substituted with one or more of the indicated substituents. If no substituents are indicated, it is meant that the group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, an amino, a mono-substituted amine group, a di-substituted amine group and an amine(Ci-C6 alkyl).

[0015] As used herein, “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.

[0016] If two “R” groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Raand Rbof an NRaRbgroup are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:Ra—Rb

[0017] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and thelike. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “ 1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted.

[0018] The term “alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1 -propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl and the like. An alkenyl group may be unsubstituted or substituted.

[0019] The term “alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.

[0020] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthal enyl, dodecahydro- IH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[l.l.l]pentyl, adamantanyl andnorbomanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0021] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0022] As used herein, “carbocyclyl” refers to a non-aromatic a mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion, as described herein. Carbocyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A carbocyclyl group may be unsubstituted or substituted. Examples of carbocyclyl groups include, but are in no way limited to, cycloalkyl groups and cycloalkenyl groups, as defined herein, and the non-aromatic portions of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-lH-indene, 5, 6,7,8-tetrahydroquinoline and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0023] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-Cw aryl group, a Ce-Cio aryl group or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0024] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 16 atomsin the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2, 3 -oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotri azole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0025] As used herein, “heterocyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic fully saturated ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle as defined herein may not contain one or more unsaturated bonds. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” refers to compounds wherein the heterocyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atomsin the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heterocyclyl may be quatemized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl” groups include but are not limited to, 1,3-dioxane, 1,4-dioxane, 1,2-di oxolane, 1,3-dioxolane, 1,4-di oxolane, 1,3-oxathiane, 1,3 -oxathiolane, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazolidine, isoxazolidine, oxazolidine, oxazolidinone, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, tetrahydrothiopyran, thiamorpholine and thiamorpholine sulfoxide, thiamorpholine sulfone. Examples of spiro heterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

[0026] As used herein, “alkylene groups” are straight-chained alkyl groups that are -CH2- tethering, forming bonds to connect molecular fragments via their terminal carbon atoms. Embodiments of alkylene groups may be represented herein by -(CH2)n- where n is an integer in the range of 1 to 30. “Lower” alkylene groups are alkylene groups that contain 1 to 6 carbon atoms. Examples of lower alkylene groups include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-). An alkylene group can be substituted by replacing one or more hydrogen of the alkylene group and / or by substituting both hydrogens on the same carbon with acycloalkyl group

[0027] As used herein, the term “hydroxy” refers to a -OH group.

[0028] As used herein, “alkoxy” refers to the Formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methyl ethoxy (iso-propoxy),n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0029] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl (alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.

[0030] A “cyano” group refers to a “-CN” group.

[0031] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0032] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0033] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0034] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0035] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0036] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0037] A “C-amido” group refers to a “-C(=O)N(RARB)” group in which R and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0038] An “N-amido” group refers to a “RC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0039] An “S-sulfonamido” group refers to a “-SC>2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0040] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0041] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0042] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0043] A “nitro” group refers to an “-NO2” group.

[0044] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0045] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0046] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0047] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted.

[0048] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0049] The term “amino” as used herein refers to a -NH2 group.

[0050] A “mono-substituted amine” group refers to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The RA may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.

[0051] A “di-substituted amine” group refers to a “-NRARB” group in which RA and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. RA and RB can independently be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, N(methyl)2, ~N(phenyl)(m ethyl), ~N(ethyl)(methyl) and the like.

[0052] As used herein, “amine(alkyl)” group refers to an -(alkylene)-NR’R” radical where R’ and R” are independently hydrogen or alkyl as defined herein. An amine(alkyl) may be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CH2NH(m ethyl), -CH2NH(phenyl), -CH2CH2NH(methyl), -CH2CH2NH(phenyl), -CH2N(methyl)2, -CH2N(phenyl)(methyl), -NCH2(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl) and the like.

[0053] Where the number of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0054] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.”

[0055] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH3+) and the positive charge can be balanced by a negatively charged counterion (such as CF).

[0056] The terms “WEE1 inhibition”, “WEE1 inhibitor” and similar terms as used herein refer to inhibiting the activity or function of a WEE 1 tyrosine kinase, e.g., by degrading WEE1 tyrosine kinase and / or by reducing the activity of WEE1 tyrosine kinase with regard to mediating phosphorylation of CDK1. A WEE1 inhibitor that functions by degrading WEE1 tyrosine kinase may be referred to herein as a WEE1 degrader.

[0057] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0058] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0059] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0060] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0061] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0062] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.

[0063] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or fromthe singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.Compounds

[0064] This disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein:Ring A is a substituted or unsubstituted Cs-Cs cycloalkyl or a substituted or unsubstituted 5- to 8-membered heterocyclyl;Ring B is a substituted or an unsubstituted 4- to 11-membered heterocyclyl;X is N or -CH;R1is a substituted or an unsubstituted Ci-Ce alkyl;R2is absent, -CH2- or -(CH2)2 -;m is 0, 1 or 2;W is absent, -CH2-, or-(CH2)2~;-91-attachment to Ring B;R3is halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; andn is 0, 1 or 2.

[0065] As defined above, the scope of the term “heterocyclyl” in Formula (I) (including pharmaceutically acceptable salts thereof) refers to fully saturated heterocyclyls, but not partially saturated heterocyclyls, and includes spiro heterocyclyls, e.g., a 7- or 8-membered spiro heterocyclyls.

[0066] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, X is -CH. In one embodiment, in a compound of Formula (I), or apharmaceutically acceptable salt thereof, X is N (nitrogen). All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0067] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic Cs-Cs cycloalkyl; a monocyclic Cs-Cs cycloalkyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; an unsubstituted monocyclic 5- to 8-membered heterocyclyl; or a monocyclic 5- to 8-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic Cs-Cs cycloalkyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic Cs-Cs cycloalkyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic 5- to 8-membered heterocyclyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic 5- to 8-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0068] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic C5-C7 cycloalkyl; a monocyclic C5-C7 cycloalkyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; an unsubstituted monocyclic 5- to 7-membered heterocyclyl; or a monocyclic 5- to 7-membered heterocyclyl substituted with one or more groups selected from F, Cl, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic C5-C7 cycloalkyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic C5-C7 cycloalkyl substituted with one or more groups selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or apharmaceutically acceptable salt thereof, Ring A is an unsubstituted monocyclic 5- to 7-membered heterocyclyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic 5- to 7-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0069] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted cycloheptanyl; a cycloheptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted cyclohexyl; a cyclohexyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted cyclopentanyl; a cyclopentanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted pyrrolidinyl; a pyrrolidinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted piperidinyl; a piperidinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted azepanyl; or an azepanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted cycloheptanyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a cycloheptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted pyrrolidinyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a pyrrolidinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is an unsubstituted piperidinyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a piperidinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. Allother variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0070] In one embodiment, in a compound of Formula (I), or a pharmaceuticallyFormula (I), or a pharmaceutically acceptable salt thereof,pharmaceutically acceptable salt thereof, (R2). In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof,(R2)m is (R2)m. In one embodiment, in a compound ofFormula (I), or a pharmaceutically acceptable salt thereof,In one embodiment, in a compound of Formula (1), or apharmaceutically acceptable salt thereof,. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof,one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof,In one embodiment, in a compound ofFormula (I), or a pharmaceutically acceptable salt thereof,ispharmaceutically acceptable salt thereof, m is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, m is 0. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, m is 1. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0071] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted monocyclic 4- to 7-membered heterocyclyl; a monocyclic 4- to 7-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; an unsubstituted spiro 7- to 11-membered heterocyclyl; or a spiro 7- to 11-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted monocyclic 4- to 7-membered heterocyclyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a monocyclic 4- to 7-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted spiro 7- to 11 -membered heterocyclyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a spiro 7- to 11 -membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0072] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted monocyclic 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom; a monocyclic 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted spiro 7- to 9-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom; or a spiro 7- to 9-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted monocyclic 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a monocyclic 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0073] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted piperidinyl; a piperidinyl substituted with one or more groups selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted morpholinyl; a morpholinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted 2-azaspiro[3.3]heptanyl; a 2-azaspiro[3.3]heptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted 2,6-diazaspiro[3.3]heptanyl; or a 2,6-diazaspiro[3.3]heptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted piperidinyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a piperidinyl substituted with one or more groups selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof,Ring B is an unsubstituted morpholinyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a morpholinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is an unsubstituted 2-azaspiro[3.3]heptanyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is a 2,6-diazaspiro[3.3]heptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0074] In one embodiment, in a compound of Formula (I), or a pharmaceuticallyN —acceptable salt thereof, Ring B is or\ -—N\A; wherein * indicates the point of attachment to L andAindicates the point of attachment to W when W is not absent or to Ring A when W is absent. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B isA; wherein * indicates the point of attachment to L andAindicates the point of attachment to W when W is not absent or to Ring A when W is absent. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B isA; wherein * indicates the point of attachment to L andAindicates the point ofattachment to W when W is not absent or to Ring A when W is absent. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is; wherein * indicates the point of attachment to L andAindicates the point of attachment to W when W is not absent or to Ring A when W is absent.. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof,\ —— NRingB isA; wherein * indicates the point of attachment to L andAindicates the point of attachment to W when W is not absent or to Ring A when W is absent. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0075] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, W is absent or -CH2-. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, W is absent. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, W is -CH2-. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0076] In one embodiment, in a compound of Formula (I), or a pharmaceutically-L --29-(R3)nO; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, Lis; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I),or a pharmaceutically acceptable salt thereof,L is; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is(R3)nO; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, Lis; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I),or a pharmaceutically acceptable salt thereof,L is; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, Lis \; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula(I), or a pharmaceutically acceptable salt thereof, L HEIGHT="88" WIDTH="146" SRC="imgf000032_0004.tif" / > is0\; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is(R3)nO; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L isdescribed in any one of the above embodiments and in any one of the following embodiments. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable saltthereof,L is. In one embodiment, in a compound of Formula (I), or a Opharmaceutically acceptable salt thereof,L is. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is O. In one embodiment, in a compound of Formula (I), or a pharmaceutically *acceptable salt thereof,L is. In one embodiment, in a compound ofFormula (I), or a pharmaceutically acceptable salt thereof,L is. In oneembodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, LY Y Y0 sisis. In one embodiment, in a compound of Formula (I), or apharmaceutically acceptable salt thereof,L is O In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is°YXX]HN^ YN^0 YA #N-NV'\. In one embodiment, in a compound of Formula (I), or a H CK. N^OXX-QYN *pharmaceutically acceptable salt thereof,L is ° \. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, L isHNYN' YNJO. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0077] In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is C1-C4 alkyl or C1-C4 haloalkyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is C1-C4 alkyl or C1-C4 fluoroalkyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is C1-C2 alkyl or C1-C2 fluoroalkyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is methyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is ethyl. In one embodiment, in a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R1is -CF3. In one embodiment, in a compound of Formula (I), or apharmaceutically acceptable salt thereof, R1is -CHF2. All other variables in Formula (I) are as described in any one of the above embodiments and in any one of the following embodiments.

[0078] Various embodiments provide a compound (e.g., a compound of Formula 0(I)), or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from those of Compound Nos. 1 to 26 as listed in the following Table 1:Table 1. Exemplary Compound Nos. 1 to 26.4"CompoundStructureNo.o=(n—O 97—hn^ MOQ1IZ N N NH\ PHA1 / Z\i- l l poI2 CAA> CA^NAA-'NANXN-3StructureStructureStructureStructureStructureStructureSynthesis

[0079] Compounds of Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein, including the Examples provided below. For example, in an embodiment, compounds of the Formula (I) are prepared in accordance with the procedures illustrated in General Scheme A provided herein. Any preliminary reaction steps required to form starting compounds or other precursors, can be carried out by those skilled in the art, for example by appropriate adjustment of the reagents and conditions described in the Examples. In General Scheme A, the variables including Ring A, Ring B, L, W, X, R1, R2, R3, m and n can be as described elsewhere herein, taking into consideration the synthetic conversions involved as understood by those of skill in the art.Pharmaceutical Compositions

[0080] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0081] The term “pharmaceutical composition” refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0082] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.

[0083] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethylsulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0084] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0085] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and / or a metalchelating agent. A “diluent” is a type of excipient.

[0086] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0087] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0088] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal andintraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.

[0089] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0090] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U. S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Uses and Methods of Treatment

[0091] Some embodiments described herein relate to a method for ameliorating and / or treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and / or treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating and / or treating a cancer described herein.

[0092] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0093] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical compositionthat includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0094] Some embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells) that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells). Stillother embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells). Some embodiments described herein relate to a method for inhibiting the activity of WEE 1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells) that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells) that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of WEE1

[0095] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells) using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compounddescribed herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells). Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and / or decreasing the overexpression of WEE1 in cells).

[0096] Some embodiments disclosed herein relate to a method for inhibiting the activity of WEE 1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1. Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1.

[0097] Examples of suitable cancers include, but are not limited to: brain cancers, cervicocerebral cancers, esophageal cancers, thyroid cancers, small cell cancers, non-small cell cancers, breast cancers, lung cancers (for example non-small cell lung cancer and small cell lung cancer), stomach cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, uterus body cancers, uterocervical cancers, renal pelvis / ureter cancers, bladder cancers, prostate cancers, penis cancers, testicular cancers, fetal cancers, Wilms' cancer, skin cancers, malignant melanoma, neuroblastomas, osteosarcomas, Ewing's tumors, soft part sarcomas, acute leukemia, chronic lymphatic leukemias, chronic myelocytic leukemias, polycythemia vera, malignant lymphomas, multiple myeloma, Hodgkin's lymphomas and non-Hodgkin’s lymphomas.

[0098] As described herein, a cancer can become resistant to one or more anticancer agents. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and / or ameliorate a cancer that has become resistant to one or more anti-cancer agents (such as one or more WEE1 inhibitors). Examples of anti-cancer agents that a subject may have developed resistance to include, but are not limited to, WEE1 inhibitors (such as AZD1775).In some embodiments, the cancer that has become resistant to one or more anti -cancer agents can be a cancer described herein.

[0099] Several known WEE1 inhibitors can cause one or more undesirable side effects in the subject being treated. Examples of undesirable side effects include, but are not limited to, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, nausea, abdominal pain, and constipation In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can decrease the number and / or severity of one or more side effects associated with a known WEE1 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving a known WEE1 inhibitor (such as AZD1775, formally known as MK1775 (CAS No.: 955365-80-7, 2-allyl-l-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-l-yl)phenylamino)-l,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is 25% less than compared to the number of side effects experienced by a subject receiving a known WEE1 inhibitor (for example, AZD1775). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of those described herein) that is less in the range of about 10% to about 30% compared to the severity of the same side effect experienced by a subject receiving a known WEE1 inhibitor (such as AZD1775). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving a known WEE1 inhibitor (for example, AZDI 775).

[0100] The one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used to treat, ameliorate and / or inhibit the growth of a cancer wherein inhibiting the activity of WEE1 is beneficial is provided in any of the embodiments described under the heading titled “Compounds” above.

[0101] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebratesand invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and / or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult.

[0102] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0103] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0104] For example, an effective amount of a compound, or radiation, is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and / or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non-small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and / or pain. As anotherexample, an effective amount, or a therapeutically effective amount of an WEE1 inhibitor and / or degrader is the amount which results in the reduction in WEE1 activity and / or phosphorylation (such as phosphorylation of CDC2). The reduction in WEE1 activity is known to those skilled in the art and can be determined by the analysis of WEE1 intrinsic kinase activity and downstream substrate phosphorylation.

[0105] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and / or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.

[0106] In general, however, a suitable dose will often be in the range of from about 0.05 mg / kg to about 10 mg / kg. For example, a suitable dose may be in the range from about 0.10 mg / kg to about 7.5 mg / kg of body weight per day, such as about 0.15 mg / kg to about 5.0 mg / kg of body weight of the recipient per day, about 0.2 mg / kg to 4.0 mg / kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.

[0107] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

[0108] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve thedesired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and / or gemcitabine)

[0109] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0110] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0111] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity inanimals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.EXAMPLES

[0112] The compounds of Formula (I) and Compounds No. 1 to 26 as described herein, as well as pharmaceutically acceptable salts thereof, are prepared using General Scheme A below.General Scheme AMethod 1Method 2Method 3

[0113] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.Intermediate 1(A)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-57 / -cyclopenta[b]pyridin-2-yl)-6- (methylsulfonyl)- l,2-dihydro-3 / / -pyrazolo[3,4-J]pyrimidin-3-one

[0114] Intermediate 1 was synthesized by following the procedure as described in WO 2019 / 173082 Al and WO 2022 / 251224 Al.Intermediate 2(A)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2-yl)-6-((2,3,4,5- tetrahydro-l / / -benzo[< ]azepin-7-yl)amino)-l,2-dihydro-3 / / -pyrazolo[3,4-t / ]pyrimidin-3-one CbzCI TFA / DCM NaHCOj 25°C THF, 0-25°C, 97% Step-1 Step-2TFAA, TEA H2, Pd / C DCM THF, 25°C THF, 0-25°C 95% F F 80% Step-3 Step-4K2CO3MeOH, 25°C 75% Step-6Step 1: Preparation of Zc / 7-butyl 7-(((benzyloxy)carbonyl)amino)-l,2,4,5-tetrahydro-377-b enzo [< ] azepine-3 -carb oxy 1 ate

[0115] To a solution of Zc / 7-butyl 7-amino-l,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (2 g, 7.62 mmol) and NaHCCh (704.47 mg, 8.39 mmol) in THF (20 mb) was added dropwise CbzCl (1.43 g, 8.39 mmol) at 0 °C over 3 min. After addition, the mixture was stirred at this temperature for 15 min, and then was stirred at 25 °C for 45 min. LCMS showed the reaction was completed and the desired product was detected. The mixture was poured into water (60 mb) and the aqueous phase was extracted with ethyl acetate (20 mb * 3). The combined organic layers were dried over sodium sulphate, fdtered, concentrated under reduced pressure and the residue obtained was purified by column chromatography (silica gel, 0-30% ethyl acetate in petroleum ether) to afford Zc / 7-butyl 7-(benzyloxycarbonylamino)-l,2,4,5- tetrahydro-3-benzazepine-3-carboxylate (2.6 g, 86%). LC / MS (EST) m / z 341.3 [M+H]+.Step 2: Preparation of benzyl (2,3,4,5-tctrahydro-17 / -bcnzo[d]azcpin-7-yl)carbamatc

[0116] A mixture of zez7-butyl 7-(benzyloxycarbonylamino)-l,2,4,5-tetrahydro -3-benzazepine-3- carboxylate (2.6 g, 6.56 mmol) in DCM (25 mb) and TFA (5 mb), was stirred at 25 °C for 1 h. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to afford benzyl N-(2,3,4,5-tetrahydro-l / 7-3-benzazepin-7-yl) carbamate (1.9 g, 97%). LC / MS (ESI) m / z 297.3 [M+H]+.Step 3: benzyl (3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lZ / -benzo[d]azepin-7-yl)carbamate

[0117] To a solution of benzyl N-(2,3,4,5-tetrahydro-l / / -3-benzazepin-7-yl) carbamate (1.9 g, 6.41 mmol) and TEA (1.95 g, 19.23 mmol) in DCM (20 mL) was added dropwise TFAA (2.02 g, 9.62 mmol) at 0 °C over 3 min. After addition, the mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed and the desired product was detected. The mixture was poured into water (60 mL) and the aqueous phase wasextracted with EA (20 mL x 3). The combined layers were washed with brine (10 mL x 3), dried with anhydrous Na2SC>4, fdtered and concentrated under reduced pressure to afford benzyl A-[3-(2,2,2-trifluoroacetyl)-l,2,4,5-tetrahydro-3-benzazepin-7-yl] carbamate (2 g, 80%), which was used for next step without further purification.rH NMR (400 MHz, DMSO-d6. 59.70 (br s, 1 H), 7.36 - 7.44 (m, 4 H), 7.33 - 7.36 (m, 1 H), 7.23 - 7.29 (m, 2 H), 7.08 (dd, J= 7.94, 6.07 Hz, 1 H), 5.14 (s, 2 H), 3.65 (br d, J= 9.76 Hz, 4 H), 2.85 - 2.95 (m, 4 H). Step 4: Preparation of l-(7-amino-l,2,4,5-tetrahydro-3Z / -benzo[z / ]azepin-3-yl)-2,2,2-trifluoroethan- 1 -one

[0118] To a solution of benzyl zV-[3-(2,2,2-trifluoroacetyl)-l,2,4,5-tetrahydro-3-benzazepin-7-yl] carbamate (1.9 g, 4.84 mmol) in THF (25 mL) was added Pd / C (10%, 1.9 g) under N2 atmosphere. The suspension was degassed under vacuum and was purged with H2 for multiple times. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 h. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was filtered with celite, and the filter cake was washed with ethyl acetate (15 mL x 3). The filtrate was concentrated under reduced pressure to afford l-(7-amino-l,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2- trifluoro-ethanone (1.2 g, 95%). ’H NMR (400 MHz, DMSO-t / 6) 5 ppm 6.81 (dd, J = 7.88, 5.75 Hz, 1 H), 6.31 - 6.41 (m, 2 H), 4.98 (br s, 2 H), 3.54 - 3.67 (m, 4 H), 2.71 - 2.84 (m, 4 H).Step 5: Preparation of (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 7-cyclopenta[Z>]pyridin-2-yl)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l / 7-benzo[c / ]azepin-7-yl)amino)-l,2-dihydro-377-pyrazolo[3,4-d]pyrimidin-3-one

[0119] A mixture of l-(7-amino-l,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone (1.2 g, 4.65 mmol) and Intermediate 1 (2.12 g, 5.11 mmol) in z-PrOH (20 mL), was stirred at 50 °C for 12 h. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filter cake was washed with z-PrOH (5 mL x 3). The filter cake was concentrated under reduced pressure to afford 2-allyl-l-[(77?)-7-hydroxy-7-methyl-5,6-dihydrocyclopenta[Z>]pyri din-2 -yl]-6-[[3-(2, 2, 2 -tri fluoroacetyl)- 1,2,4, 5-tetrahydro-3-benzazepin-7-yl] amino] pyrazolo[3,4- ] pyrimidin-3-one (1.9 g, 70%) which was used for next step without further purification. LC / MS (ESI) m / z 594.3 [M+H]+.Step 6: Preparation of (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[Z>]pyridin-2-yl)-6-((2,3,4,5-tetrahydro-17 / -benzo[d]azepin-7-yl)amino)-l,2-dihydro-377-pyrazolo[3,4-<7]pyrimidin-3-one

[0120] To a solution of 2-allyl-l-[(7A)-7-hydroxy-7-methyl-5,6-dihydrocyclopenta[Z>]pyri din-2 -yl]-6-[[3-(2, 2, 2-trifluoroacetyl)- 1,2,4, 5-tetrahydro-3-benzazepin-7-yl]amino] pyrazolo[3,4-<7]pyrimidin-3-one (1.9 g, 3.28 mmol) in MeOH (10 mb) was added K2CO3 (2.27 g, 16.39 mmol). The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The mixture was poured into water (30 mL) and the aqueous phase was extracted with / -PrOH: CHCh = 1:4 (15 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-allyl-l-[(77?)-7-hydroxy-7-methyl-5,6-dihydrocyclopenta[Z>]pyridin-2-yl]-6-(2,3,4,5-tetrahydro-17f-3-benzazepin-7-ylamino) pyrazolo[3,4-<7] pyrimidin-3-one (1.2 g, 75%) which was used for next step without further purification. LC / MS (ESI) m / z 498.3 [M+H]+. 'H NMR (400 MHz, DMSO- s) 8 ppm 10.17 (br d, J=1.11 Hz, 1 H) 8.86 (s, 1 H) 7.82 - 7.89 (m, 1 H) 7.70 (d, 7=8.04 Hz, 1 H) 7.57 (br s, 1 H) 7.33 - 7.42 (m, 1 H) 7.00 - 7.11 (m, 1 H) 5.67 (ddt, 7=16.78, 10.62, 5.85, 5.85 Hz, 1 H) 5.06 (br s, 1 H) 5.00 (d, 7=10.27 Hz, 1 H) 4.85 (dd, 7=17.07, 0.99 Hz, 1 H) 4.75 (br dd, 7=15.71, 4.82 Hz, 1 H) 4.56 (br dd, 7=16.08, 6.19 Hz, 1 H) 3.47 (br d, 7=12.62 Hz, 4 H) 2.91 - 3.02 (m, 1 H) 2.80 (br d, 7=7.05 Hz, 6 H) 2.20 (ddd, 7=13.52, 8.26, 5.69 Hz, 1 H) 1.95 - 2.07 (m, 1 H) 1.81 - 1.95 (m, 1 H) 1.62 - 1.78 (m, 1 H) 0.86 (t,.7=7.36 Hz, 3 H).Intermediate 32-(3-(2,4-dioxotetrahydropyrimidin-l(27)-yl)phenyl)-2-azaspiro[3.3]heptane-6- carbaldehydeTFA, DCM rt, 1 hStep 1 dioxane, Pd-PEPPSI-iHeptCI Cs2CO390°C, 4 hStep 2ODMP, DCMrt, 1 hStep 3Step 1: Preparation of (2-azaspiro[3.3]heptan-6-yl)methanol 2,2,2-trifluoroacetate

[0121] To the solution of / c / V-butyl 2-(hydroxymethyl)-6-azaspiro[3.3]heptane-6-carboxylate (500 mg, 2.2 mmol) in DCM (2 mL) was added TFA (1 mL, 13.07 mmol). The reaction was stirred at rt for 1.5 h. The reaction mixture was concentrated, and the residue was treated with Et2O and sonicated. The product was collected by centrifuge and dried. The (2-azaspiro[3.3]heptan-6-yl)methanol 2,2,2-trifluoroacetate (518 mg, 98%) was obtained as brown wax. LC / MS (ESI) m / z 128.1 [M+H]+.Step 2: Preparation of l-(3-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-dione

[0122] In a vial (40 mL) was loaded l-(3-bromophenyl)dihydropyrimidine-2,4(177,377)-dione (500 mg, 1.858 mmol), 1,4-Dioxane (6 mL), (2-azaspiro[3.3]heptan-6-yl)methanol 2,2,2-trifluoroacetate (448 mg, 1.858 mmol), cesium carbonate (1816 mg, 5.57 mmol). The mixture was bubbled with nitrogen for 1 min before Pd-PEPPSI-iHeptCl (302 mg, 0.310 mmol) was added. The vial was heated at 120°C for 4 h. The reaction was diluted with EtOAc (50 mL) and brine (50 mL). The organic layer was separated and aqueous was extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, 0-100% ethyl acetate in petroleum ether) to give l-(3-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-dione (50 mg, 9%) as yellow wax. LC / MS (ESI) m / z 316.2 [M+H]+.Step 3: 2-(3-(2,4-dioxotetrahydropyrimidin-l(27 / )-yl)phenyl)-2-azaspiro[3.3]heptane-6-carb aldehyde

[0123] To a solution of l-(3-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 37 / )-dione (52 mg, 0.165 mmol) in DCM (3 mL) was added DMP (84 mg, 0.198 mmol). The reaction was stirred at rt for 2 h. Then 10% sodium metabisulfite solution (10 mL) was added and extracted with DCM (30 mL x 3). Thecombined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0-100% ethyl acetate in petroleum ether). The 2-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)phenyl)-2-azaspiro[3.3]heptane-6-carbaldehyde (14 mg, 27%) was obtained as brown wax. LC / MS (ESI) m z 314.2 [M+H]+.Intermediate 42-(6-((2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)methyl)pyridin-3-yl)-2-azaspiro[3.3]heptane- 6-carbaldehydedioxane, Pd-PEPPSI-iHeptCl Cs2CO390°C, 4 h Step 1Step 1: l-((5-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)methyl)dihydropyrimidine-2,4(l H,3 Z7)-dione

[0124] To a vial (40 mL) was loaded l-((5-bromopyridin-2-yl)methyl)dihydropyrimidine-2, 4(1 / 7, 317)-di one (250 mg, 0.880 mmol), 1,4-di oxane (6 mL), (2-azaspiro

[0003] heptan-6-yl)methanol 2,2,2-trifluoroacetate (212 mg, 0.880 mmol), cesium carbonate (860 mg, 2.64 mmol). The mixture was bubbled with nitrogen for 1 min before adding Pd-PEPPSI-iHeptCl (86 mg, 0.088 mmol). The vial was heated at 90°C for 4 h. The reaction was diluted with EtOAc (50 mL) and brine (50 mL). The organic layer was separated and aqueous was extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, 0-100% ethyl acetate in petroleum ether) to give l-((5-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)methyl)dihydropyrimidine-2,4(l / / ,3 / / )-dione (94 mg, 32%) as yellow wax. LC / MS (ESI) m / z 331.1 [M+H]+.Step 2: 2-(6-((2,4-dioxotetrahydropyrimidin-l(27 / )-yl)methyl)pyridin-3-yl)-2-azaspiro[3.3]heptane-6-carbaldehyde

[0125] To a solution of l-((5-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)methyl)dihydropyrimidine-2,4(l / f,3 / / )-dione (114 mg, 0.345 mmol) in DCM (3 mL) was added DMP (176 mg, 0.414 mmol). The reaction was stirred at rt for 2 h. The 10% sodium metabisulfite solution (10 mL) was added and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (100 mL), dried overNazSCL, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0-100% ethyl acetate in petroleum ether). The 2-(6-((2,4-dioxotetrahydropyrimidin-l(2 / / )-yl)methyl)pyridin-3-yl)-2-azaspiro[3.3]heptane-6-carbaldehyde (28 mg, 25%) was obtained as brown wax. LC / MS (ESI) m / z 329.1 [M+H]+.Example 1(?)-l-(3-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[b]pyridin-2-yl)-3- oxo-2,3-dihydro-17 / -pyrazolo[3,4- ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-377- benzo[d]azepin-3-yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2,4(l / 7,377)-dione (Compound 1)Pd-PEPPSI-iHeptCI2CS2CO3 (3 eq), dioxane, 100°C, 12 h 42% Step-1Step 1: Preparation of l-(3-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)dihydropyrimidine-2,4(177,37 )-dione

[0126] A mixture of 1 -(3 -bromophenyl) hexahydropyrimidine-2, 4-dione (2 g, 7.43 mmol), 4-(dimethoxymethyl) piperidine (1.3 g, 8.18 mmol), CS2CO3 (7.26 g, 22.3 mmol) and Pd-PEPPSI-iHeptCl (723 mg, 743pmol) in dioxane (20 mb) was degassed and purged with N2 multiple times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was fdtered, and the fdter cake was washed with EA (10 mL x 3). The filtrate was concentrated under reduced pressure to give the crude product which was purified column chromatography (silica gel, 0-30% ethyl acetate in petroleum ether) to afford l-[3-[4-(dimethoxymethyl)-l-piperidyl]phenyl]hexahydropyrimidine-2, 4-dione (1.1 g, 42%). LC / MS (ESI) m / z 348.1 [M+H]+.Step 2: Preparation of l-(3-(2,4-dioxotetrahydropyrimidin-l(27)-yl)phenyl)piperidine-4-carbaldehyde

[0127] A solution of l-[3-[4-(dimethoxymethyl)-l-piperidyl] phenyl] hexahydropyrimidine -2,4- dione (500 mg, 1.44 mmol) in formic acid (6 mL) was stirred at 50 °C for 1 h. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was concentrated under reduced pressure to afford 1 -[3 -(2,4-dioxohexahydropyrimidin-l-yl)phenyl]piperidine-4-carbaldehyde (400 mg, 92%) which was used for next step without further purification. LC / MS (ESI) m / z 302.3 [M+H]+.Step 3: Preparation of (J?)-l-(3-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-177-pyrazolo[3,4-J]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2,4(177,3 / )-dione

[0128] To a solution of Intermediate 2 (396.3 mg, 796.44 pmol) and l-[3-(2,4-dioxohexahydropyrimidin-l-yl)phenyl] piperidine -4-carbaldehyde (400 mg, 796.44 pmol) in DCM (500 mL), the mixture was stirred at 25 °C for 0.5 h, and then NaBH(OAc)3 (253.20 mg, 1.19 mmol) was added. The resulting mixture was stirred at 25 °C for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC to afford ( / ?)-1 -(3 -(4-((7 -((2-allyl - 1 -(7-ethyl -7 -hy droxy-6, 7-dihy dro-517-cy clopenta[b]pyridin-2-y l)-3 -oxo-2,3-dihydro-l / / -pyrazolo[3,4-<7]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)piperidin- l-yl)phenyl)dihydropyrimidine-2, 4(177, 37 / )-di one (196.6 mg, 31%). LC / MS (ESI) m z 783.3 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 10.30 (s, 1 H), 10.12 - 10.24 (m, 1 H), 8.86 (s, 1 H), 7.87 (d, J= 8.17 Hz, 1 H), 7.70 (d, J = 8.17 Hz, 1 H), 7.56 (br s, 1 H), 7.39 (dd, J = 8.10, 1.55 Hz, 1 H), 7.19 (t, J = 8.10 Hz, 1 H), 7.04 (d, J= 8.29 Hz, 1 H), 6.88 (s, 1 H), 6.82 (br d, J= 8.29 Hz, 1 H), 6.68 (d, J= 7.67 Hz, 1 H), 5.60 - 5.74 (m, 1 H), 5.06 (s, 1 H), 5.00 (d, J= 10.27 Hz, 1 H), 4.85 (br d, J = 17.32 Hz, 1 H), 4.75 (br dd, J= 15.90, 4.52 Hz, 1 H), 4.56 (br dd, J= 15.96, 6.19 Hz, 1 H), 3.60 - 3.84 (m, 4 H), 2.91 - 3.01 (m, 1 H), 2.76 - 2.86 (m, 5 H), 2.62 - 2.76 (m, 5 H), 2.52 - 2.59 (m, 3 H), 2.29 (br d, J= 6.93 Hz, 2 H), 2.20 (ddd, J= 13.55, 8.10, 5.81 Hz, 1 H), 2.01 (ddd, J = 13.39, 8.26, 5.32 Hz, 1 H), 1.79 - 1.93 (m, 3 H), 1.64 - 1.76 (m, 2 H), 1.16 - 1.29 (m, 2 H), 0.86 (t, J = 7.42 Hz, 3 H).Example 2(7?)-l-(3-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[b]pyridin-2-yl)-3- oxo-2,3-dihydro-177-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(177)- yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-di one (Compound 2)NaBH(OAc)3(2 eq), THF, 25°CStep 1: Preparation of l-(3-(4-((7-nitro-3,4-dihydroisoquinolin-2(l / / )-yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2, 4(1 / 7, 3Z / )-dione

[0129] To a mixture of l-[3-(2,4-dioxohexahydropyrimidin-l-yl)phenyl]piperidine-4-carbaldehyde (260 mg, 603.97 pmol, Step-2, Example 1) and 7-nitro- 1,2,3,4-tetrahydroisoquinoline (129.64 mg, 603.97 pmol) in THF (6 mL) was added AcOH (3.63 mg, 60.40 pmol). After stirring for 0.5 h, NaBH(OAc)3 (256.01 mg, 1.21 mmol) was added to the reaction and the resulting mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was quenched by water 20 mL and extracted with DCM 30 mL (10 mL x 3). The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure to give a residue which was purified by preparative -TLC (SiCh, PE: EtOAc = 0:1) to afford l-[3-[4-[(7-nitro-3,4-dihydro-177-isoquinolin-2-yl)methyl]-l- piperidyl]phenyl]hexahydropyrimidine-2, 4-dione (260 mg, 93%). LC / MS (ESI) m / z 464.1 [M+H]+.Step 2: Preparation of l-(3-(4-((7-amino-3,4-dihydroisoquinolin-2(l / 7)-yl)methyl)piperidin- l-yl)phenyl)dihydropyrimidine-2,4(l / 7,3 / / )-dione

[0130] A mixture of Pd / C (70.00 mg, 65.78 pmol) and l-[3-[4-[(7-nitro-3,4- dihydro-1 / 7- isoquinolin-2-yl)methyl]-l-piperidyl]phenyl]hexahydropyrimidine-2, 4-dione (140 mg, 302.03 pmol,) in TFE (10 mL) was degassed and purged with H2 multiple times, and then the mixture was stirred at 25 °C for 2 h under H2 atmosphere (15 psi). LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated to give l-[3-[4-[(7-amino-3,4- dihydro-l / 7-isoquinolin-2-yl)methyl]-l-piperidyl]phenyl]hexahydropyrimidine-2, 4-dione (130 mg, 99%). LC / MS (ESI) m / z 434.4 [M+H]+.Step 3: Preparation of (R)-l-(3-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / 7- cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(l / / )-yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2,4(l / / ,3 / / )-dione

[0131] A mixture of l-[3-[4-[(7-amino-3,4-dihydro-l / f-isoquinolin-2-yl)methyl]-l-piperidyl]phenyl] hexahydropyrimidine-2, 4-dione (130 mg, 299.85 pmol) and Intermediate 1 (124.58 mg, 299.85 pmol,) in i-PrOH (6 mL) was stirred at 50 °C for 12 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the residue. The residue was purified by reverse phase-HPLC to afford l-[3-[4- [[7-[[2-allyl-l-[(7R)-7-ethyl-7-hydroxy-5,6-dihydrocyclopenta[Z>]pyridin-2-yl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-l / 7-isoquinolin-2-yl]methyl]-l-piperidyl]phenyl]-hexahydropyrimidine-2, 4-dione (53.0 mg, 22%). LC / MS (ESI) m / z 769.4 [M+H]+.JH NMR (400 MHz, DMSO-tfc): 6 10.29 (s, 1H), 10.27 - 10.13 (m, 1H), 8.86 (s, 1H), 7.86 (d, J= 8.2 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.61 (br s, 1H), 7.36 (br d, J= 7.8 Hz, 1H), 7.19 (t, J= 8.0 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.88 (s, 1H), 6.82 (br d, J= 8.3 Hz, 1H), 6.68 (d, J= 7.8 Hz, 1H), 5.74 - 5.61 (m, 1H), 5.08 (s, 1H), 4.99 (d, J= 10.4 Hz, 1H), 4.85 (br d, J= 17.1 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.63 -4.50 (m, 1H), 3.77 - 3.72 (m, 2H), 3.68 (br s, 2H), 3.51 (br s, 2H), 3.01 - 2.90 (m, 1H), 2.81 -2.74 (m, 3H), 2.72 - 2.62 (m, 6H), 2.37 (br d, J= 6.3 Hz, 2H), 2.25 - 2.15 (m, 1H), 2.06 - 1.97 (m, 1H), 1.91 - 1.78 (m, 4H), 1.74 - 1.64 (m, 1H), 1.32 - 1.20 (m, 2H), 0.85 (t, J= 7.4 Hz, 3H).Example 3(J?)-l-(3-(4-((6-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5Z / -cyclopenta[ >]pyridin-2-yl)-3- oxo-2, 3-dihy dro- l / / -pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-3, 4-dihydroisoquinolin-2(17 )- yl)methyl)piperidin-l-yl)phenyl)dihydropyrimidine-2, 4(1 / 7, 3 / )-dione (Compound 3)

[0132] Compound 3 was synthesized (11% yield in final step) by following a similar procedure as described in the synthesis of Compound 2 using 6-nitro-l,2,3,4-tetrahydroisoquinoline instead of 7-nitro-l,2,3,4-tetrahydroisoquinoline (Step-1). LC / MS(ESI) m / z 769.4 [M+H]+.JH NMR (400 MHz, DMSO-fifc): 5 ppm 10.46 (s, 1H), 10.43 - 10.29 (m, 1H), 9.05 (d, J= 1.5 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.82 (br s, 1H), 7.58 (br d, J= 8.3 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.19 (d, J= 7.9 Hz, 1H), 7.06 (s, 1H), 7.00 (br d, J= 8.8 Hz, 1H), 6.87 (d, J= 7.7 Hz, 1H), 5.93 - 5.80 (m, 1H), 5.25 (d, J= 1.7 Hz, 1H), 5.19 (br d, J= 10.1 Hz, 1H), 5.04 (br d, J= 16.9 Hz, 1H), 5.00 - 4.89 (m, 1H), 4.83 -4.68 (m, 1H), 3.95 - 3.85 (m, 4H), 3.69 (s, 2H), 3.21 - 3.11 (m, 1H), 2.98 (br d, J= 5.9 Hz, 3H), 2.92 - 2.83 (m, 6H), 2.53 (br d, J= 6.4 Hz, 2H), 2.43 - 2.36 (m, 1H), 2.25 - 2.16 (m, 1H), 2.12 - 1.96 (m, 4H), 1.93 - 1.83 (m, 1H), 1.48 - 1.37 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H).Example 4l-(3-((7?)-2-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[Z>]pyri din-2- yl)-3-oxo-2,3-dihydro-177-pyrazolo[3,4-J]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-377- benzo[t / ] azepin-3-yl)methyl)morpholino)phenyl)dihydropyrimidine-2, 4(1 / 7, 3Z / )-dione (Compound 4)Step 1: Preparation of tert-butyl (7?)-2-((7-(((benzyloxy)carbonyl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)morpholine-4-carboxylate

[0133] To a mixture of benzyl / V-(2,3,4,5-tetrahydro-177-3-benzazepin-7-yl)carbamate (500 mg, 1.69 mmol) and tert-butyl (25)-2-(methylsulfonyloxymethyl)morpholine-4- carboxylate (747.44 mg, 2.53 mmol) in DMSO (5 mb) was added DIEA (1.09 g, 8.44 mmol) and Nal (252.89 mg, 1.69 mmol). The resulting mixture was stirred at 100 °C for 12 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was quenched by water 5 m and extracted with EtOAc 15 mL (5 mb x 3). The combined organic layers were washed with brine 15 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in petroleum ether) to afford te / 7-butyl (27?)-2-[[7-(benzyloxy carbonylamino)-!,2,4,5-tetrahydro-3-benzazepin-3-yl]methyl]morpholine-4-carboxylate (550 mg, 65%). LC / MS (ESI) m / z 496.2 [M+H]1.Step 2: Preparation of benzyl (5)-(3-(morpholin-2-ylmethyl)-2,3,4,5-tetrahydro-lZ7-b enzo [t / ] azepin- 7 -y l)carb am ate

[0134] To a solution of tert-butyl (2A)-2-[[7-(benzyloxycarbonylamino)-l, 2,4,5-tetrahydro-3- benzazepin-3-yl]methyl]morpholine-4-carboxylate (550 mg, 1.11 mmol) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol). The resulting mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was concentrated and adjusted to pH>9 with aq. Na2CO3, and extracted with EtOAc 30 mL (10 mL x 3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to afford benzyl A-[3-[[(25)-morpholin-2-yl]methyl]-l,2,4,5-tetrahydro-3-benzazepin-7-yl] carbamate (420 mg, 1.06 mmol, 95%) which was used to next step without further purification. LC / MS (ESI) m'z 396.4 [M+H]+.Step 3: Preparation of benzyl (7?)-(3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)morpholin-2-yl)methyl)-2,3,4,5-tetrahydro-l / / -benzo[d]azepin-7-yl)carbamate

[0135] A mixture of benzyl A-[3-[[(2S)-morpholin-2-yl]methyl]-l, 2,4,5-tetrahydro-3-benzazepin- 7-yl]carbamate (370 mg, 935.54 pmol), l-(3-bromophenyl)hexahydropyrimidine- 2,4-dione (251.75 mg, 935.54 pmol), Z-BuONa (179.82mg, 1.87 mmol) and Pd-PEPPSI-IHeptCl (91.01 mg, 93.55 pmol) in DMF (15 mL) was degassed and purged with N2 multiple times, and then the mixture was stirred at 80 °C for 12 h under N2 atmosphere. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was quenched by water 30 mL and extracted with EtOAc 45 mL (15 mL x 3). The combined organic layers were washed with brine 40 mL, dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, EtOAc: MeOH = 10: 1) to afford benzyl (A)-(3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)phenyl)morpholin-2-yl)methyl)- 2.3.4.5-tetrahydro-l / / -benzo[c / ]azepin-7-yl)carbamate (150 mg, 27%). LC / MS (ESI) m'z 584.2 [M+H]+.Step 4: Preparation of (A)-l-(3-(2-((7-amino-l,2,4,5-tetrahydro-3 / f-benzo[ ]azepin-3-yl)methyl)morpholino)phenyl)dihydropyrimidine-2, 4(1 / 7, 3 / / )-dione

[0136] A mixture of Pd / C (65 mg, 61.08 pmol) and benzyl A-[3-[[(2 / ?)-4-[3-(2,4-dioxohexahydropyrimidin-l-yl)phenyl]morpholin-2-yl]methyl]- 1,2,4, 5 -tetrahydro-3 -benzazepin-7-yl]carbamate (130 mg, 222.73 pmol) in THF (10 mL) was degassed and purged with H2 multiple times, and then the mixture was stirred at 25 °C for 12 h under H2 atmosphere. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated to give l-[3-[(2A)-2-[(7-amino-l,2,4,5-tetrahydro-3-benzazepin-3-yl)methyl]morpholin-4-yl]phenyl]hexahydropyrimidine-2, 4-dione (100 mg, 99%) which was used to next step without further purification. LC / MS (ESI) m / z 450.1 [M+H]+.Step 5: l-(3-(( / ?)-2-((7-((2-allyl-l-(( / ?)-7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[Z’]pyridin-2-yl)-3-oxo-2,3-dihydro-177-pyrazolo[3,4-t7]pyrimidin-6-yl)amino)- 1.2.4.5-tetrahydro-3 / 7-benzo[< / ]azepin-3-yl)methyl)morpholino)phenyl)dihydropyrimidine-2,4(l / 7,3 / 7)-dione

[0137] A mixture of l-[3-[(27?)-2-[(7-amino-l,2,4,5-tetrahydro-3-benzazepin-3-yl)methyl]morpholin- 4-yl]phenyl]hexahydropyrimidine-2, 4-dione (100 mg, 222.45 pmol) and Intermediate 1 (184.84 mg, 444.90 pmol) in z-PrOH (5 mL) was stirred at 50 °C for 12 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the residue. The residue was purified by reverse phase HPLC to afford l-[3-[(2 / ?)- 2-[[7-[[2-allyl-l-[(7A)-7-ethyl-7-hydroxy-5,6-dihydrocyclopenta[Z>]pyridin-2-yl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-l,2,4,5-tetrahydro-3-benzazepin-3-yl]methyl]morpholin-4-yl]phenyl]hexahydropyrimidine-2,4-dione (33.6 mg, 18%). LC / MS (ESI) m / z 785.3 [M+H]+. 'H NMR (400 MHz, DMSO-tifc): 5 ppm 10.31 (s, 1H), 10.26 - 10.09 (m, 1H), 8.86 (s, 1H), 7.87 (d, J= 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.57 (br s, 1H), 7.41 - 7.31 (m, 1H), 7.24 (t, J= 8.1 Hz, 1H), 7.05 (d, J = 8.2Hz, 1H), 6.91 (s, 1H), 6.87 - 6.80 (m, 1H), 6.75 (d, J= 7.8 Hz, 1H), 5.74 - 5.61 (m, 1H), 5.06 (s, 1H), 5.00 (d, J= 9.5 Hz, 1H), 4.89 - 4.81 (m, 1H), 4.80 - 4.70 (m, 1H), 4.61 - 4.51 (m, 1H), 3.94 (br d, J= 10.9 Hz, 1H), 3.75 (t, J= 6.6 Hz, 3H), 3.68 - 3.58 (m, 2H), 3.50 (br d, J= 11.5 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.82 (br s, 4H), 2.79 - 2.67 (m, 6H), 2.67 - 2.55 (m, 4H), 2.47 -2.40 (m, 1H), 2.24 - 2.16 (m, 1H), 2.05 - 1.97 (m, 1H), 1.94 - 1.84 (m, 1H), 1.75 - 1.65 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H).Example 53-(5-(4-((7-((2-allyl-l-((A)-7-ethyl-7-hydroxy-6,7-dihydro-5Z / -cyclopenta[ >]pyridin-2-yl)-3- oxo-2,3-dihydro-l / / -pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / 7- benzo[d]azepin-3-yl)methyl)piperidin-l-yl)pyrazin-2-yl)piperidine-2, 6-dione (Compound 5)o.Step 1: Preparation of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(dimethoxymethyl)piperidin- l-yl)pyrazine

[0138] A mixture of 2-bromo-5-(2,6-dibenzyloxy-3-pyridyl) pyrazine (1 g, 2.23 mmol), 4-(dimethoxymethyl) piperidine (426.20 mg, 2.68 mmol), CS2CO3 (2.18 g, 6.69 mmol) and XPhos Pd G3 (188.81 mg, 223.06 pmol) in dioxane (15 mL) was degassed and purged with N2 multiple times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mLx3). The filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography (silica gel, 30-50% ethyl acetate in petroleum ether) to afford 2-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-l-piperidyl] pyrazine (500 mg, 42%). LC / MS (ESI) m 'z 527.4 [M+H]+.Step 2: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)pyrazin-2-yl)piperidine-2,6- dione

[0139] To a solution of 2-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)- 1 -piperidyl] pyrazine (500 mg, 949.44 pmol) in THF (10 mL) was added Pd / C (10%, 500 mg) under N2 atmosphere. The suspension was degassed and purged with H2 multiple times. The mixture was stirred under H2 (15 Psi) at 60 °C for 1 h. LCMS showed the reaction was completed and the desired product was detected. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure to afford 3-[5-[4-(dimethoxymethyl)-l-piperidyl] pyrazin-2-yl] piperidine- 2, 6-dione (150 mg, 45%). LC / MS (ESI) m / z 349.1 [M+H]+.Step 3: Preparation of l-(5-(2,6-dioxopiperidin-3-yl)pyrazin-2-yl)piperidine-4-carbaldehyde

[0140] A solution of 3-[5-[4-(dimethoxymethyl)-l-piperidyl] pyrazin-2-yl] piperidine-2, 6-dione (150 mg, 430.54 pmol) in HCOOH (2 mL) was stirred at 50 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford l-[5-(2,6-dioxo-3-piperidyl)pyrazin-2-yl] piperidine-4-carbaldehyde (100 mg, 76%). which was used to next step without further purification. LC / MS (ESI) m / z 303.4 [M+H]+.Step 4: Preparation of 3-(5-(4-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z»]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-cZ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[<7]azepin-3-yl)methyl)piperidin-l-yl)pyrazin-2-yl)piperidine-2, 6-dione

[0141] To a solution of l-[5-(2,6-dioxo-3-piperidyl)pyrazin-2-yl]piperidine-4-carbaldehyde (100 mg, 330.77 pmol) and Intermediate 2 (181.05 mg, 363.84 pmol) in THF (5 mL), the mixture was stirred at 25 °C for 30 min, and then NaBH(OAc)3 (105.15 mg, 496.15 pmol) was added. The resulting mixture was stirred at 25 °C for 1.5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent to give a crude product which was purified by reverse phase-HPLC to afford 3-[5-[4-[[7-[[2-allyl-l-[(77?)-7-ethyl-7-hydroxy-5,6-dihydrocyclopenta[Z>] pyridin-2-yl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-l,2,4,5-tetrahydro-3-benzazepin-3-yl]methyl]-l-piperidyl]pyrazin-2-yl]piperidine-2, 6-dione (35.5 mg, 13%). LC / MS (ESI) m'z 828.4 [M+H]+. ‘HNMR (400 MHz, DMSO-tL) 8 ppm 10.83 (s, 1H), 10.16 (br dd,, / 3.55, 2.32 Hz, 1H), 8.86 (s, 1H), 8.24 (s, 1H), 8.03 (d, J= 1.10 Hz, 1H), 7.87 (d, J= 8.19 Hz, 1H), 7.70 (d, J = 8.07 Hz, 1H), 7.55 (br s, 1H), 7.39 (dd, J= 8.13, 1.90 Hz, 1H), 7.05 (d, J= 8.31 Hz, 1H), 5.67 (ddt, J= 16.86, 10.65, 5.93, 5.93 Hz, 1H), 5.06 (s, 1H), 5.00 (dd, J= 10.21, 1.04 Hz, 1H), 4.85 (dd, <7 = 17.12, 1.10 Hz, 1H), 4.71 - 4.80 (m, 1H), 4.56 (br dd, J= 15.89, 6.24 Hz, 1H), 4.32 (br d, J = 11.74 Hz, 2H), 3.90 (dd, J = 10.09, 5.07 Hz, 1H), 2.89 - 3.01 (m, 2H), 2.74 - 2.88 (m, 6H), 2.62 - 2.69 (m, 1H), 2.61 (br s, 3H), 2.52 - 2.55 (m, 2H), 2.25 - 2.33 (m, 2H), 2.15 - 2.25 (m, 2H), 1.97 - 2.11 (m, 2H), 1.78 - 1.94 (m, 4H), 1.64 - 1.75 (m, 1H), 1.06 - 1.19 (m, 2H), 0.86 (t, J= 7.46 Hz, 3H).Example 63-(4-(4-((7-((2-allyl-l-((?)-7-ethyl-7-hydroxy-6,7-dihydro-5 7-cyclopenta[b]pyridin-2-yl)-3- oxo-2,3-dihydro-l / 7-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / 7- benzo[<7]azepin-3-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione (Compound 6)Step 1: Preparation of 3-(4-(4-((7-nitro-l,2,4,5-tetrahydro-3Z7-benzo[d]azepin-3-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione

[0142] To a solution of l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (150 mg, 0.499 mmol) in DCE (4.9 mb) was added N, iV-Diisopropylethylamine (261 pL, 1.498 mmol) at 0 °C. To this mixture was added 7-nitro-2,3,4,5-tetrahydro-177-benzo[< ]azepine (163 mg, 0.849 mmol). The reaction mixture was stirred at rt for Ih. Then to this mixture was added Sodium triacetoxyborohydride (212 mg, 0.999 mmol) at 0 °C. The reaction mixture continued to stir at rt for another Ih. LCMS shows the formation of product. Partitioned the reaction mixture with DCM / Water. Separated the organic layer, dried over Na2SC>4, concentrated and was purified by column chromatography (silica gel, 0-70% Methanol in dichloromethane) to afford 3-(4-(4-((7-nitro-l,2,4,5-tetrahydro-37f-benzo[<7]azepin-3-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (170 mg, 0.357 mmol, 71%) which was used for next step. LC / MS (ESI) m / z 477.2 [M+H]+.Step 2: Preparation of 3-(4-(4-((7-amino-l,2,4,5-tetrahydro-3 / 7-benzo[ ]azepin-3-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione

[0143] To a solution of 3-(4-(4-((7-nitro-l,2,4,5-tetrahydro-377-benzo[t / ]azepin-3 -yl)m ethyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione (100 mg, 0.210 mmol) in MeOH (1.749 mb) and DCM (350 pL) was added Nanopalladium (20 mg, 0.019 mmol). The mixture was backfilled with Th multiple times and was stirred at rt under Th for 12 h. LCMS shows the formation of product. It was filtered using celite pad and the filtrate was evaporated to afford 3-(4-(4-((7-amino- 1,2,4, 5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)piperi din- 1-yl)phenyl)piperidine-2, 6-dione (98 mg, 0.219 mmol, quantitative). LC / MS (ESI) m / z 447.3 [M+H]+.Step 3: Preparation of 3-(4-(4-((7-((2-allyl-l-((J?)-7-ethyl-7-hydroxy-6,7-dihydro-5 7-cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-1 7-pyrazolo[3,4-t7]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-377-benzo[<7]azepin-3-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6-di one

[0144] To a solution of 3-(4-(4-((7-amino-l,2,4,5-tetrahydro-31 / -benzo[t / ]azepin-3 -yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione (94 mg, 0.21 mmol) in THF (2.1 mL) was added A, A-Diisopropylethylamine (110 pL, 0.630 mmol). To this mixture was added Intermediate 1 (61.1 mg, 0.147 mmol). The reaction mixture was stirred at 80 °C for 3h (not very soluble). LCMS shows product formation, and some SM. Added 0.6 mL of DCM and heated at 80 °C for Ih. LCMS did not show much difference. Partitioned the reaction mixture with DCM / Water. Separated the organic layer, dried over Na2SC>4, concentrated and was purified by column chromatography (silica gel, 0-9% methanol in dichloromethane) to give the impure product which was further purified by reverse phase HPLC to afford 3-(4-(4-((7-((2-allyl-l-((J?)-7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,4, 5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (33 mg, 0.042 mmol, 20%). LC / MS (ESI) m / z 782.4 [M+H]+.1HNMR(400MHz, DMSO-t76): 8 ppm 10.82 - 10.76 (m, IH), 10.27 - 10.10 (m, IH), 8.90 - 8.81 (m, IH), 8.25 - 8.19 (m, IH), 7.93 - 7.83 (m, IH), 7.75 - 7.66 (m, IH), 7.64 - 7.49 (m, IH), 7.39 (dd, J = 2.0, 8.1 Hz, IH), 7.10 - 6.98 (m, 3H), 6.97 - 6.83 (m, 2H), 5.76 - 5.59 (m, IH), 5.13 - 4.95 (m, 2H), 4.90 - 4.70 (m, 2H), 4.62 - 4.48 (m, IH), 3.76 - 3.61 (m, 3H), 3.03 - 2.90 (m, IH), 2.88 - 2.72 (m, 5H), 2.72 - 2.53 (m, 6H), 2.47 - 2.40 (m,1H), 2.37 -1.95 (m, 6H), 1.95 - 1.77 (m, 3H), 1.77 - 1.61 (m, 2H), 1.32 - 1.15 (m, 2H), 0.94 -0.80 (m, 3H).Example 7(A)-l-(6-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[ / >]pyridin-2-yl)-3- oxo-2, 3-dihy dro-l / / -pyrazolo[3,4-<7]pyrimidin-6-yl)amino)- 1,2,4, 5-tetrahydro-3 / 7- benzo[<7]azepin-3 -yl)methyl)piperidin- 1 -yl)- 1 -methyl- l / / -indazol-3 -yl)dihydropyrimidine- 2,4(l / / ,3 / / )-dione (Compound 7)

[0145] Compound 7 was synthesized (10% yield for the final step) by following a similar procedure as described in the synthesis of Compound 6 using l-(3-(2,4-dioxotetrahydropyrimidin- 1 (2Z / )-yl)- 1 -methyl- 177-indazol-6-yl)piperidine-4-carbaldehyde (WO 2023 / 249970 Al) instead of l-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperidine-4-carbaldehyde (Step-1). LC / MS (ESI) m / z 837.4 [M+H]+. ’H NMR (400 MHz, DMSO-t / d): 5 ppm 10.55 - 10.49 (m, 1H), 10.27 - 10.13 (m, 1H), 8.89 - 8.84 (m, 1H), 8.30 - 8.25 (m, 1H), 7.91 - 7.83 (m, 1H), 7.75 - 7.67 (m, 1H), 7.61 - 7.51 (m, 1H), 7.47 - 7.36 (m, 2H), 7.10 - 7.01 (m, 1H), 6.96 - 6.87 (m, 1H), 6.86 - 6.79 (m, 1H), 5.75 - 5.61 (m, 1H), 5.10 -4.96 (m, 2H), 4.91 - 4.71 (m, 2H), 4.63 - 4.48 (m, 1H), 3.96 - 3.91 (m, 1H), 3.86 - 3.77 (m, 2H), 3.05 - 2.91 (m, 1H), 2.90 - 2.70 (m, 10H), 2.63 - 2.52 (m, 4H), 2.37 - 2.26 (m, 2H), 2.26 - 2.14 (m, 1H), 2.10 - 1.96 (m, 1H), 1.96 - 1.63 (m, 6H), 1.38 - 1.18 (m, 3H), 0.93 - 0.80 (m, 3H).Example 83-(3-(4-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[6]pyridin-2-yl)-3- oxo-2,3-dihydro-l / / -pyrazolo[3,4-< ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / - benzo[<7]azepin-3-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione (Compound 8)Step-5Step 1: Preparation of tert-butyl 4-((7-nitro-l,2,4,5-tetrahydro-377-benzo[<7]azepin-3-yl)methyl)piperidine-l -carboxylate

[0146] To a solution of 7-nitro-2,3,4,5-tetrahydro-l / / -benzo[t / ]azepine (460 mg, 2.393 mmol) in DMSO (4.7 mb) was added tert-butyl 4-((tosyloxy)methyl)piperidine-l-carboxylate (884 mg, 2.393 mmol) and Sodium Iodide (359 mg, 2.393 mmol). The reaction mixture was heated at 100 °C for 12h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SC>4, concentrated and was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane) to afford tert-butyl 4-((7-nitro-l,2,4,5-tetrahydro-3Z / -benzo[<7]azepin-3-yl)methyl)pi peri dine- 1 -carboxylate (410 mg, 1.053 mmol, 44%). LC / MS (ESI) m, 334.1 [M-terM3ut]+.Step 2: Preparation of 7-nitro-3-(piperidin-4-ylmethyl)-2,3,4,5-tetrahydro-lLf-benzo[ ] azepine

[0147] To a solution of tert-butyl 4-((7-nitro-l,2,4,5-tetrahydro-377-benzo[<7]azepin-3-yl)methyl)piperidine-l-carboxylate (90 mg, 0.231 mmol) in DCM (2.1 mL) was added TFA (210 pl) and was stirred at rt for 2h. LCMS shows the formation of product. All the solvents were evaporated, then co-evaporated with hexane. The residue obtained was triturated with hexane (to remove excess of TFA which is soluble in hexane). Pipetted out the hexane, and the residue was dried to afford the crude 7-nitro-3-(piperidin-4-ylmethyl)-2, 3,4,5-tetrahydro-177-benzo[ ]azepine which was used for next step without further purification. LC / MS (APCI) m / z 290.2 [M+H]+.Step 3: Preparation of 7-nitro-3-(piperidin-4-ylmethyl)-2,3,4,5-tetrahydro-l / 7-benzo[ ] azepine

[0148] To a solution of 7-nitro-3-(piperidin-4-ylmethyl)-2,3,4,5-tetrahydro-lZf-benzo[t / ]azepine (66.8 mg, 0.231 mmol), and 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (103 mg, 0.231 mmol) in Dioxane (1.1 mL) was added Cesium carbonate (376 mg, 1.155 mmol). The mixture was degassed under vacuum and was purged with N2 multiple times. To this mixture was added Pd-PEPPSI-iHeptCl (45 mg, 0.046 mmol) in dioxane (1.2 mL) was degassed and purged with N2 multiple times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SO4, concentrated and was purified by column chromatography (silica gel, 0-7% methanol in dichloromethane) to afford 3 -(( 1 -(3 -(2,6-bis(benzyloxy)pyridin-3 -yl)phenyl)piperidin-4-yl)methyl)-7 -nitro-2,3,4,5-tetrahydro-l / 7-benzo[d]azepine (60 mg, 0.092 mmol, 39%). LC / MS (APCI) m / z 655.30 [M+H]+.Step 4: Preparation of 3-(3-(4-((7-amino-l,2,4,5-tetrahydro-377-benzo[6 / ]azepin-3-yl)methyl )piperi din- l-yl)phenyl)piperidine-2, 6-dione

[0149] To a solution of 3-((l-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methyl)-7-nitro-2,3,4,5-tetrahydro-17 / -benzo[<7]azepine (60 mg, 0.092 mmol) in THF (0.916 mL) was added Nanopalladium (19.50 mg, 0.183 mmol) andPlatinum(TV)oxidehydrate (20.81 mg, 0.092 mmol). The reaction mixture was degassed under vacuum and was purged with H2 several times. It was stirred under H2 at rt for 16h. LCMS shows some product with NO2 reduced SM. Filtered the reaction mixture using a celite pad. Filtrate was collected and was concentrated. The residue obtained was dissolved in MeOH and was added Pd and PtO2 (same amount as earlier). Stirred the reaction mixture under H2 overnight. LCMS shows product and still shows some NO2 reduced starting material. The reaction mixture was filtered through a celite pad using DCM as solvent. The filtrate was collected and was concentrated to afford the impure 3-(3-(4-((7-amino-l,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione which was used for next step. LC / MS (APCI) m / z 447.50 [M+H]+.Step 5: Preparation of 3-(3-(4-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-5 7-cyclopenta[Z»]pyridin-2-yl)-3-oxo-2,3-dihydro-1 7-pyrazolo[3,4-t7]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[< / ]azepin-3-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6-di one

[0150] To a solution of 3-(3-(4-((7-amino-l,2,4,5-tetrahydro-31 / -benzo[t / ]azepin-3 -yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione (41.1 mg, 0.092 mmol) in THF (920 pL) was added Triethylamine (38.5 pl, 0.276 mmol) followed by Intermediate 1 (19.11 mg, 0.046 mmol). The reaction mixture was heated at 60 °C for 2h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SO4, concentrated and was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane) to afford the impure product which was further purified by reverse phase HPLC to afford 3-(3-(4-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cy cl openta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-67]pyrimi din-6-yl)amino)- 1,2,4, 5-tetrahydro-377-benzo[ ] azepin-3-yl)methyl)piperidin- 1-yl)phenyl)piperidine-2, 6-dione (3.5 mg, 4.48 pmol, 5%). LC / MS (ESI) m / z 782.4 [M+H]+.Example 93-(5-(4-((7-((2-allyl-l-((A)-7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[6]pyridin-2-yl)-3- oxo-2,3-dihydro-l / / -pyrazolo[3,4-< ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / - benzo[ ]azepin-3-yl)methyl)piperidin-l-yl)pyridin-2-yl)piperidine-2, 6-dione (Compound 9)

[0151] To a solution of Intermediate 2 (75 mg, 0.151 mmol) in DCE (2.1 m ) was added A, M-Diisopropylethylamine (140 mg, 1.080 mmol) followed by l-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde (65.1 mg, 0.216 mmol, Ref: WO 2024 / 162828 Al). The reaction mixture was stirred at rt for Ih. It was then cooled to 0 °C and was added Sodium triacetoxyborohydride (92 mg, 0.432 mmol) and was stirred for 2h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SO4, concentrated and was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane) to afford impure product which was further purified by purified by reverse phase HPLC to afford 3-(5-(4-((7-((2-allyl-l-((R)-7-ethyl-7-hydroxy-6,7-dihydro-57 / -cyclopenta[ / >]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-J]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3J7-benzo[ ]azepin-3-yl)methyl)piperidin-l-yl)pyridin-2-yl)piperidine-2, 6-dione (30 mg, 0.038 mmol, 18%). LC / MS (ESI) m,'z 783.4 [M+H]+. ’H NMR (400 MHz, DMSO4) 8 ppm 10.81 - 10.74 (m, IH), 10.27 - 10.06 (m, IH), 8.89 - 8.84 (m, IH), 8.25 - 8.16 (m, IH), 7.92 - 7.83 (m, IH), 7.73 - 7.68 (m, IH), 7.61 - 7.51 (m, IH), 7.42 - 7.27 (m, 2H), 7.21 - 7.13 (m, IH), 7.09 - 6.99 (m, IH), 5.75 - 5.61 (m, IH), 5.11 - 4.97 (m, 2H), 4.90 - 4.68 (m, 2H), 4.63 - 4.50 (m, IH), 3.92 - 3.85 (m, IH), 3.80 - 3.67 (m, 2H), 3.04 - 2.90 (m, IH), 2.89 - 2.65 (m, 6H), 2.63 - 2.51 (m, 6H), 2.36 - 1.96 (m, 7H), 1.94 - 1.79 (m, 3H), 1.79 - 1.64 (m, 2H), 1.31 - 1.13 (m, 2H), 0.92 - 0.80 (m, 3H).Example 103-(4-((S)-2-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-57 / -cyclopenta[Z>]pyridin-2- yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-tZ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3Z7- benzo[t / ]azepin-3-yl)methyl)morpholino)phenyl)piperidine-2, 6-dione (Compound 10)Step 1: Preparation of 3-(4-((5)-2-((7-((2-allyl-l-((A)-7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[ / >]pyridin-2-yl)-3-oxo-2,3-dihydro-l / / -pyrazolo[3,4- ]pyrimidin-6-yl)amino)-1,2, 4, 5-tetrahydro-37 / -benzo[<7]azepin-3-yl)methyl)morpholino)phenyl)piperidine-2, 6-dione

[0152] To a solution of Intermediate 2 (56.4 mg, 0.113 mmol,) in DMSO (284 pL) was added A, A-Diisopropylethylamine (55.0 mg, 0.425 mmol) followed by ((2A)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate (65 mg, 0.142 mmol, WO 2023 / 220640 Al) and Nal (21.25 mg, 0.142 mmol). It was heated at 100 °C for 12h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SO4, concentrated and was purified by column chromatography (silica gel, 0-8% methanol in dichloromethane) to afford the impure product which was further purified by reverse phase HPLC to afford 3-(4-((S)-2-((7-((2-allyl-l-(( )-7-ethyl-7-hydroxy-6,7-dihydro-57 / -cyclopenta[ / >]pyridin-2-yl)-3-oxo-2,3-dihydro-lH-pyrazolo[3,4-e / ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3Z7-benzo[ ]azepin-3-yl)methyl) morpholino)phenyl)piperidine-2, 6-dione (27 mg, 0.034 mmol, 24%). LC / MS (ESI) m / z 784.4 [M+H]+. 'H NMR (400 MHz, DMSO-c / r,) 8 ppm 10.81 - 10.74 (m, 1H), 10.26 - 10.07 (m, 1H), 8.89 - 8.83 (m, 1H), 7.92 - 7.81 (m, 1H), 7.75 - 7.66 (m, 1H), 7.64 - 7.51 (m, 1H), 7.43 - 7.33 (m, 1H), 7.13 - 7.00 (m, 3H), 6.97 - 6.85 (m, 2H), 5.75 - 5.60(m, 1H), 5.12 - 4.97 (m, 2H), 4.92 - 4.70 (m, 2H), 4.63 - 4.50 (tn, 1H), 3.99 - 3.88 (m, 1H), 3.81 - 3.43 (m, 5H), 3.03 - 2.91 (m, 1H), 2.88 - 2.53 (m, 5H), 2.50 (td, J= 1.8, 3.7 Hz, 8H), 2.48 -2.30 (m, 2H), 2.30 - 1.95 (m, 4H), 1.95 - 1.79 (tn, 1H), 1.79 - 1.63 (m, 1H), 0.92 - 0.81 (m, 3H).Example 113-(4-((R)-2-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[ / >]pyri din-2- yl)-3-oxo-2,3-dihydro-l / / -pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3Z / - benzo[tZ]azepin-3-yl)methyl)morpholino)phenyl)piperidine-2, 6-dione (Compound 11)

[0153] Compound 11 was synthesized (10% yield in final step) by following a similar procedure as described in the synthesis of Compound 10 using ((2 )-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate instead of ((27?)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate. LC / MS (APCI) m'z 784.40 [M+H]+. 'H NMR (400 MHz, DMSO-d&) 5 ppm 10.82 - 10.74 (m, 1H), 10.26 - 10.08 (m, 1H), 8.90 - 8.81 (m, 1H), 7.91 - 7.84 (m, 1H), 7.76 - 7.67 (m, 1H), 7.65 - 7.52 (m, 1H), 7.43 - 7.31 (m, 1H), 7.14 - 7.00 (m, 3H), 6.97 - 6.86 (m, 2H), 5.75 - 5.59 (m, 1H), 5.10 - 4.96 (m, 2H), 4.91 - 4.70 (m, 2H), 4.62 - 4.50 (m, 1H), 3.99 - 3.88 (m, 1H), 3.81 - 3.56 (m, 4H), 3.56 - 3.44 (m, 2H), 3.05 - 2.90 (m, 2H), 2.88 - 2.54 (m, 9H), 2.47 - 2.31 (m, 3H), 2.29 - 1.95 (m, 5H), 1.95 - 1.81 (m, 1H), 1.78 - 1.63 (m, 1H), 0.95 - 0.79 (m, 3H).Example 12( / )-! -((5-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopcnta[ / ]pyridin-2-yl)- 3-oxo-2,3-dihydro-l / / -pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / - benzo[ ]azepin-3-yl)methyl)piperidin-l-yl)pyridin-2-yl)methyl)dihydropyrimidine- 2,4(l / f,3 / / )-dione (Compound 12)dioxane, 100°C, 12 h Step-3 oDCM, 25°C Step-51 -((5 -bromopyridin-2-yl)m ethyl )-3 -(4-methoxybenzyl)dihy dropyrimidine-2, 4(1 / 7, 3Z / )-dione

[0154] To a solution of 3 -[(4-methoxyphenyl)methyl]hexahy dropyrimidine-2, 4-dione (6 g, 25.61 mmol) in THF (60 mL) at 0 °C was added NaH (2.05 g, 51.23 mmol, 60% purity). The mixture was stirred at 0 °C for 0.5 h. A solution of 5-bromo-2-(bromomethyl)pyridine (6.43 g, 25.61 mmol) in THF (30 mL) was added to above mixture at 0 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the formation of product. The mixture was cooled to 0 °C and poured into NH4CI solution (100 mL) and stirred for 5 min.The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered, and concentrated in vacuum to give a residue. The residue purified by column chromatography (silica gel, 10-90% ethyl acetate in petroleum ether) to afford l-[(5-bromo-2-pyridyl)methyl]-3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (6 g, 53%). LC / MS (ESI) m / z 404.3 [M+H79Br]+, 406.3 [M+H81Br]+.Step 2: Preparation of l-((5-bromopyridin-2-yl)methyl)dihydropyrimidine-2, 4(177, 377)-dione

[0155] A solution of l-((5-bromopyridin-2-yl)methyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(177,3Z7)-dione (1 g, 2.4 mmol) in TFA: TfOH, 10: 1, (8 mL) was stirred at 60 °C for 6 h. LCMS showed the reaction was completed and the desired product was formed. The mixture was concentrated in vacuum to afford l-((5-bromopyridin-2-yl)methyl)dihydropyrimidine-2, 4(1 / 7, 3 / / )-dione (0.618 mg, 91%) which was used to next step directly without further purification. LC / MS (ESI) m z 284.3 [M+H79Br]+, 286.3 [M+H81Br]+.Step 3: Preparation of l-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyridin-2-yl)methyl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0156] To a solution of l-((5-bromopyridin-2-yl)methyl)dihydropyrimidine-2,4(l / 7,377)-dione (250 mg, 0.880 mmol), Piperidine, 4-(dimethoxymethyl)- (280 mg, 1.760 mmol) and Cesium carbonate (573 mg, 1.760 mmol) in Dioxane (4.4 mL) (pre-degassed) was added Pd-PEPPSLiHeptCI (129 mg, 0.132 mmol). The reaction mixture was degassed under vacuum and was purged with N2 multiple times. Stirred at 100 °C for 6h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over Na2SC>4, concentrated and was purified by column chromatography (silica gel, 0-10% methanol in dichloromethane) to afford l-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyridin-2-yl)methyl)dihydropyrimidine-2,4(l / 7,3 / / )-dione (280 mg, 0.773 mmol, 88%). LC / MS (APCI) m / z 363.15 [M+H]+.Step 4: Preparation of l-(6-((2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)methyl)pyri din-3 -yl)piperidine-4-carbaldehyde

[0157] A solution of l-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyridin-2-yl)methyl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-di one (100 mg, 0.276 mmol) in DCM (2.5 mL) and TFA (251 pL) was stirred at rt for 2h. LCMS shows the formation of product. All the solventswere evaporated, then co-evaporated with hexane. The residue obtained was triturated with hexane (to remove excess of TFA which is soluble in hexane). Pipetted out the hexane, and the residue was dried to afford the crude l-(6-((2,4-dioxotetrahydropyrimidin-l(2H)-yl)methyl)pyridin-3-yl)piperidine-4-carbaldehyde as TFA salt. LC / MS (APCI) m / z 317.1 [M+H]+.Step 5: Preparation of (A)-l-((5-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / f-cyclopenta[Z»]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[< / ]azepin-3-yl)methyl)piperidin-l-yl)pyridin-2-yl)methyl)dihydropyrimidine-2, 4(1 / 7, 3 / / )-dione

[0158] To a solution of Intermediate 2 (96 mg, 0.193 mmol,) in DCE (2.7 mL) was added A, A-Diisopropylethylamine (240 pL, 1.380 mmol) followed by l-(6-((2,4-dioxotetrahydropyrimidin-l(2 / / )-yl)methyl)pyridin-3-yl)piperidine-4-carbaldehyde (87 mg, 0.276 mmol). The reaction mixture was stirred at rt for Ih. It was then cooled to 0 °C and was added Sodium triacetoxyborohydride (117 mg, 0.552 mmol) and was stirred for 2h. LCMS shows the formation of product. Partitioned the reaction mixture with DCM and water. Separated the organic layer, dried over NazSC, concentrated and was purified by column chromatography (silica gel, 0-10% methanol in dichloromethane) to afford impure product which was further purified by reverse phase HPLC to afford (7?)-l-((5-(4-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / 7-cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-l / 7-pyrazolo[3,4-< / ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3 / / -benzo[d]azepin-3-yl)methyl)piperidin-l-yl)pyridin-2-yl)methyl) dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (30 mg, 0.038 mmol, 14%). LC / MS (APCI) m / z 798.4 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 10.23 - 10.10 (m, 2H), 8.90 - 8.83 (m, IH), 8.27 - 8.20 (m, IH), 7.91 - 7.84 (m, IH), 7.73 - 7.67 (m, 1H),7.61 - 7.51 (m, IH), 7.43 - 7.35 (m, IH), 7.35 - 7.27 (m, IH), 7.17 - 7.10 (m, IH), 7.09 - 7.00 (m, IH), 5.74 - 5.60 (m, IH), 5.11 - 4.96 (m, 2H), 4.92 - 4.81(m, IH), 4.81 -4.69 (m, IH), 4.61 - 4.46 (m, 3H), 3.80 - 3.68 (m, 2H), 3.03 - 2.90 (m, IH), 2.88 - 2.64 (m, 8H), 2.61 - 2.52 (m, 6H), 2.37 - 2.15 (m, 3H), 2.09- 1.95 (m, IH), 1.95 - 1.78 (m, 3H), 1.78 -1.63 (m, 2H), 1.31 - 1.14 (m, 2H), 0.92 - 0.81 (m, 3H).Example 133-(4-(4-((7-((2-allyl-l-((7?)-7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z»]pyridin-2-yl)-3- oxo-2,3-dihydro-177-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-377- benzo[<7]azepin-3-yl)methyl)piperidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-177- benzo[t7]imidazol-l-yl)piperidine-2, 6-dione (Compound 13)

[0159] Compound 13 was synthesized (36% yield in final step) by following a similar procedure as described in the synthesis of Compound 12 using l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-177-benzo[d]imidazol-4-yl)piperidine-4-carbaldehyde instead of l-(6-((2,4-dioxotetrahydropyrimidin-l(277)-yl)methyl)pyri din-3 -yl)piperidine-4-carbaldehyde (Step-4). LC / MS (ESI) m'z 852.4 [M+H]+. *HNMR (400 MHz, DMSO-rA) 6 ppm 11.13 - 11.04 (m, 1H), 10.27 - 10.06 (m, 1H), 8.91 - 8.82 (m, 1H), 8.26 - 8.19 (m, 1H), 7.92 - 7.84 (m, 1H),7.76 - 7.66 (m, 1H), 7.64 - 7.52 (m, 1H), 7.45 - 7.35 (m, 1H), 7.10 - 6.83 (m, 4H), 5.75 - 5.60 (m, 1H), 5.41 - 5.30 (m, 1H), 5.13 - 4.94 (m, 2H), 4.93 - 4.67(m, 3H), 4.64 - 4.49 (m, 1H), 3.69 - 3.61 (m, 4H), 3.18 - 3.07 (m, 3H), 3.05 - 2.52 (m, 11H), 2.43 - 2.30 (m, 2H), 2.27 - 2.15 (m, 1H), 2.11 - 1.94 (m, 4H), 1.94- 1.82 (m, 3H), 1.77 - 1.62 (m, 2H), 0.93 - 0.82 (m, 3H).Example 14(7?)-l-(3-(6-((5-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[6]pyridin-2-yl)-3- oxo-2,3-dihydro-17f-pyrazolo[3,4-d]pyrimidin-6-yl)amino)isoindolin-2-yl)methyl)-2- azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-di one (Compound 14) HCI TFAA, DIEA Pd-C, H2rt, 1 h MeOH, 2 h HN NO2Step 1 Step 2THF, DIEA, rt, 18 h Step 3oDCM, STAB, rt, 3 h Step 5Step 1: 2,2,2-trifluoro-l-(5-nitroisoindolin-2-yl)ethan-l-one

[0160] To a solution of 5-nitro-2,3-dihydro-177-isoindole hydrochloride (730 mg, 3.64 mmol) in DCM (10 mL) was added DIEA (2.54 mL, 14.55 mmol). The solution was cooled in ice water and the trifluoroacetic anhydride (0.759 mL, 5.46 mmol) was dropped into above solution. The reaction was raised to rt and stirred overnight. The reaction was diluted with DCM (100 mL) and brine (100 mL). The product was extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0-10% methanol in dichloromethane). The product 2,2,2-trifluoro-l-(5-nitroisoindolin-2-yl)ethan-l-one (797 mg, 84%) was obtained as yellow solid. The compound is not ionizable and confirmed by the next hydrogenation step.Step 2: l-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-l-one

[0161] To a flask (100 mL) was loaded 2,2,2-trifluoro-l-(5-nitroisoindolin-2-yl)ethan-l-one (388 mg, 1.491 mmol) in MeOH (10 mL) and DCM (2 mL). The solution was bubbled with nitrogen for 1 min before adding Pd-C (10%). The suspension was bubbled hydrogen for 1 min. The hydrogenation was taken 2 h under hydrogen balloon. The catalystwas filtered off and the filtrate was concentrated and dried. The l-(5-aminoisoindolin-2-yl)- 2.2.2-trifluoroethan-l-one (320 mg, 93%) was afforded as yellow solid. LC / MS (ESI) m / z 231.1 [M+H]+.Step 3: (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-57 / -cyclopenta[Z>]pyridin-2-yl)-6-((2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-l,2-dihydro-377-pyrazolo[3,4-J]pyrimidin-3-one

[0162] To a solution of l-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-l-one (170 mg, 0.739 mmol) in THF (5 mL) were added Intermediate 1 (307 mg, 0.739 mmol) and DIEA (1 ml, 5.74 mmol). The reaction mixture was stirred at rt for 18 hours. The reaction material was loaded to column using celite and purified by column chromatography (silica gel, 0-100% ethyl acetate in petroleum ether). The (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[Z>]pyridin-2-yl)-6-((2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)- 1.2-dihydro-377-pyrazolo[3,4-t / ]pyrimidin-3-one (108 mg, 26%) was obtained as yellow wax. LC / MS (ESI) m / z 566.2 [M+H]+.Step 4: (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5Z / -cyclopenta[6]pyridin-2-yl)-6-(isoindolin-5-ylamino)-l,2-dihydro-3 / / -pyrazolo[3,4- ]pyrimidin-3-one

[0163] To a solution of (A)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[Z>]pyridin-2-yl)-6-((2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-l,2-dihydro-37 / -pyrazolo[3,4- ]pyrimidin-3-one (108 mg, 0.191 mmol) in MeOH (10 mL) was added potassium carbonate (545 mg, 3.94 mmol). The reaction mixture was stirred at rt for 20 hours. The reaction mixture was loaded to column with celite. The product was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane) and afforded (7?)-2-allyl- 1 -(7-ethyl-7-hydroxy-6, 7-dihydro-5 / / -cyclopenta[Z>]pyri din-2 -yl)-6-(isoindolin-5-ylamino)-l,2-dihydro-377-pyrazolo[3,4-t / ]pyrimidin-3-one (57 mg, 64%) as white solid. LC / MS (ESI) m / z 470.2 [M+H]+.Step 5: (J?)-l-(3-(6-((5-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)isoindolin-2-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2,4(l / / ,3 / / )-dione

[0164] To a stirred solution of Intermediate 3 (14 mg, 0.045 mmol) in DCM (4 mL) was added (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z>]pyridin-2-yl)-6-(isoindolin-5-ylamino)-l,2-dihydro-3Z7-pyrazolo[3,4-J]pyrimidin-3-one (20.98 mg,0.045 mmol). The reaction mixture was stirred at rt for 1 h. Sodium triacetoxyborohydride (18.9 mg, 0.089 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was loaded to column with celite. The product was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane). The product was further purified by reverse phase HPLC. The pure product fractions were combined and was added saturated NaHCCh (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The product was dissolved in MeCN (1 mL) and water (1 mL) and frozen and lyophilized for 2 days. The (7?)-l-(3-(6-((5-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro- 177-pyrazolo[3,4- ]pyrimidin-6-yl)amino)isoindolin-2-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-dione (6.6 mg, 17%) was obtained as yellow solid. LC / MS (ESI) m / z 767.4 [M+H]+.1H NMR (400 MHz, DMSO-tL) 8 ppm 10.31 (s, 1H), 10.27 (s, 1H), 8.88 (s, 1H), 7.93 - 7.84 (m, 1H), 7.78 - 7.63 (m, 2H), 7.52 - 7.13 (m, 1H), 7.23 - 7.07 (m, 2H), 6.69 - 6.52 (m, 1H), 6.41 - 6.34 (m, 1H), 6.34 - 6.24 (m, 1H), 5.75 - 5.58 (m, 1H), 5.12 - 5.06 (m, 1H), 5.06 - 4.94 (m, 1H), 4.94 - 4.81 (m, 1H), 4.81 - 4.69 (m, 1H), 4.64 - 4.48 (m, 1H), 3.88 - 3.84 (m, 2H), 3.83 - 3.80 (m, 2H), 3.79 - 3.76 (m, 2H), 3.76 - 3.69 (m, 4H), 3.05 - 2.91 (m, 1H), 2.86 - 2.74 (m, 1H), 2.74 - 2.65 (m, 4H), 2.38 - 2.33 (m, 2H), 2.26 - 2.17 (m, 1H), 2.09 - 1.83 (m, 5H), 1.77 - 1.64 (m, 1H), 0.87 (t, <7= 7.4 Hz, 3H).Example 15(7?)-l-(3-(6-((5-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[7]pyridin-2-yl)-3- oxo-2, 3 -dihydro- 177-pyrazolo[3, 4-<7]pyrimidin-6-yl)amino)isoindolin-2 -yl)methyl)-2- azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2, 4(177, 3 7)-dione (Compound 15)

[0165] To a stirred solution of Intermediate 3 (20 mg, 0.064 mmol) in DCE (4 mL) was added (J?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[Z»]pyridin-2-yl)-6-((2,3,4,5-tetrahydro- 177-benzo[<7]azepin-7-yl)amino)-l,2-dihydro-377-pyrazolo[3,4-t / ]pyrimidin-3-one (20 mg, 0.040 mmol). The reaction mixture was stirred at 60 °C for 1 h. Sodium cyanoborohydride (7.58 mg, 0.121 mmol) was added and the mixture was stirred at 60 °C for 3 h. The reaction mixture was loaded to column with celite. The product was purified by column chromatography (silica gel, 0-10% methanol in dichloromethane) to afforded (R)-l-(3-(6-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5 / / -cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-17 / -pyrazolo[3,4-J]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3Z / -benzo[t / ]azepin-3-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)dihydropyrimidine-2,4(l / f,3 / / )-dione (6 mg, 18%) as yellow solid. LC / MS (ESI) m / z 795.4 [M+H]+. ’H NMR (400 MHz, DMSO-6 / e) 5 ppm_10.30 (s, 1H), 10.22 - 10.13 (m, 1H), 8.86 (s, 1H), 7.91 - 7.80 (m, J= 8.2Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.56 (br s, 1H), 7.41 - 7.30 (m, 1H), 7.21 - 7.09 (m, 1H), 7.04 (d, J= 8.3 Hz, 1H), 6.59 (dd, J= 1.1, 7.9 Hz, 1H), 6.37 - 6.32 (m, 1H), 6.27 (dd, J = 1.6, 8.1 Hz, 1H), 5.76 - 5.57 (m, J= 5.9, 5.9, 10.5, 16.8 Hz, 1H), 5.06 (s, 1H), 5.02 -4.96 (m, 1H), 4.88 - 4.80 (m, 1H), 4.79 - 4.68 (m, 1H), 4.61 - 4.49 (m, 1H), 3.82 (s, 2H), 3.75 - 3.65 (m, 4H), 3.04 - 2.89 (m, 1H), 2.88 - 2.72 (m, 5H), 2.71 - 2.63 (m, 3H), 2.34 - 2.25 (m, 2H), 2.23 - 2.14 (m, 1H), 2.06 - 1.94 (m, 1H), 1.94 - 1.79 (m, 3H), 1.75 - 1.61 (m, 1H), 1.33 - 1.12 (m, 6H), 0.89 - 0.83 (m, 3H).Example 16(7?)-l-((5-(6-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[ / >]pyridin-2-yl)- 3-oxo-2,3-dihydro-17 / -pyrazolo[3,4-tZ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-3Z / - benzo[ ]azepin-3-yl)methyl)-2'-azaspiro[3.3]heptan-2-yl)pyridin-2- yl)methyl)dihy dropyrimidine-2, 4(177, 37 / )-di one (Compound 16)

[0166] To a stirred solution of Intermediate 4 (28 mg, 0.085 mmol) in DCE (4 mL) was added (7?)-2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z»]pyridin-2-yl)-6-((2,3,4,5-tetrahydro-177-benzo[« ]azepin-7-yl)amino)-l,2-dihydro-377-pyrazolo[3,4-t7]pyrimidin-3-one (42.4 mg, 0.085 mmol). The reaction mixture was stirred at rt for 1 h. Sodium triacetoxyborohydride (54.2 mg, 0.256 mmol) was added and the mixture was stirred at rt for 1.5 h. The reaction mixture was loaded to column with celite. The product was purified by column chromatography (silica gel, 0-10% methanol in di chloromethane). The product was further purified by reverse phase HPLC. The pure product fractions were combined and was added saturated NaHCCh (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered, concentrated. The product was dissolved in MeCN (1 mL) and water (1 mL) and frozen and lyophilized for 2 days. The (R)-l-((5-(6-((7-((2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-577-cyclopenta[Z>]pyridin-2-yl)-3-oxo-2,3-dihydro-177-pyrazolo[3,4-< ]pyrimidin-6-yl)amino)-l,2,4,5-tetrahydro-377-benzo[t / ]azepin-3-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)methyl)dihydropyrimidine-2, 4(177, 377)-dione (16.5 mg, 24%) was obtained as white solid. LC / MS (ESI) m / z 810.3 [M+H]+.XH NMR (400 MHz, DMSO-tL) 5 ppm 10.19 (s, 1H), 10.15 (s, 1H), 8.87 (s, 1H), 7.93 - 7.82 (m, 1H), 7.76 - 7.66 (m, 2H), 7.62 - 7.51 (m, 1H), 7.44 - 7.31 (m, 1H), 7.13 - 7.08 (m, 1H), 7.07 - 7.02 (m, 1H), 6.82 - 6.77 (m, 1H), 5.78 - 5.56 (m, 1H), 5.08 - 5.05 (m, 1H), 5.03 - 4.98 (m, 1H), 4.90 - 4.81 (m, 1H), 4.81 - 4.71 (m, 1H), 4.61 - 4.52(m, 1H), 4.49 - 4.45 (m, 2H), 3.94 - 3.84 (m, 2H), 3.83 - 3.60 (m, 2H), 3.03 - 2.91 (m, 1H), 2.86 - 2.73 (m, 6H), 2.63 - 2.57 (m, 2H), 2.57 - 2.53 (m, 4H), 2.44 - 2.39 (m, 1H), 2.36 - 2.26 (m, 3H), 2.25 - 2.15 (m, 1H), 2.07 - 1.97 (m, 1H), 1.95 - 1.81 (m, 3H), 1.77 - 1.64 (m, 1H), 1.33 - 1.18 (m, 2H), 0.90 - 0.84 (m, 3H).Example 17Cell proliferation assay

[0167] Cell proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability Assay. The assay involved the addition of a single reagent (CellTiter-Glo® Reagent) directly to cells cultured in serum-supplemented medium. A427 cells (ATCC, HTB-53), OVCAR3 (ATCC, HTB-161) and MDA-MB-231 (ATCC, CRM-HTB-26) cells were cultured according to ATCC recommendations and were seeded at 3,000 cells for A427, 5000 cells for OVCAR3 and 3000 for MDA-MB-231 cells per well.

[0168] Each compound evaluated was prepared as a DMSO stock solution (10 mM). Compounds were tested in duplicate on each plate, with a 10-point serial dilution curve (1:3 dilution). The highest compound concentration was 10 pM (final), with a 0.1% final DMSO concentration. Plates were then incubated at 37 °C, 5% CO2 for 72 h for A427 or 6 day for OVCAR3 and MDA-MB-231, and then were equilibrated at rt for approximately 30 mins. An equi-volume amount of CellTiter-Glo® Reagent (100 pL) was added to each well. Plates were mixed for 2 mins on an orbital shaker to induce cell lysis and then incubated at rt for 10 mins to stabilize the luminescent signal. Luminescence was recorded using a Spectramax i3x (Molecular Devices) plate reader according to CellTiter-Glo protocol. IC50 determination was performed using a non-linear regression, variable slope (four parameter), inhibitor v. response equation (Prism 9.0). IC50 values are provided in Table 2. For comparison, Table 2 also includes IC50 values for reference compound ZN-c3.Table 2. IC50 values.A427 OVCAR3 MDA-MB-231 Compound No.(nM) (nM) (nM)1 A A A 2 B B B 3 B B B4 B ND NDA427 OVCAR3 MDA-MB-231 Compound No.(nM) (nM) (nM)5 A B A 6 A B A 7 A ND A 8 A A A 9 A A A 10 B B B 11 B ND ND 12 ND ND ND 13 ND ND ND 14 B ND ND 15 A ND ND 16 A A A 17 ND ND ND 18 ND ND ND 19 ND ND ND 20 ND ND ND ZN-c3B B B(Reference)For A427, OVCAR3 and MDA-MB-231 CTG IC50: A = a single IC50 < 100 nM; B = a single IC50 >100 nM and < 500 nM; C = a single IC50 >500 nM, ND: Not DeterminedExample 18Protein degradation assay in MOLT-4 cells

[0169] 1.5 million MOLT-4 cells (ATCC, CRL-1582) were incubated with vehicle (DMSO) or 10 pM, 1 pM, 0.1 pM, or 0.01 pM concentrations of the indicated compounds for 5 hours. After treatment, the cells were harvested in RIPA lysis buffer supplemented with 1% Phosphatase Inhibitor and Protease Inhibitor Cocktail and protein concentration was determined by BCA assay. An equal amount of protein (3.5 pg / lane) from each cell extract was loaded onto 12-230 KDa Separation 25 Capillary Cartridges from ProteinSimple and probed with WEE1 (1:200 dilution, final concentration of 1 pg / mL) and -Actin (1:100 dilution, final concentration of 5 pg / mL) antibodies on a ProteinSimple Jess system according to ProteinSimple / SimpleWestern protocols. The area under the curve (AUC) from the resulting eletropherograms for each protein peak at the concentrations tested was used to calculate percent degradation for WEE1 using the equation percent degradation = 100 - [100*(WEEl / p-Actin) / (WEElDMso / p-ActinDMso)]. For illustrative purposes, electopherograms were exported as virtual blots using Compass for SW v 6.0 (ProteinSimple).The WEE-1 antibody (sc-5285) was purchased from Santa Cruz Biotechnology and P-actin (MAB8929) was purchased from R& D Systems. Percent remaining of WEE1 after 5 hour treatment in MOLT-4 cells at the tested concentrations are provided in Table 3. A “hook effect” is observed at higher concentrations, however these results indicate that many of the exemplified compounds are potent degraders of WEE1.Table 3. Percent of remaining WEE1.Percent remaining of WEE1 after 5 hours in MOLT-4 cells Compound No. 0.001 pM 0.01 pM 0.1 pM 1 pM1 32 12 9 132 86 53 41 53 3 50 16 14 23 4 75 38 25 36 5 41 16 7 116 54 16 11 27 7 30 8 9 24 8 64 33 13 26 9 49 15 11 17 10 111 51 26 58 11 25 15 17 27 12 ND ND ND ND 13 ND ND ND ND 15 69 33 28 50 16 51 20 27 71 17 56 29 28 54 18 ND ND ND ND 19 ND ND ND ND20 ND ND ND ND

[0170] Compounds of Formula (I) provided herein exhibit highly desirable properties for a DNA damage response (DDR) kinase inhibitor / degrader, including cancer cell proliferation and WEE1 kinase degradation as demonstrated in the data presented in Tables 2 and 3. In addition, compounds of Formula (I) exhibit superior solubility as well asin vivo safety and pharmacokinetic-pharmacodynamic properties as characterized using assay methods readily known by a person having ordinary skill in the art, such as the methods described in the following Examples 19-22.Example 19Metabolic stability of WEE 1 inhibitor / degrader compounds in mouse, rat, dog, monkey, and human microsomes

[0171] 222.5 L of the master solution (100 mM phosphate buffer; 1 mg / mL liver microsomes) and 25 pL of 20 mM NADPH solution were added to the incubation plates and pre-warmed for 10 min. Each reaction was started with the addition of 2.5 pL of 100 pM control compound or test compound solutions. Verapamil was used as positive control in this study. The final concentration of control compound and test compounds were 1 pM. Aliquots of 25 pL were taken from the reaction solution at 0.5, 15, 30, 60 and 120 min. Each reaction was stopped by the addition of 5 volumes of cold acetonitrile with IS (100 nM Alprazolam, 200 nM Caffeine, 200 nM Labetalol and 100 nM tolbutamide). Samples were centrifuged at 3, 220 g for 30 min. Aliquots of 100 pL of the supernatant were mixed with 100 pL of ultra-pure H2O and then used for LC-MS / MS analysis.

[0172] All calculations were carried out using Microsoft Excel. Peak area ratios were determined from extracted ion chromatograms. Percent compounds remaining at each time point were calculated by the following equation:Remaining Percentage tmin (%) = [Peak Area Ratio t min / Peak Area Ratio 0 min] x 100% Where:Peak Area Ratio t min is peak area ratio of control and test compounds at t min;Peak Area Ratio 0 min is peak area ratio of control and test compounds at zero time point.

[0173] Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.

[0174] The in vitro half-life (in vitroti / 2) was determined from the slope value: / n tro t_ = - (0.693 / H

[0175] Conversion of the in vitron / 2 (min) into the in vitro intrinsic clearance (in vitro CLint, in pL / min / mg protein) was done using the following equation (mean of duplicate determinations):0>693 volume of incubation (pl)fa vitrn ££„, ~ - ) * { -amount of proteins (mg)

[0176] The calculations of Clint (mL / min / kg), Pred Cl (mL / min / kg) and ER (endoplasmic reticulum) were done using the following equations:Clint = (0.693 / T1 / 2) x (1 / (microsomal protein concentration (0.5 mg / mL))) x Scaling Factors (see Table for scaling factors)Clhep = (QH X Clint X fub) / (QH + Clint x fub)ER = Clhep / QH, where QH is the hepatic blood flow (mL / min / kg) (Table 4), fub is the fraction of unbound drug in plasma which is assumed to be 1.Table 4. Scaling factors for intrinsic clearance prediction in mouse, rat, dog, monkey, and human microsomes.LiverMicrosomalWeight per HepaticProtein ScalingSpecies Kilogram of Blood Flowper Gram of Factor3Body (mL / min / kg) LiverWeightHuman 40 25.7 1028 21Monkey 40 30 1200 44Dog 55 32 1760 31Rat 46 40 1840 78Mouse 47 88 4136 126aScaling Factor = (microsomal protein per gram of liver) x (liver weight per kilogram of body weight)Example 20LogD determination of WEE1 inhibitors / degraders in 1-octanol / PBS pH 7.4

[0177] LogD is a distribution coefficient widely used to measure the lipophilicity of ionizable compounds, where the partition is a function of the pH.

[0178] The stock solutions of test compounds and the control compound were prepared in DMSO at the concentration of 10 mM. To prepare sodium phosphatebuffer / octanol, equal amounts of freshly prepared 10 mM sodium phosphate buffer pH 7.4 and octanol were mixed and the two layers were vortexed thoroughly. The two layers were allowed to separate for several days in one glass separatory funnel. The first 5 mL of buffer from the separation funnel was discarded before filling the dispenser. The octanol -saturated of phosphate buffer was in the lower layer; the upper layer was octanol saturated with buffer.

[0179] 5 pL of stock solutions (10 mM) of each sample was placed in order into a 96-well plate. DMSO was added to make a total volume of 50 pL, with the final concentration of each test compound being 1 mM. 10 pL of l mM working solution of each compound was placed in order into their respective vials on the 96-well plate. 500 pL of saturated octanol was added into each vial of the plate, followed by the addition of 500 pL of saturated phosphate buffer. The plate was then sealed and transferred to the Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C, 2,000 rpm for 2 hours. The samples were centrifuged at 4,000 rpm at 25°C for 30 min to separate the phases. 5 pL of the octanol samples was transferred to a new 96-well plate, followed by addition of 495 pL of a mixture of H2O and acetonitrile containing internal standard (1:1) as 100-fold octanol samples. The mixtures were vortexed for 5 min at 1,000 rpm. 50 pL of 100-fold samples were transferred to new 96-well plate, followed by addition of 450 pL of a mixture of H2O and acetonitrile containing internal standard (1:1) as 1,000-fold octanol samples. The samples were vortexed for 5 minutes at 1,000 rpm. 50 pL of the buffer samples were transferred to new 96-well plate, followed by addition of 450 pL of a mixture of H2O and acetonitrile containing internal standard (1: 1) as 10-fold buffer samples. The mixtures were vortexed for 5 min at 1,000 rpm.

[0180] The samples were evaluated by LC-MS / MS analysis. All calculations were carried out using Microsoft Excel. The LogD value of each compound was calculated as follows, with DF = dilution factor:_ ( AREA^ xDF ]LogD Log- - - - I\AREA^ *DF }Example 21CYP inhibition studies with midazolam

[0181] The CYP inhibition was determined by incubation of human liver microsome (HLM) with CYP substrates (for example, midazolam for CYP3A4 isoform) inpresence of test compounds or control compounds. The incubations were carried out in 96-deep well plates. The following volumes were dispensed into each well of an incubation plate: 179 pL of the substrate solution (containing 1 pM substrate) and HLM mixture in phosphate buffer (100 mM, pH 7.4) and 1 pL of each test compound (at the concentrations 0, 20, 60, 200, 600, 2000 and 6000 pM in DMSO) and positive control working solution (ketoconazole at the concentrations 0, 0.0015, 0.005, 0.015, 0.05, 0.15 and 0.5 pM), or the vehicle. The incubation plate was placed into the water bath and pre-warmed at 37°C for 15 minutes before the reactions were started by the addition of 20 pL of 10 mM NADPH solution in phosphate buffer. After the addition of NADPH, the incubation plate was incubated at 37°C for 5 min. The assays were performed in duplicates.

[0182] At the end of the incubation, the reactions were quenched by the addition of 1 volume (200 pL) of cold acetonitrile containing 3% formic acid and internal standards (IS, 250 nM labetalol, 80 nM alprazolam and 300 nM tolbutamide). The plate was centrifuged at 4000 rpm for 30 min. The plate was then placed for 20 min on ice, then centrifuged at 4000 rpm for 30 min again to precipitate protein. 100 pL of the supernatant was transferred to a new plate. Samples were using UPLC / MS / MS. The automatic peak integration areas were checked for all of the samples, including the Analyte Peak Area and Internal Standard Peak Area. The inhibition of each P450 enzyme in human liver microsomes was measured as the percentage decrease in the activity of marker metabolite formation compared to non-inhibited controls (= 100% activity):Area Ratio = Peak Area Analyte / Peak Area Internal Standard Remaining Activity (%) = Area Ratio test compound / Area Ratiovehicie*100%>

[0183] ICso values (compound concentration which produces 50% inhibition) were determined using Excel XLfit 5.3.1.3.Example 22Pharmacokinetic studies of WEE1 inhibitors / degraders in mice, rats, and dogs

[0184] Pharmacokinetic (PK) studies of test compounds and a control compound via oral gavage (PO) and intravenous (IV) administrations in male CD1 mice (6-8 weeks, -20-30 g), male SD rats (6-8 weeks, -200-300 g), and male beagle dogs (1-2.5 years, -8-12 kg) were carried in accordance with the study designs described in Tables 5-7 below:Table 5. PK mice study design for each test and control compound.Dose Level Dose Volume Cone. Administration No. of Group Treatment(mg / kg) (mL / kg) (nig / niL) Route Animals 1 3 5 0.6 IV 3MALE COMPOUND2 10 10 1 PO 3MALETable 6. PK rat study design for each test and control compound.Dose Level Dose Volume Cone. Administration No. of Group Treatment(mg / kg) (mL / kg) (ing / inL) Route Animals 1 3 5 0.6 IV 3MALE COMPOUND2 60 10 6 PO 3MALETable 7. PK dog study design for each test and control compound.Dose Level Dose Volume Cone. Administration No. of Group Treatment(mg / kg) (mL / kg) (nig / niL) Route Animals 1 3 2 1.5 IV 3MALE COMPOUND2 10 5 2 PO 3MALE

[0185] With mice, all animals for IV and PO administration were not fasted prior to dosing. With rats, animals were food fasted overnight prior to dosing and were fed 4 hours after dosing. With dogs, the animals for PO administration were food fasted overnight prior to dosing and will be fed approximately 2 hours after dosing. The animals for IV groups had free access to food and water.

[0186] With all animals, the dose formulations were always freshly prepared on the day of dosing, with the vehicle composition being: DMSO / PEG400 / 30% HP-P-CD in water (5 / 20 / 75) for IV; 25% HP- -CD in 25 mM citrate buffer (pH 3.0) for PO.

[0187] All animals were subject to the following PK schedule. The blood collection sites for the animals were the dorsal metatarsal vein (for mice), jugular vein (for rats), and peripheral veins (for dogs).Table 8. PK schedule for mice, rats, and dogs.Group PK time pointsIV 9 Time points: 5, 15, 30 min, 1, 2, 4, 8, 12 and 24 hrs post dose. PO 8 Time points: 15, 30 min, 1, 2, 4, 8, 12 and 24 hrs post dose.

[0188] Verapamil and dexamethasone are normally used as internal standards. The standard curves were run in duplicates with a minimum of six standards, and a minimum of five standards and the LLOQ should fall within ±20% of the nominal value. The lower limit of quantitation (LLOQ) had a minimum signal to noise ratio of 3. A minimum of duplicate quality controls (QC’s) at three concentrations (low, mid, and high QC) were incorporated into each run with the low QC no more than 3 x LLOQ, the mid QC around the middle of the curve, and the high QC were 80% of the ULOQ for the run. The results of the QC’s provided the basis for accepting or rejecting the run. At least 67% of all QC’s, or four of six should be within 20% of their respective nominal values; 33% of the QC’s fell outside 20% of nominal value. At least 50% of the of the QC’s at the same concentration were within 20% of their respective nominal values. The simplest model that adequately describes the concentration-response relationship was used. Linear or quadratic regressions were also used.

[0189] Concentrations of each test or control compound in the plasma samples were analyzed using an LC-MS / MS method.

[0190] WinNonlin (Phoenix™, version 8.3) or other similar software will be used for pharmacokinetic calculations. The following pharmacokinetic parameters will be calculated, whenever possible, from the plasma concentration versus time data:IV administration: T1 / 2, Co, AUCiast, AUCo-24h, AUCinf, MRTinf, Cl, Vss, Number of Points for Regression.PO administration: T1 / 2, Cmax, Tmax, AUCiast, AUCo-24h, AUCinf, Bioavailability (F).

[0191] The pharmacokinetic data was described using descriptive statistics such as mean, standard deviation.

[0192] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be madewithout departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.

Claims

WHAT TS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein:Ring A is a substituted or unsubstituted Cs- cycloalkyl or a substituted or unsubstituted 5- to 8-membered heterocyclyl;Ring B is a substituted or an unsubstituted 4- to 11-membered heterocyclyl;X is N or -CH;R1is a substituted or an unsubstituted Ci-Ce alkyl;R2is halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;m is 0, 1 or 2;W is absent, -CH2-, or -(CH2)2 -;O, wherein * indicates the point of attachment to Ring B;R3is halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; andn is 0, 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -CH.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted monocyclic Cs-Cs cycloalkyl; a monocyclic C5-Cs cycloalkyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; an unsubstituted monocyclic 5- to 8-membered heterocyclyl; or a monocyclic 5- to 8-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted monocyclic C5-C7 cycloalkyl; a monocyclic C5-C7 cycloalkyl substituted with one or more groups selected from halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted monocyclic 5- to 7-membered heterocyclyl; or a monocyclic 5- to 7-membered heterocyclyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted monocyclic 5- to 7-membered heterocyclyl containing 1 or 2 nitrogen atoms; or a monocyclic 5- to 7-membered heterocyclyl containing 1 or 2 nitrogen atoms and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted cycloheptanyl; a cycloheptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted cyclohexyl; a cyclohexyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted cyclopentanyl; a cyclopentanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted pyrrolidinyl; a pyrrolidinyl substituted with one or more groups selected from F, Cl, -CN, Ci- C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted piperidinyl; a piperidinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted azepanyl; or an azepanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

7. The compound of any one of claims 1 to 4, or a pharmaceuticallyThe compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is an unsubstituted monocyclic 4- to 7-membered heterocyclyl; a monocyclic 4- to 7-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; an unsubstituted spiro 7- to 11-membered heterocyclyl; or a spiro 7- to 11-membered heterocyclyl substituted with one or more groups selected from halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Ring B is an unsubstituted monocyclic 5- or 6-membered heterocyclyl; a monocyclic 5- or 6-membered heterocyclyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted spiro 7- to 9-membered heterocyclyl; or a spiro 7- to 9-membered heterocyclyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring B is an unsubstituted monocyclic 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom; a monocyclic 5-or 6-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted spiro 7- to 9-membered heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 oxygen atom; or a spiro 7- to 9-membered heterocyclylcontaining 1 or 2 nitrogen atoms and optionally 1 oxygen atom and is substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring B is an unsubstituted piperidinyl; a piperidinyl substituted with one or more groups selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted morpholinyl; a morpholinyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted 2-azaspiro[3,3]heptanyl; a 2-azaspiro[3 3]heptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy; an unsubstituted 2,6-diazaspiro[3.3]heptanyl; or a 2,6-diazaspiro[3.3]heptanyl substituted with one or more groups selected from F, Cl, -CN, C1-C2 alkyl, C1-C2 haloalkyl and C1-C2 alkoxy.

13. The compound of any one of claims 1 to 12, or a pharmaceuticallyN5 A acceptable salt thereof, wherein Ring B isN —; wherein * indicates the point of attachment to L andAindicates the point of attachment to W when W is not absent or to Ring A when W is absent.

14. The compound of any one of claims 1 to 13, or pharmaceutically acceptable salt thereof, wherein W is absent or -CH2-.The compound of any one of claims 1 to 14, or pharmaceuticallyacceptable salt thereof, wherein L is-Ill-or; wherein R3is F, -CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0 or 1.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R1is an unsubstituted C1-C4 alkyl or a C1-C4 haloalkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R1is ethyl.

20. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from those of Compound Nos. 1 to 26 as listed in Table 1.

21. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

22. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21 in the manufacture of a medicament for ameliorating or treating a cancer, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer, a stomach cancer, a gallbladder / bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

23. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21 in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer, a stomach cancer, a gallbladder / bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

24. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21 in the manufacture of a medicament for ameliorating or treating a malignant growth or tumor, wherein the malignantgrowth or tumor is due to a cancer selected from a brain cancer, a cervi cocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer, a stomach cancer, a gallbladder / bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

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