Substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones

Abstract

To provide compounds useful for treating diseases or conditions, including conditions characterized by excessive cellular proliferation such as breast cancer.SOLUTION: A compound of Formula (I) or a pharmaceutically acceptable salt thereof, in which R1 is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl; Ring A is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5-6-membered monocyclic heteroaryl; Ring B is selected from the group consisting of substituted or unsubstituted monocyclic 5-7-membered carbocyclyl and substituted or unsubstituted 5-7-membered monocyclic heterocyclyl; and R2 is, for example, a group having an indole ring.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Incorporation by reference of any priority application Any and all applications for which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application, including, for example, U.S. Provisional Application No. 62 / 641,149, filed March 9, 2018, and U.S. Provisional Application No. 62 / 755,163, filed November 2, 2018, are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6.

[0002] This application relates to compounds that are WEE1 inhibitors and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer. [Background technology]

[0003] WEE1 kinase plays a role in arrest at the G2-M cell cycle checkpoint for DNA repair before the onset of mitosis. Normal cells repair damaged DNA during G1 arrest. Cancer cells often lack the G1-S checkpoint and rely on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types. Summary of the Invention

[0004] Some embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0005] Some embodiments disclosed herein relate to pharmaceutical compositions that can include an effective amount of one or more compounds of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0006] Some embodiments described herein relate to methods for ameliorating and / or treating a cancer described herein, which may include administering to a subject having a cancer described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Another embodiment described herein relates to the use of a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., 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. Yet another embodiment described herein relates to a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for ameliorating and / or treating a cancer described herein.

[0007] Some embodiments described herein relate to methods of inhibiting malignant growth or tumor replication, which may include contacting the malignant growth or tumor with an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Another embodiment described herein relates to the preparation of a medicament for inhibiting malignant growth or tumor replication.

[0023] Yet another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a therapeutic agent for treating malignant growth or tumors, wherein the malignant growth or tumor is due to a cancer described herein. Yet another embodiment described herein relates to a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the replication of malignant growth or tumors, wherein the malignant growth or tumor is due to a cancer described herein.

[0008] Some embodiments described herein relate to methods for ameliorating or treating a cancer described herein in a subject having a cancer described herein, which may include contacting the malignant growth or tumor with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., 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, which may include contacting the malignant growth or tumor with a compound described herein, wherein the malignant growth or tumor is due to a cancer described herein. Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described in the present invention, which may include contacting the malignant growth or tumor with the cancer described herein, wherein the malignant growth or tumor is due to a cancer described herein.

[0009] Some embodiments described herein relate to methods of inhibiting the activity of WEE1 in a cell (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in a cell), which may include providing an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a cancer cell derived from a cancer described herein. Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells).

[0010] Some embodiments described herein involve inhibiting the activity of WEE1 (e.g., inhibiting WEE1 activity in TP53 mutant cells) using an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., 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 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described in the present invention by inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). DETAILED DESCRIPTION OF THE INVENTION

[0011] WEE1 is a tyrosine kinase that is a key component of the ATR-mediated G2 cell cycle checkpoint, which blocks the initiation of mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which then activates WEE1, resulting in the selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyr15, thereby stabilizing the CDK1-cyclin B complex and halting cell cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA before the onset of mitosis. Inhibition of WEE1 inhibits the G2 checkpoint, causing cancer cells with DNA damage to enter unscheduled mitosis and undergo cell death by mitotic apoptosis. Therefore, inhibition of WEE1 has the potential to sensitize tumors to DNA-damaging agents such as cisplatin and induce tumor cell death.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as 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 otherwise stated. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0013] Whenever a group is described as being "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are specified, it means that the specified "optionally substituted" or "substituted" 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, amino, monosubstituted amine group, disubstituted amine group, and amine(C1-C6 alkyl).

[0014] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b " refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified, the broadest ranges described by these definitions are intended.

[0015] When two "R" groups are described as being "together," the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic ring. For example, without limitation, NR a R b Group R a and R b When are shown to be "together," it is meant that they are covalently linked to each other to form a ring. [ka]

[0016] 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-chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl, and the like. 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 within the given range; for example, "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 30 carbon atoms; however, this definition also includes the occurrence of the term "alkyl" without a specified numerical range). The alkyl group may also be a medium-sized alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0017] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing carbon double bond(s), including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. Alkenyl groups can be unsubstituted or substituted.

[0018] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing a carbon triple bond(s), including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, etc. Alkynyl groups can be unsubstituted or substituted.

[0019] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). 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 that share one bond with two atoms. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom, where the two rings are connected by a bridge. The cycloalkyl groups are not bonded to each other. 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). Cycloalkyl groups can be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0020] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise the group is an "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 more than one ring, the rings may be connected together in a fused, bridged, or spiro fashion. Cycloalkenyl groups can be unsubstituted or substituted.

[0021] As used herein, "carbocyclyl" refers to a non-aromatic monocyclic or polycyclic 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. A carbocyclyl group 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 can be unsubstituted or substituted. Examples of carbocyclyl groups include, but are in no way limited to, cycloalkyl and cycloalkenyl groups, as defined herein, and the non-aromatic moieties of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0022] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0023] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements 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, a heteroaryl group can have 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), e.g., 9 carbon atoms and 1 heteroatom, 8 carbon atoms and 2 heteroatoms, 7 carbon atoms and 3 heteroatoms, 8 carbon atoms and 1 heteroatom, 7 carbon atoms and 2 heteroatoms, 6 carbon atoms and 3 heteroatoms, 5 carbon atoms and 4 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms. , 3 carbon atoms and 3 heteroatoms, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, or 2 carbon atoms and 3 heteroatoms. Additionally, the term "heteroaryl" includes fused ring systems, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, in which two 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, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0024] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms and one to five heteroatoms together comprise said ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a fully delocalized π-electron system does not occur throughout all rings. Heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of more than one ring, the rings may be fused, bridged, or joined together in a spiro fashion. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which a heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom, and the two rings are not joined by a bridge. Heterocyclyl and heteroalicyclyl 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). For example, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 1 carbon atom and 4 heteroatoms, 3 carbon atoms and 1 heteroatom, or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in the heteroalicyclic ring may be quaternized. The heterocyclyl or heteroalicyclic group may be substituted or unsubstituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopyridine, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, tetrahydro-1,4-thi ... Perazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydropyran. Examples of heterocyclyl groups include, but are not limited to, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl 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.

[0025] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected as a substituent via a lower alkylene group. The lower alkylene and aryl groups of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0026] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.

[0027] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group connected as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0028] As used herein, a "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group is also a cycloalkyl group (e.g., [ka] ) by replacing one or more hydrogens on a lower alkylene group and / or by replacing both hydrogens on the same carbon.

[0029] As used herein, the term "hydroxy" refers to an --OH group.

[0030] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy includes methoxy, ethoxy, n-propoxy, 1-methyleth ... Alkoxy is substituted or unsubstituted, and examples of alkoxy include butoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy.

[0031] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0032] A "cyano" group refers to a "-CN" group.

[0033] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0034] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0035] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B ) group, where R A and RB may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0036] The "N-carbamyl" group is "ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0037] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0038] The "N-thiocarbamyl" group is "ROC(=S)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0039] A "C-amido" group is defined as "-C(=O)N(R A R B ) group, where R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0040] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0041] The "S-sulfonamide" group is defined as "-SO2N(R A R B ) group, where R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0042] The "N-sulfonamide" group is "RSO2N(R A )-" group, where R and R Amay independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0043] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxy can be substituted or unsubstituted.

[0044] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0045] A "nitro" group refers to a "-NO2" group.

[0046] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Sulfenyl can be substituted or unsubstituted.

[0047] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0048] A "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0049] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been 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. Haloalkyl may be substituted or unsubstituted.

[0050] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms has been 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. Haloalkoxy can be substituted or unsubstituted.

[0051] As used herein, the term "amino" refers to the group --NH.sub.2.

[0052] The "monosubstituted amine" group is defined as "-NHR A " group, where R A R may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. Amay be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0053] A "disubstituted amine" group is defined as "-NR A R B " group, where R A and R B R may independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A and R B may be independently substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -N(methyl), -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0054] As used herein, an "amine(alkyl)" group refers to a -(alkylene)-NRR'R" group, where R' and R" are independently hydrogen or alkyl, as defined herein. Amine(alkyl) groups can be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CHNH(methyl), -CHNH(phenyl), -CHCHNH(methyl), -CHCHNH(phenyl), -CHN(methyl), -CHN(phenyl)(methyl), -NCH(ethyl)(methyl), -CHCHN(methyl), -CHCHN(phenyl)(methyl), -NCHCH(ethyl)(methyl), and the like.

[0055] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be 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 1, 2, or 3 atoms.

[0056] As used herein, a radical refers to a species having a single unpaired electron such that the radical-containing species can be covalently bonded to another species. Thus, in this context, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule. The term "radical" may be used interchangeably with the term "group."

[0057] 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 abolish 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 an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical Salts can also be obtained by reacting a compound with an organic acid, for example, an aliphatic or aromatic carboxylic or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. With respect to compounds of formula (I), one skilled in the art will recognize that when a salt is formed by protonation of a nitrogen-based group (e.g., NH), the nitrogen-based group may be associated with a positive charge (e.g., NH becomes NH + ), and the positive charge can be replaced by a negatively charged counterion (Cl- We understand that balance can be achieved by

[0058] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. Additionally, in any compound described herein having one or more double bond(s) that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0059] When the compounds disclosed herein have unsatisfied valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0060] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element 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 as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0061] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. will be done.

[0062] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0063] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring" and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood to imply that a particular feature is critical, essential, or even important to its structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be synonymous 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.

[0064] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for 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 thereof.

[0065] compound Some embodiments disclosed herein relate to compounds of formula (I) having the following structure: [ka] In the formula, R 1 may be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl; ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; ring B may be selected from substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R 2 teeth, [ka] m may be 0, 1, 2, or 3; R 3 may be selected from halogen and substituted or unsubstituted C1-C6 alkyl, and X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6-amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y may be CH or N (nitrogen); Y 1 is CR 4A or N (nitrogen), and Y 2 is CR 4B or N (nitrogen), and ring C may be a substituted or unsubstituted C to C 10 aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R 4A and R 4B are independently hydrogen, halogen, and unsubstituted C 1-4 alkyl, R 5 may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

[0066] Some embodiments disclosed herein relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 may be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl; ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; ring B may be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R 2 teeth, [ka] m may be 0, 1, 2, or 3; R 3may be selected from halogen and substituted or unsubstituted C1-C6 alkyl, and X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6 -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y may be CH or N (nitrogen); Y 1 is CR 4A or N (nitrogen), and Y 2 is CR 4B or N (nitrogen), and ring C may be a substituted or unsubstituted C to C 10 Aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R 4A and R 4B are independently hydrogen, halogen, and unsubstituted C 1-4 It may be selected from alkyl.

[0067] In some embodiments, R 1 may be selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, ring A may be selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring B may be selected from the group consisting of substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl. In some embodiments, R 2 teeth, [ka] In some embodiments, m may be 0, 1, 2, or 3. In some embodiments, R 3 may be selected from the group consisting of halogen and substituted or unsubstituted C1-C6 alkyl. In some embodiments, X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine(C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6 In some embodiments, Y may be selected from the group consisting of substituted or unsubstituted C-amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl. In some embodiments, Y may be CH or N. In some embodiments, Y 1 is CR 4A or N. In some embodiments, Y 2 is CR 4B or N. In some embodiments, ring C is a substituted or unsubstituted C-C 10 In some embodiments, R may be selected from the group consisting of aryl, substituted or unsubstituted monocyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, and substituted or unsubstituted 7-10 membered bicyclic heterocyclyl. 4A and R 4B are independently hydrogen, halogen, and unsubstituted C 1-4 It may be selected from the group consisting of alkyl.

[0068] In some embodiments, R 1 may be selected from hydrogen, halogen, and C1-C6 alkyl. In some embodiments, R 1 may be hydrogen. In other embodiments, R1 may be halogen. In some embodiments, R 1 may be fluoro. In yet other embodiments, R 1 may be an unsubstituted C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (straight or branched chain), or hexyl (straight or branched chain)). In some embodiments, R 1 may be unsubstituted methyl. In some embodiments, R 1 may be a substituted C1-C6 alkyl, such as those described herein. In some embodiments, R 1 may be an unsubstituted C1-C6 haloalkyl (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, R 1 may be -CHF2, -CF3, -CF2CH3, or -CH2CF3.

[0069] In some embodiments, ring A is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5-phenyl. to 6-membered monocyclic heteroaryl.

[0070] In some embodiments, ring A can be substituted phenyl. In other embodiments, ring A can be unsubstituted phenyl.

[0071] In some embodiments, ring A can be a substituted 5-6 membered monocyclic heteroaryl. In some embodiments, ring A can be an unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, ring A can be selected from substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyridazine.

[0072] When substituted, ring A can be substituted with one or more substituents selected from halogen, unsubstituted C1-C4 haloalkyl, and unsubstituted C1-C4 alkyl. In some embodiments, ring A is monosubstituted with halogen (e.g., fluoro).

[0073] In some embodiments, [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments, [ka] is substituted or unsubstituted [ka] In some embodiments, [ka] is substituted or unsubstituted [ka] wherein ring A is unsubstituted. In other embodiments, [ka] is substituted or unsubstituted [ka] Substituted or unsubstituted [ka] and substituted or unsubstituted [ka] As described herein, [ka] The Ring A portion of may be unsubstituted.

[0074] In some embodiments, Ring B may be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

[0075] In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl. In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In other embodiments, ring B can be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In still other embodiments, ring B can be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0076] In some embodiments, [ka] Each of the foregoing groups may be substituted or unsubstituted.

[0077] In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5- to 7-membered heterocyclyl. In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5-membered heterocyclyl. In other embodiments, ring B can be a substituted or unsubstituted monocyclic 6-membered heterocyclyl. In still other embodiments, ring B can be a substituted or unsubstituted monocyclic 7-membered heterocyclyl.

[0078] In some embodiments, [ka] Each of the foregoing groups may be substituted or unsubstituted, including any -NH groups.

[0079] In some embodiments, ring B is [ka] wherein each of the foregoing groups is substituted or unsubstituted, including any -NH group. In some embodiments, Ring B is substituted or unsubstituted [ka] It may be.

[0080] In some embodiments, when ring B is substituted, it can be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-bonded amido (e.g., —NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, when ring B is substituted, it can be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-bonded amido (e.g., —NHC(O)C1-C6 alkyl), and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring B is substituted with fluoro, hydroxy, amino, unsubstituted —NHC(O)C1-C6 alkyl. In some embodiments, Ring B can be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy-CF, -CHF, -CFCH, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH.

[0081] In some embodiments, [ka] Each of the foregoing groups may be substituted or unsubstituted, including any -NH groups.

[0082] In some embodiments, [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments, [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments, [ka] is substituted or unsubstituted [ka] In some embodiments, [ka] may be substituted, or [ka] It may be.

[0083] Both Ring A and Ring B can be substituted or unsubstituted. In some embodiments, [ka] Ring A and ring B of the formula (I) may be independently substituted or unsubstituted. [ka] Ring A and ring B of the formula (I) may both be unsubstituted. In some embodiments, [ka] Ring A and ring B of the formula (I) may both be independently substituted. In some embodiments, [ka] wherein ring A is optionally substituted; [ka] Ring B of the formula (I) may be unsubstituted. In some embodiments, [ka] Ring A may be unsubstituted; [ka] Ring B of the formula (I) may be substituted. In some embodiments, [ka] Ring A may be unsubstituted; [ka] Ring B of the formula (I) may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, and substituted or unsubstituted C1-C6 alkyl (such as those described herein). [ka] Ring A may be unsubstituted; [ka] Ring B of can be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted N-linked amido (e.g., —NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, [ka] Ring A may be unsubstituted; [ka] Ring B may be substituted with one or two substituents independently selected from fluoro, hydroxy, amino, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0084] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It may be.

[0085] In some embodiments, Y can be CH or N (nitrogen). In some embodiments, Y can be CH. In some embodiments, Y can be N (nitrogen).

[0086] In some embodiments, R 3 may be selected from halogen and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3 may be halogen. In some embodiments, R 3 may be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3 can be an unsubstituted C1-C6 alkyl (such as those described herein).

[0087] In some embodiments, m can be 0, 1, 2, or 3. In some embodiments, m can be 0. In some embodiments, m can be 1. In some embodiments, m can be 2. In some embodiments, m can be 3. m is 2 or 3, R 3 The groups may be the same or different from one another.

[0088] In some embodiments, X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6-amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy (straight or branched chain), or hexoxy (straight or branched chain)), substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy), substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl.

[0089] In some embodiments, X can be hydrogen. In other embodiments, X can be halogen. In some embodiments, X can be fluoro. In some embodiments, X can be chloro. In still other embodiments, X can be hydroxy. In still yet other embodiments, X can be cyano. In some embodiments, X can be amino.

[0090] In some embodiments, X can be an unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, X can be unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In some embodiments, X can be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, X can be an unsubstituted C1-C6 haloalkyl (such as a C1-C6 fluoroalkyl, a C1-C6 chloroalkyl, or a C1-C6 chlorofluoroalkyl). In some embodiments, X can be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, X can be an unsubstituted C1-C6 hydroxyalkyl (such as a C1-C6 monohydroxyalkyl or a C1-C6 dihydroxyalkyl). In some embodiments, X can be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3). In some embodiments, X can be an unsubstituted C1-C6 cyanoalkyl (such as a C1-C6 monocyanoalkyl or a C1-C6 dicyanoalkyl). [ka] In some embodiments, X may be selected from: In some embodiments, X may be an unsubstituted C1-C6 alkoxyalkyl (such as a C1-C6 monoalkoxyalkyl or a C1-C6 dialkoxyalkyl). In some embodiments, X may be selected from: [ka] In some embodiments, X may be selected from: [ka] It may be a substituted C1-C6 alkyl selected from:

[0091] In some embodiments, X can be an unsubstituted C1-C6 alkoxy (such as those described herein). In some embodiments, X can be an unsubstituted methoxy, unsubstituted ethoxy, or unsubstituted isopropoxy. In some embodiments, X can be a substituted C1-C6 alkoxy (such as those described herein). In some embodiments, X can be a C1-C6 alkoxy substituted with one, two, or three substituents independently selected from halogen, amino, a monosubstituted amine (such as those described herein), and a disubstituted amine (such as those described herein). In some embodiments, X can be a C1-C6 alkoxy substituted with one substituent selected from halogen, amino, a monosubstituted amine (such as those described herein), and a disubstituted amine (such as those described herein).

[0092] In some embodiments, X is [ka] You may choose from.

[0093] In some embodiments, X can be a substituted C3-C6 cycloalkoxy (such as those described herein). In some embodiments, X can be an unsubstituted C3-C6 cycloalkoxy (such as those described herein).

[0094] In some embodiments, X can be substituted (C1-C6 alkyl) acyl, such as substituted -(CO)-CH3. In some embodiments, X can be unsubstituted (C1-C6 alkyl) acyl, such as unsubstituted -(CO)-CH3.

[0095] In some embodiments, X can be a substituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be an unsubstituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be selected from azetidine, oxetane, diazetidine, azaoxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, and dioxane, each of the foregoing groups being substituted or unsubstituted, including any -NH group. (blank space). In some embodiments, X can be [ka] Each of the foregoing groups may be substituted or unsubstituted, including any -NH groups.

[0096] In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl (such as those described herein) substituted with one or two substituents independently selected from halogen, substituted or unsubstituted C1-C6 alkyl (such as those described herein), monosubstituted amine (such as those described herein), disubstituted amine (such as those described herein), amino, substituted or unsubstituted amine(C1-C6 alkyl), and substituted or unsubstituted (C1-C6 alkyl)acyl. In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl substituted with one or two substituents independently selected from fluoro, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, -CH2OH, and -N(CH3)2. In some embodiments, X can be [ka] You may choose from.

[0097] In some embodiments, X can be a substituted amine(C1-C6 alkyl). In some embodiments, X can be an unsubstituted amine(C1-C6 alkyl). In some embodiments, X can be [ka] Each of the above groups may be substituted or unsubstituted, including any -NH group. (blank space).

[0098] In some embodiments, X is a substituted -NH-(CH) 1-6 In some embodiments, X is an unsubstituted —NH—(CH) 1-6 In some embodiments, X may be an amine. [ka] Each of the foregoing groups may be substituted or unsubstituted, including any -NH groups.

[0099] In some embodiments, X can be a monosubstituted amine. In some embodiments, the substituent of the monosubstituted amine is an unsubstituted C1-C6 alkyl (such as those described herein) or an unsubstituted C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0100] In some embodiments, X can be a disubstituted amine, in which the two substituents of the disubstituted amine are independently selected from unsubstituted C1-C6 alkyl (such as those described herein) and unsubstituted C3-C6 cycloalkyl (such as those described herein).

[0101] In some embodiments, X is [ka] You may choose from.

[0102] In some embodiments, X may be substituted or unsubstituted C-amido. In some embodiments, X may be substituted or unsubstituted N-amido. In some embodiments, X may be substituted or unsubstituted C-carboxy. In some embodiments, X may be substituted or unsubstituted O-carboxy. In some embodiments, X may be substituted or unsubstituted O-carbamyl. In some embodiments, X may be substituted or unsubstituted N-carbamyl. In some embodiments, X may be monosubstituted with unsubstituted C1-C6 hydroxyalkoxy (such as those described herein).

[0103] In some embodiments, Y 1 is CR 4A or N (nitrogen). In some embodiments, Y 1 is CR 4A In some embodiments, Y 1 may be N (nitrogen).

[0104] In some embodiments, Y 2 is CR 4B or N (nitrogen). In some embodiments, Y 2 is CR 4B In some embodiments, Y 2 may be N (nitrogen).

[0105] In some embodiments, Y 1 and Y 2 may each be N (nitrogen). In some embodiments, Y 1 is CR 4A and Y 2 is CR 4B In some embodiments, Y 1 is CR 4A and Y 2 may be N (nitrogen). In some embodiments, Y 1 may be N (nitrogen), and Y 2 is CR 4B It may be.

[0106] In some embodiments, R 4A may be hydrogen. In some embodiments, R 4A may be halogen. In some embodiments, R 4A is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0107] In some embodiments, R 4B may be hydrogen. In some embodiments, R 4B may be halogen. In some embodiments, R 4B is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0108] In some embodiments, R 4A and R 4B and R may each be hydrogen. 4A and R 4B may each be a halogen (wherein (The groups may be the same or different from each other.) In some embodiments, R 4A and R 4B are unsubstituted C 1~4 Alkyl (such as those described herein, where C 1~4 In some embodiments, R 4A and R 4B may be hydrogen, and R 4A and R 4B The other of R may be halogen. 4A and R 4B may be hydrogen, and R 4A and R 4B The other is unsubstituted C 1~4 In some embodiments, R 4A and R 4B One of R may be halogen;4A and R 4B The other is unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0109] In some embodiments, R 2 teeth [ka] For example, R 2 teeth, [ka] R 2 but [ka] In some embodiments, when 5 may be a substituted 5- to 7-membered monocyclic heterocyclyl. 5 R may be an unsubstituted 5- to 7-membered monocyclic heterocyclyl. 5 Exemplary groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azepanyl. When substituted, R 5 The substituents that can be introduced include unsubstituted C 1~4 Alkyl, halogen, hydroxy, and unsubstituted C 1~4 Haloalkyl is an example.

[0110] In some embodiments, ring C is a substituted or unsubstituted C-C 10 It may be selected from aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl.

[0111] In some embodiments, ring C is a substituted C-C 10In some embodiments, ring C is an unsubstituted C-C aryl. 10 In some embodiments, ring C may be substituted C aryl. In some embodiments, ring C may be unsubstituted C aryl.

[0112] In some embodiments, ring C can be a substituted 5-10 membered heteroaryl. In some embodiments, ring C can be an unsubstituted 5-10 membered heteroaryl. In some embodiments, ring C can be a substituted 5-6 membered heteroaryl. In some embodiments, ring C can be an unsubstituted 5-6 membered heteroaryl. In some embodiments, ring C can be selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, benzimidazole, indole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, quinoline, isoquinoline, quinazoline, and quinoxaline, each of the foregoing groups being substituted or unsubstituted, including an optional -NH group.

[0113] In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0114] In some embodiments, Ring C can be Ring C and can be a substituted or unsubstituted 5-membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 6-membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 7-membered monocyclic heterocyclyl. In some embodiments, Ring C can be selected from imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, tetrahydropyran, azepine, oxepine, and diazepine, each of the foregoing groups being substituted or unsubstituted, including any -NH group.

[0115] In some embodiments, Ring C can be a substituted or unsubstituted 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be selected from pyrrolizidine, indoline, 1,2,3,4 tetrahydroquinoline, 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, each of the foregoing groups being substituted or unsubstituted, including any -NH group.

[0116] In some embodiments, Ring C can be substituted with one or more substituents independently selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl. In some embodiments, Ring C can be substituted with one substituent selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl.

[0117] In some embodiments, R 2 teeth, [ka] and each of the foregoing groups may be substituted or unsubstituted.

[0118] Examples of compounds of formula (I) include: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the above.

[0119] synthesis The compounds of formula (I) or pharmaceutically acceptable salts thereof can be made in a variety of ways by those skilled in the art using known techniques guided by the detailed teachings provided herein. For example, in embodiments, compounds of formula (I) are prepared according to general Scheme 1 shown herein.

[0120] Generally, the coupling reaction between compounds of general formula A and B to form compounds of formula (I) shown in General Scheme 1 can be carried out in a similar manner to the reactions described in the Examples herein, with appropriate adjustment of the reagents and conditions described in the Examples. Any pre-reaction steps required to form starting compounds or other precursors of general formula A and B can be carried out by one skilled in the art. In General Scheme 1, ring A, ring B, R 1 , and R 2 may be as described herein. [ka]

[0121] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0122] 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. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored for a specific intended route of administration.

[0123] The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not neutralize the biological activity and properties of the compound or cause substantial damage or injury to the animal to which the composition is intended to be delivered.

[0124] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0125] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no appreciable pharmacological activity, but that may be pharmaceutically necessary or desirable. For example, a diluent may be useful in manufacturing and / or It may be used to increase the bulk of potent drugs whose mass is too small for administration. It may also be a liquid for dissolving drugs to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0126] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0127] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions in which the pharmaceutical composition is mixed with other active ingredients as a combination therapy, or with a carrier, diluent, excipient, or combination thereof. The appropriate formulation will depend on the route of administration selected. Techniques for formulating and administering the compounds described herein are known to those skilled in the art.

[0128] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. In addition, the active ingredient is 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.

[0129] Multiple techniques of administering compounds, salts, and / or compositions exist in the art, including, but not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.

[0130] The compounds, salts, and / or compositions may also be administered locally rather than systemically, for example, by directly injecting or implanting the compound into the affected area, often in a depot or sustained-release formulation. Furthermore, the compounds may be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. Liposomes are selectively targeted and taken up by organs. For example, intranasal or intrapulmonary delivery may be desirable to target respiratory diseases or conditions.

[0131] 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 have a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of drugs, which notice reflects the agency's approval of the drug form for human or animal administration. Such notice may, for example, be the label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the compounds and / or salts described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0132] Uses and Treatment Methods Some embodiments described herein may comprise administering to a subject an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or an effective amount of a compound described herein. The present invention relates to a method for ameliorating and / or treating a cancer described herein, which can include administering a pharmaceutical composition comprising a compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., 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. Yet another embodiment described herein relates to a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for ameliorating and / or treating a cancer described herein.

[0133] Some embodiments described herein relate to methods of inhibiting malignant growth or tumor replication, which may include contacting the malignant growth or tumor with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting malignant growth or tumor replication, wherein the malignant growth or tumor is due to a cancer described herein. Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting malignant growth or tumor replication, wherein the malignant growth or tumor is due to a cancer described herein.

[0134] Some embodiments described herein relate to methods for ameliorating or treating a cancer described herein in a subject having a cancer described herein, which may include contacting the malignant growth or tumor with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating cancer, which may include contacting the malignant growth or tumor with a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating cancer, which may include contacting the malignant growth or tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0135] Some embodiments described herein relate to methods of inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to cancer cells derived from a cancer described herein. Another embodiment described herein relates to methods of inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells, which may include providing an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to cancer cells derived from a cancer described herein. The present invention relates to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Yet another embodiment described herein relates to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Some embodiments described herein relate to methods of inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to cancer cells derived from a cancer described herein.Another embodiment described herein relates to a method of inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include inhibiting the activity of WEE1 by contacting cancer cells derived from a cancer described herein with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof).

[0136] Some embodiments described herein relate to methods of ameliorating or treating cancer as described herein, which may include inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells) using an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Another embodiment described herein relates to the use of an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described in the present invention by inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Still other embodiments described herein relate to pharmaceutical compositions comprising an effective amount of a compound described herein (e.g., 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 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Some embodiments described herein relate to pharmaceutical compositions comprising an effective amount of a compound described herein (e.g., 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 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Some embodiments described herein relate to pharmaceutical compositions comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). and / or a compound that inhibits the activity of WEE1 (e.g., inhibits the activity of WEE1 in TP53 mutant cells, inhibits the activity of WEE1 in TP53 wild-type cells, inhibits the activity of WEE1 in p53-deficient cells, and / or reduces the overexpression of WEE1 in the cells).

[0137] Some embodiments disclosed herein relate to methods of inhibiting the activity of WEE1, which may include providing an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein, or cancer cells derived from a cancer described herein. Another embodiment disclosed herein relates to the use of an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1. Yet another embodiment disclosed herein relates to a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1.

[0138] Examples of suitable cancers include, but are not limited to, brain cancer, brain and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), stomach cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0139] As described herein, cancers may become resistant to one or more anti-cancer agents. In some embodiments, a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and / or ameliorate cancers that have become resistant to one or more anti-cancer agents (e.g., one or more WEE1 inhibitors). Examples of anti-cancer agents to which a subject may become resistant include, but are not limited to, WEE1 inhibitors (e.g., AZD1775). In some embodiments, the cancer that has become resistant to one or more anti-cancer agents may be a cancer described herein.

[0140] Some known WEE1 inhibitors may cause one or more undesirable side effects in treated subjects. Examples of undesirable side effects include, but are not limited to, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, nausea, abdominal pain, and constipation. In some embodiments, the compounds described herein (e.g., compounds of Formula (I) or pharmaceutically acceptable salts thereof) can reduce the number and / or severity of one or more side effects associated with known WEE1 inhibitors. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may result in a severity of a side effect (such as one of those described herein) that is 25% less severe than the severity of the same side effect experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775, formally known as MK1775 (CAS Number: 955365-80-7, 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). ... A pharmaceutically acceptable salt of the compound of formula (I) may result in a number of side effects that is 25% or less compared to the number of side effects experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects (such as one of those described herein) that are about 10% to about 30% less severe compared to the severity of the same side effect experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is about 10% to about 30% less severe compared to the number of side effects experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775).

[0141] One or more compounds of formula (I), or pharmaceutically acceptable salts thereof, that can be used to treat, ameliorate, and / or inhibit the growth of cancers in which inhibition of WEE1 activity is beneficial, are provided in any of the embodiments described in paragraphs

[0064] to

[0112] under the heading "Compounds."

[0142] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0143] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily imply a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Furthermore, treatment may include actions that may worsen a subject's overall sense of health or appearance.

[0144] The terms "therapeutically effective amount" and "effective amount" are used to refer to an amount of an active compound or agent that elicits the indicated biological or medical response. For example, a therapeutically effective amount of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to 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. Determining an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The therapeutically effective amount of a compound disclosed herein required as a dose will depend on the route of administration, the type of animal, such as a human, being treated, and the physical characteristics of the particular animal under consideration. Dosage may be tailored to achieve the desired effect, depending on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical field would recognize.

[0145] For example, an effective amount of a compound or radiation is an amount that results in (a) relief, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) tumor elimination, and / or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (e.g., non-small cell lung cancer), a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and / or pain. As another example, an effective amount, or therapeutically effective amount, of a WEE1 inhibitor is an amount that results in reduced WEE1 activity and / or phosphorylation (e.g., CDC2 phosphorylation). Reductions in WEE1 activity are known to those skilled in the art and can be determined by analyzing WEE1 endogenous kinase activity and phosphorylation of downstream substrates.

[0146] The amount of the compound of formula (I) or its pharmaceutically acceptable salt required for therapeutic use 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 is ultimately at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges set forth herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.

[0147] In general, however, suitable doses are often within the range of about 0.05 mg / kg to about 10 mg / kg. For example, suitable doses may be within the range of about 0.10 mg / kg to about 7.5 mg / kg of body weight per day, e.g., about 0.15 mg / kg to about 5.0 mg / kg of the recipient's body weight per day, about 0.2 mg / kg to 4.0 mg / kg of the recipient's body weight per day, or any amount therebetween. The compound may be administered in unit dosage form, e.g., containing 1 to 500 mg, 10 to 100 mg, or 5 to 50 mg of active ingredient per unit dosage form, or any amount therebetween.

[0148] 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, for example, into a number of discrete loosely spaced administrations.

[0149] As will be readily apparent to those skilled in the art, useful in vivo dosages and specific administration methods will vary depending on the age, weight, severity of the affliction, and mammalian species being treated, the specific compound used, and the specific application for which these compounds are being used. Determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of compounds 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 comparisons can be made by comparison with established drugs such as cisplatin and / or gemcitabine.

[0150] The dosage and interval should be determined based on the modulating effect or minimal effective concentration. The dose may be individually adjusted to provide plasma levels of the active moiety sufficient to maintain the MEC (Meaning of the Endocrine Negative Concentration [MEC]). The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0151] It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary depending on the severity of the disease or condition to be treated and the route of administration. The severity of the disease or condition may, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps the number of doses will also vary depending on the age, weight, and response of the individual patient. Similar to those discussed above The program may be used in veterinary medicine.

[0152] The 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 subset of compounds sharing a particular chemical moiety can be established by determining in vitro toxicity on cell lines, such as mammalian, and preferably human, cell lines. The results of such studies often predict toxicity in animals, such as mammals, or particularly humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, dog, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, those skilled in the art can be guided by the state of the art to select the appropriate model, dose, route of administration, and / or regimen. [Example]

[0153] Further embodiments are disclosed in more detail in the following examples, which in no way limit the scope of the claims.

[0154] Intermediate 1 2-Allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 1 was prepared according to the procedure described by Matheson et al., ACS Chem. Biol. (2016) 11:2066-2067. MS (LCMS) 223.0 [M+H] + .

[0155] Intermediate 2 2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] Step 1. A mixture of propiolamide (62 g, 898.55 mmol), ethyl 2-oxocyclopentanecarboxylate (140.35 g, 898.55 mmol), and Na2CO3 (94.3 g, 898.55 mmol) in water (2.25 L) was stirred at room temperature for 18 hours. The mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give ethyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentanecarboxylate (40 g, 20%) as an off-white solid. MS (LCMS) 226.3 [M+H] + .

[0156] Step 2. A solution of ethyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentanecarboxylate (39 g, 173.33 mmol) in concentrated HCl (390 mL) was stirred in a sealed tube at 110 °C for 18 h. The solvent was removed and aqueous NaHCO3 was added to adjust the pH to 8-9 at 0 °C. The resulting solid was filtered. Washing with EtO (2 x 100 mL) gave 6,7-dihydro-1H-cyclopenta[b]pyridin-2(5H)-one (15 g, 64% yield) as an off-white solid. MS (LCMS) 135.9 [M+H] + .

[0157] Step 3. A solution of 6,7-dihydro-1H-cyclopenta[b]pyridin-2(5H)-one (18 g, 133.33 mmol) in PBr (180 mL) was heated at 180 °C for 18 h. The reaction was then allowed to cool to room temperature and poured into ice-cold water. The pH was adjusted to 8-9 with saturated NaHCO. The resulting solution was filtered through a pad of Celite. The filtrate was extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (NaSO) and concentrated to give 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (7 g, 26%) as an off-white solid. MS (LCMS) 197.8 [M+H] + .

[0158] Step 4. To a stirred solution of 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (4 g, 20.41 mmol) in DCM (120 mL) was added m-CPBA (10.5 g, 61.22 mmol). The mixture was heated at reflux for 16 h, quenched with saturated NaHCO3, and extracted with 5% MeOH / DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (3.3 g, 76% yield) as an off-white solid. MS (LCMS) 213.8 [M+H] + .

[0159] Step 5. A solution of 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-1-oxide (3.2 g, 15.09 mmol) in AcO (30 mL) was heated at 100 °C for 16 h. The AcO was removed under reduced pressure. The residue was purified by flash chromatography (SiO, 7% EtOAc / petroleum ether) to give 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (2 g, 52%) as an oil. MS (LCMS) 255.9 [M+H] + .

[0160] Step 6. To a stirred solution of 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (2 g, 7.84 mmol) in THF / HO (20 mL, 1:1) was added LiOH·HO (0.755 g, 31.49 mmol) at room temperature. The reaction was stirred for 3 h, then diluted with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried (NaSO) and concentrated. The residue was purified by flash chromatography (SiO, 40% EtOAc / petroleum ether) to give Intermediate 2 (1.2 g, 71%) as a brown solid. MS (LCMS) 214.1 [M+H] + .

[0161] Intermediate 3 2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one [ka] Intermediate 1 (450 mg, 2.02 mmol) in 1,4-dioxane (30 mL), To a solution of intermediate 2 (558 mg, 2.62 mmol), CuI (384 mg, 2.02 mmol), and KCO (390 mg, 2.83 mmol) was added N,N'-dimethylethylenediamine (0.43 mL, 4.02 mmol) at 80 °C. The suspension was heated at 95 °C for 18 h. The mixture was cooled to room temperature, diluted with aqueous NHOH (30 mL), and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried (NaSO), and evaporated to dryness. The residue was purified by flash chromatography (SiO, 40% EtOAc / petroleum ether) to give intermediate 3 (280 mg, 38%) as a pale yellow oil. MS (ESI) 356.4 [M+H] + .

[0162] Example 1A (S)-2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 1B (R)-2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] To a solution of Intermediate 3 (280 mg, 0.79 mmol) in toluene (20 mL) was added m-CPBA (201 mg, 1.17 mmol), and the mixture was stirred at room temperature for 1 hour. DIPEA (0.69 mL, 3.94 mmol) and 4-(4-methylpiperidin-1-yl)aniline (178 mg, 0.93 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Saturated NaHCO (25 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried (NaSO), and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / water) to give racemic 2-allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (87 mg, 30% yield) as a yellow solid. The enantiomers were separated by SFC chromatography (Chiralpak AD-H, 40% (0.5% DEA in ethanol)) to give peak 1 (Example 1A, 19 mg) and peak 2 (Example 1B, 25 mg). Example 1A :Yellow solid; 1H NMR(DMSO-d6,400MHz)δ 10.08(brs,1H),8.81(s,1H),7.93(d,J=8.0Hz,1H),7.66(d,J=8.4Hz,1H),7.60 -7.53(m,2H),6.90(d,J=8.8Hz,2H),5.73-5.62(m,1H),5.57-5.39(m,1H),5.04- 4.86(m,3H),4.68-4.52(m,2H),3.13-3.06(m,4H),3.05-2.94(m,1H),2.86-2.75 (m,1H),2.47-2.37(m,5H),2.22(s,3H),1.92-1.83(m,1H);MS(LCMS)499.3[M+H] + Example 1B: Yellow solid; 1 H NMR(DMSO-d6,400MHz)δ 10.05(brs,1H),8.80(s,1H),7.93(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.60 -7.53(m,2H),6.90(d,J=8.8Hz,2H),5.73-5.62(m,1H),5.57-5.39(m,1H),5.04- 4.86(m,3H),4.68-4.52(m,2H),3.13-3.06(m,4H),3.05-2.94(m,1H),2.86-2.75 (m,1H),2.47-2.37(m,5H),2.22(s,3H),1.91-1.83(m,1H);MS(LCMS)499.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 1A and 1B.

[0163] Intermediate 4 2-Bromo-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] Step 1. To a stirred solution of racemic 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (1.4 g, 6.60 mmol) in DCM (15 mL) was added Dess-Martin periodinane (3.0 g, 7.26 mmol). The mixture was stirred at room temperature for 16 h, quenched with saturated NaHCO3 solution, and extracted with DCM (2 x 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 40% EtOAc / petroleum ether) to give 2-bromo-5H-cyclopenta[b]pyridin-7(6H)-one (780 mg, 60%) as an off-white solid. MS (LCMS) 212.0 [M+H] + .

[0164] Step 2. To a stirred solution of 2-bromo-5H-cyclopenta[b]pyridin-7(6H)-one (400 mg, 1.90 mmol) in THF (10 mL) at 0 °C was added methylmagnesium iodide (2 M THF, 7.5 mL). The reaction was stirred from 0 °C to room temperature for 16 h, quenched with saturated aqueous NH4Cl, and extracted with EtOAc (2 x 40 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, 30% EtOAc / petroleum ether) to give Intermediate 4 (200 mg, 46%) as an off-white solid. MS (LCMS) 227.9 [M+H] + .

[0165] Intermediate 5 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 5 was prepared using Intermediate 1 and Intermediate 4 according to the procedure described for Intermediate 3. MS (LCMS) 370.1 [M+H] + .

[0166] Example 2A (S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 2B (R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] To a stirred solution of Intermediate 5 (330 mg, 0.89 mmol) in THF / HO (20 mL, 1:1) was added Oxone (673 mg, 2.68 mmol), and the mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure to give a mixture of sulfoxide and sulfone (330 mg, 0.822 mmol) as a semi-solid. To the mixture of sulfoxide and sulfone (330 mg, 0.82 mmol) in toluene (10 mL) was added DIPEA (0.43 mL, 2.46 mmol), followed by 4-(4-methylpiperazin-1-yl)aniline (188 mg, 0.99 mmol), and the reaction was stirred at room temperature for 16 h. The mixture was stirred for 1 hour. The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure, and the residue was purified by flash chromatography (neutral alumina, 5% methanol / DCM) to give racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (260 mg) as an off-white solid. The enantiomers were separated by SFC chromatography (Chiralpak AD-H, 15% (15 mM ammonia in methanol)) to give peak 1 (Example 2A, 105 mg) and peak 2 (Example 2B, 96 mg). Example 2A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.81(s,1H),7.92(d,J=6.8Hz,1H),7.68(d,J=8.0Hz,1H),7.62-7.55(m,2H ),6.91(d,J=9.2Hz,2H),5.71-5.63(m,1H),5.17(s,1H),4.99(d,J=9.6Hz,1H),4.86(d,J =17.2Hz,1H),4.79-4.55(m,2H),3.12-3.07(m,4H),3.02-2.91(m,1H),2.85-2.72(m,1H) ,2.47-2.42(m,4H),2.22(s,3H),2.12(t,J=7.2Hz,2H),1.45(s,3H);MS(LCMS)513.4[M+H] + Example 2B: as a yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.82(s,1H),7.97-7.89(m,1H),7.68(d,J=8.4Hz,1H),7.62-7.55(m,2H),6.91(d,J=9.6Hz,2H),5.71-5.63(m,1H),5.17(br s,1H),4.98(d,J=9.6Hz,1H),4.85(d,J=16.4Hz,1H),4.79-4.55(m,2H),3.12-3.07(m,4H),3.02-2.91(m,1H) ,2.85-2.72(m,1H),2.47-2.42(m,4H),2.22(s,3H),2.12(t,J=7.2Hz,2H),1.45(s,3H);MS(LCMS)513.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 2A and 2B.

[0167] Intermediate 6 2-Bromo-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] To a stirred solution of 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1.5 g, 7.08 mmol) in THF (20 mL) was added TMSCF (3.2 mL, 21.23 mmol) followed by TBAF (1 M in THF) (0.7 mL, 0.71 mmol) at 0 °C. The reaction was stirred from 0 °C to room temperature for 12 h, quenched with 6 N HCl, and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried (Na SO ) and concentrated. The residue was purified by flash chromatography (SiO , 30% EtOAc / petroleum ether) to give intermediate 6 (825 mg, 41%) as a brown solid. MS (LCMS) 281.9 [M+H] + .

[0168] Intermediate 7 2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 7 was prepared using Intermediate 1 and Intermediate 6 according to the procedure described for Intermediate 3. MS (LCMS) 424.3 [M+H] + .

[0169] Example 3A (S)-2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 3B (R)-2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 3A and 3B were prepared using Intermediate 7 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (330 mg). The enantiomers were separated by SFC chromatography (Chiralpak AD-H, 40% (15 mM ammonia in methanol)) to give Peak 1 (Example 3A, 126 mg) and Peak 2 (Example 3B, 150 mg). Example 3A: Yellow solid; 1 H NMR (400 MHz,DMSO-d6)δ 10.20(s,1H),8.84(s,1H),8.07(br s,1H),7.92(d,J=8.0Hz,1H),7.65-7.58(m,2H),6.94(d,J=8.8Hz,2H),6.79(s,1H),5.68-5.60(m,1H),4.96(d,J=10.0Hz,1H), 4.79(d,J=16.4Hz,2H),4.61-4.53(m,1H),3.14-3.02(m,5H),3.00-2.90(m,1H),2.61-2.60(m,1H),2.49-2.44(m,4H),2.22(br s, 4H); MS (LCMS) 567.5 [M+H] + Example 3B: Yellow solid; 1 HNMR(400MHz,DMSO-d6)δ 10.20(s,1H),8.84(s,1H),8.07(br s,1H),7.92(d,J=8.0Hz,1H),7.65-7.58(m,2H),6.94(d,J=8.8Hz,2H),6.79(s,1H),5.70-5.60(m,1H),4.96(d,J=10.0Hz,1H), 4.79(d,J=16.4Hz,2H),4.61-4.53(m,1H),3.16-3.02(m,5H),3.00-2.90(m,1H),2.61-2.56(m,1H),2.49-2.44(m,4H),2.25(br s, 4H); MS (LCMS) 567.6 [M+H] +Absolute stereochemistry has been arbitrarily assigned to Examples 3A and 3B.

[0170] Intermediate 8 5-Bromo-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-ol [ka] Step 1. Prepare 2,3-dihydrofuro[3,2-b]pyridin-5-amine according to WO 2008 / 069311. MS (LCMS) 137.1 [M+H] + .

[0171] Step 2. To a stirred solution of 2,3-dihydrofuro[3,2-b]pyridin-5-amine (9.0 g, 66.17 mmol) in CH2Br2 (200 mL) was added CuBr2 (7.303 g, 33.08 mmol), followed by the dropwise addition of isoamyl nitrite (8.515 g, 72.78 mmol). The reaction was stirred at room temperature for 2 h, quenched with saturated aqueous NaHCO3 (50 mL), and filtered through a Celite pad. The filtrate was extracted with DCM (3 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc / petroleum ether) to afford 5-bromo-2,3-dihydrofuro[3,2-b]pyridine (6.0 g, 45%) as a brown solid. MS (ESI) 200.2 [M+H] + .

[0172] Step 3. To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2-b]pyridine (6.0 g, 30.15 mmol) in DCM (100 mL) was added m-CPBA (6.27 g, 36.18 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with n-pentane and dried to give crude 5-bromo-2,3-dihydrofuro[3,2-b]pyridine 4-oxide (9.5 g) as an off-white solid. MS (ESI) 216.2 [M+H] +Acetic anhydride (100 mL) was added to 5-bromo-2,3-dihydrofuro[3,2-b]pyridine 4-oxide (9.5 g, 44.18 mmol) and heated at 90 °C for 1 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with saturated aqueous NaHCO (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, EtOAc / petroleum ether). Purification by HPLC (ethyl ether) gave 5-bromo-2,3-dihydrofuro[3,2-b]pyridin-3-yl acetate (5.0 g, 65%) as a brown solid. MS (ESI) 258.2 [M+H] + .

[0173] Step 4. To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2-b]pyridin-3-yl acetate (5.0 g, 19.45 mmol) in THF / HO (1:1, 30 mL), LiOH·HO (2.45 g, 58.35 mmol) was added and stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to give 5-bromo-2,3-dihydrofuro[3,2-b]pyridin-3-ol (2.5 g, 59%) as an off-white solid. MS (ESI) 216.1 [M+H] + .

[0174] Step 5. To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2-b]pyridin-3-ol (2.6 g, 12.09 mmol) in acetone (30 mL) was added freshly prepared Jones reagent (25 mL, CrO (3 equiv.) and aqueous HSO (3 equiv.) at 0 °C, and the reaction was stirred at 0 °C for 30 min. The reaction was diluted with EtOAc (60 mL) and washed with ice-cold water (50 mL) and brine (50 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to give 5-bromofuro[3,2-b]pyridin-3(2H)-one (1.2 g, 46% yield) as a brown solid. MS (ESI) 214.4 [M+H]+ .

[0175] Step 6. To a solution of 5-bromofuro[3,2-b]pyridin-3(2H)-one (1.1 g, 5.16 mmol) in EtO (15 mL) at 0 °C, methylmagnesium iodide (8.6 mL, 3.0 M in EtO, 25.80 mmol) was added. The reaction was stirred at 0 °C for 1 h, quenched with aqueous NHCl (30 mL), and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 30% EtOAc / petroleum ether) to give intermediate 8 (510 mg, 43% yield) as a brown solid. MS (ESI) 230.3 [M+H] + .

[0176] Intermediate 9 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 9 was prepared using Intermediate 1 and Intermediate 8 following the procedure described for Intermediate 3; MS(ESI) 372.6 [M+H] + .

[0177] Example 4A (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)furo[3,2-b]pyridin-5-yl)- (phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 4B (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 9 was used to prepare Examples 4A and 4B according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (350 mg). The enantiomers were separated by SFC chromatography (Chiralpak AD-H, 40% (0.5% DEA in ethanol)) to give Peak 1 (Example 4A, 120 mg) and Peak 2 (Example 4B, 120 mg). Example 4A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.10(br s,1H),8.81(s,1H),7.70-7.53(m,4H),6.85(d,J=16.8Hz,2H),5.81(s,1H),5.71-5.64(m,1H),5.01(d,J=9.2Hz,1H),4.89(d, MS(ESI)515.6[M+H] + Example 4B: as a yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.10(br s,1H),8.81(s,1H),7.70-7.53(m,4H),6.85(d,J=16.8Hz,2H),5.81(s,1H),5.71-5.64(m,1H),5.01(d,J=9.2Hz,1H),4.89(d, MS(ESI)515.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 4A and 4B.

[0178] Intermediate 10 3-Ethyl-5-iodo-2,3-dihydrobenzofuran-3-ol [ka] Step 1. 5-Iodobenzofuran-3(2H)-one was prepared according to WO 2008 / 068974. MS (ESI) m / z 260.9 [M+H] + .

[0179] Step 2. To a stirred solution of 5-iodobenzofuran-3(2H)-one (2 g, 7.69 mmol) in toluene (20 mL) at 0 °C, 3.0 M EtMgBr (12.82 mL, 38.46 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 h. After completion by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 20% EtOAc / petroleum ether) to give Intermediate 10 (1.5 g, 67%) as a yellow solid. MS (ESI) 272.9 [M+H-HO] + .

[0180] Intermediate 11 2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 11 was prepared using Intermediate 1 and Intermediate 10 according to the procedure described for Intermediate 3. MS (ESI) 385.1 [M+H] + .

[0181] Example 5A (R)-2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 5B (S)-2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 5A and 5B were prepared using Intermediate 11 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (380 mg). The enantiomers were separated by SFC chromatography (Chiralpak AD-H, 45% (0.5% DEA in ethanol)) to give Peak 1 (Example 5A, 123 mg) and Peak 2 (Example 5B, 141 mg). Example 5A: Yellow solid;1 H NMR(400MHz,DMSO-d6)δ 9.95(br s,1H),8.77(s,1H),7.51(d,J=2Hz,2H),7.30-7.28(m,2H),6.97(d,J=8.8Hz,1H),6.82(d ,J=8.8Hz,2H),5.70-5.64(m,1H),5.55(s,1H),5.08(d,J=10.4Hz,1H),4.93(d,J=10.4Hz) ,1H),4.46(d,J=10.4Hz,1H),4.32(d,J=10.4Hz,1H),4.20(s,2H),3.05-3.03(m,4H),2.4 4-2.42(m,4H),2.20(s,3H),1.91-1.82(m,2H),0.84(t,J=7.2Hz,3H);MS(ESI)528.2[M+H] + Example 5B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 9.95(brs,1H),8.77(s,1H),7.51(d,J=2Hz,2H),7.30-7.28(m,2H),6.97(d,J=8.8Hz,1H),6 .82(d,J=8.8Hz,2H),5.70-5.64(m,1H),5.55(s,1H),5.08(d,J=10.4Hz,1H),4.93(d,J=10. 4Hz,1H),4.46(d,J=10.4Hz,1H),4.32(d,J=10.4Hz,1H),4.20(s,2H),3.05-3.03(m,4H),2. 44-2.42(m,4H),2.20(s,3H),1.91-1.82(m,2H),0.84(t,J=7.2Hz,3H);MS(ESI)528.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 5A and Example 5B.

[0182] Intermediate 12 5-Bromo-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-ol [ka] A 1 / 1 mixture by weight of KOH / Celite was finely ground. KOH / Celite Mixture The product (720 mg) was loaded into a glass dropper. 5-Bromofuro[3,2-b]pyridin-3(2H)-one (500 mg, 2.35 mmol) and MeSiCF (666 mg, 4.69 mmol) were dissolved in DMF (2.0 mL). The solution was added to the glass dropper using a syringe. The product was eluted with 4.0 mL of DMF. The reaction was repeated on a 4 × 500 mg scale. The combined reaction mixture was quenched with saturated NHCl (50 mL). The aqueous layer was extracted with EtO (2 × 75 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 20% EtOAc / petroleum ether) to give Intermediate 12 (530 mg, 16%) as an off-white solid. MS(ESI)284.2[M+H] + .

[0183] Intermediate 13 2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 13 was prepared using Intermediate 1 and Intermediate 12 following the procedure described for Intermediate 3. MS (ESI) 426.4 [M+H] + .

[0184] Example 6A (R)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 6B (S)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 6A and 6B were prepared using Intermediate 13 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (170 mg). The enantiomers were separated by SFC chromatography (Chiral Pak IG, 40.0%, (0.5% DEA in MeOH)) to give Peak 1 (Example 6A, 35 mg) and Peak 2 (Example 6B, 40 mg). Example 6A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.2(br s,1H),8.84(s,1H),7.87-7.85(m,2H),7.60-7.55(m,2H),6.91(d,J=9.2Hz,2H),5.67-5.62(m,1H),5.00-4.93(m,2H),4.83(d,J=16Hz,1 H),4.63(d,J=12Hz,1H),4.59(d,J=12Hz,2H),4.48-4.42(m,1H),3.10-3.08(m,4H),2.47-2.44(m,4H),2.22(s,3H);MS(ESI)569.2[M+H] + Example 6B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.2(br s,1H),8.84(s,1H),7.87-7.85(m,2H),7.60-7.55(m,2H),6.91(d,J=9.2Hz,2H),5.67-5.62(m,1H),5.00-4.93(m,2H),4.83(d,J=16Hz,1 H),4.63(d,J=12Hz,1H),4.59(d,J=12Hz,2H),4.48-4.42(m,1H),3.10-3.08(m,4H),2.47-2.44(m,4H),2.22(s,3H);MS(ESI)569.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 6A and Example 6B.

[0185] Intermediate 14 2-Bromo-7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine [ka] To a stirred, room-temperature solution of 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (2.0 g, 9.43 mmol) in DCM (50 mL) was added DAST (3.7 mL, 28.30 mmol), and the mixture was stirred at room temperature for 4 days. The reaction was quenched with aqueous NaHCO (25 mL) at 0 °C and extracted with DCM (3 × 30 mL). The organic layer was dried (Na SO ), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO , 3% EtOAc / petroleum ether) to give intermediate 14 (0.8 g, 36% yield) as an off-white solid. MS (ESI) 233.9 [M+H] + .

[0186] Intermediate 15 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 15 was prepared using Intermediate 1 and Intermediate 14 following the procedure described for Intermediate 3; MS(ESI) 376.4 [M+H] + .

[0187] Example 7 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1. Following the procedures described for Examples 2A and 2B, tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate and Intermediate 15 were used to give tert-butyl 4-(4-((2-allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate (120 mg, 19% yield). MS (ESI) 605.2 [M+H] + .

[0188] Step 2. To a stirred solution of tert-butyl 4-(4-((2-allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate (250 mg, 0.41 mmol) in EtO (10 mL) was added 2 M HCl in EtO (5 mL) at 0° C. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and triturated with EtO to give the hydrochloride salt form of Example 7 (94 mg, 42%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 10.28(br s,1H),8.95(br s,2H),8.87(s,1H),8.17(d,J=8.4Hz,1H),8.05(d,J=8.0Hz,1H),7.62(br s,2H),7.00(d,J=8.8Hz,2H),5.75-5.65(m,1H),5.01(d,J=10.4Hz,1H),4 .86(d,J=17.6Hz,1H),4.61(d,J=5.6Hz,2H),3.38-3.20(m,8H),3.14-3.05(m,2H),2.78-2.62(m,2H);MS(ESI)505.4[M+H] + .

[0189] Example 8 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Following the procedures described for Examples 2A and 2B, 4-(4-methylpiperazin-1-yl)aniline and Intermediate 15 was used to provide Example 8 (120 mg, 19%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.24(br s,1H),8.85(s,1H),8.18(br s,1H),8.06(br s,1H),7.57(br s,2H),6.94(d,J=8.8Hz,2H),5.75-5.65(m,1H),5.00(d,J=10.4Hz,1H),4.85(d,J=17.2Hz,1H),4.61(d,J=5.2Hz,2H),3.10(br MS(ESI)519.3[M+H] + .

[0190] Intermediate 16 2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] To a 0°C solution of 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (2 g, 9.43 mmol) in PhMe (20 mL) was added 3 M EtMgBr in DEE (9.4 mL, 28.29 mmol) dropwise. The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was cooled to 0°C, quenched with saturated NH4Cl (30 mL) solution, and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30% EtOAc / hexanes) to give Intermediate 16 (860 mg, 38%) as an oil. MS (ESI) 244.2 [M+H] + .

[0191] Intermediate 17 2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 17 was prepared using Intermediate 1 and Intermediate 16 according to the procedure described for Intermediate 3. MS (LCMS) 384.5 [M+H] + .

[0192] Example 9A (S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 9B (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] To a solution of Intermediate 17 (4.5 g, 11.7 mmol) in toluene (90 mL) at 0 °C was added m-CPBA (3.7 g, 12.9 mmol). The ice bath was removed and the reaction was stirred for 30 minutes. After completion by TLC, 4-(4-methylpiperazin-1-yl)aniline (2.9 g, 15.2 mmol) and DIPEA (10.9 mL, 61.05 mmol) were added at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 16 hours. After the reaction was judged complete by TLC, water (100 mL) was added to the reaction and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaHCO3 solution (250 mL), brine (300 mL), dried (Na2SO4), and evaporated under reduced pressure. The crude material was 30% E Trituration using t2O / pentane gave racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.2 g, 84%). The racemic material (3.5 g) was separated by SFC chromatography (Chiralpak AD-H, 35% (0.5% DEA in methanol)) to give peak 1 (Example 9A, 1.38 g) and peak 2 (Example 9B, 1.26 g). Example 9A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.05(br s,1H),8.82(s,1H),7.92(br s,1H),7.70(d,J=8.4Hz,1H),7.58(br s,2H),6.92(d,J=8.8Hz,2H),5.70-5.63(m,1H),5.05(s,1H),4.99(d,J=10.4Hz,1H),4.85(d,J=17.6Hz,1H),4.74(br s,1H),4.56(d,J=10.8Hz,1H)3.09-3.08(m,4H)3.01-2.81(m,1H),2.80-2.74(m,1H),2.46-2.44(m,4H),2.22(s,3H), 2.20-2.17(m,1H),2.03-1.98(m,1H),1.91-1.86(m,1H),1.73-1.67(m,1H),0.87(t,J=7.2Hz,3H);MS(ESI)527.5[M+H] + .Example 9B; yellow solid matter; 1 H NMR(400MHz,DMSO-d6)δ 10.05(br s,1H),8.82(s,1H),7.92(br s,1H),7.70(d,J=8.4Hz,1H),7.58(br s,2H),6.92(d,J=8.8Hz,2H),5.70-5.63(m,1H),5.05(s,1H),4.99(d,J=10.4Hz,1H),4.85(d,J=17.6Hz,1H),4.74(br s,1H),4.56(d,J=10.8Hz,1H)3.09-3.08(m,4H)3.01-2.81(m,1H),2.80-2.74(m,1H),2.46-2.44(m,4H),2.22(s,3H), 2.20-2.17(m,1H),2.03-1.98(m,1H),1.91-1.86(m,1H),1.73-1.67(m,1H),0.87(t,J=7.2Hz,3H);MS(ESI)527.5[M+H] + .The absolute stereochemistry of Example 9A and Example 9B is arbitrary and the same.

[0193] Example 10A (S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 10B (R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 10A and 10B were prepared using Intermediate 5 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak AD-H, 20% (15 mM ammonia in methanol)) to give Peak 1 (Example 10A, 120 mg) and Peak 2 (Example 10B, 125 mg). Example 10A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.13(br s,1H),8.84(s,1H),7.90(d,J=7.6Hz,1H),7.71(d,J=8.4Hz,1H),7.66(br s,1H)7.41(d,J=8.8Hz,1H),6.98(d,J=8.4Hz,1H),5.72-5.63(m,1H),5.1 9(s,1H),4.99(d,J=10.0Hz,1H),4.85(d,J=17.2Hz,1H),4.79-4.69(m,1H ),4.66-4.56(m,1H),3.02-2.93(m,1H),2.84-2.75(m,5H),2.51-2.42(m, 4H),2.23(s,6H),2.13(t,J=6.8Hz,2H),1.45(s,3H);MS(ESI)527.5[M+H] + Example 10B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.13(br s,1H),8.84(s,1H),7.90(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.66(br s,1H)7.41(q,J=8.4,2Hz,1H),6.98(d,J=8.4Hz,1H),5.72-5.63(m,1H),5.19 (s,1H),4.99(d,J=10.0Hz,1H),4.85(d,J=17.2Hz,1H),4.78-4.68(m,1H),4. 64-4.56(m,1H),2.99-2.93(m,1H),2.82-2.77(m,5H),2.51-2.42(m,4H),2.2 4(s,3H),2.23(s,3H),2.13(t,J=6.8Hz,2H),1.44(s,3H);MS(ESI)527.4[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 10A and Example 10B.

[0194] Example 11A (S)-2-Allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 11B (R)-2-Allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 11A and 11B were prepared using Intermediate 5 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (370 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 25%, (0.5% DEA in EtOH)) to give Peak 1 (Example 11A, 90 mg) and Peak 2 (Example 11B, 90 mg). Example 11A: Yellow solid; 1 H NMR(300MHz,DMSO-d6)δ 10.25(br s,1H),8.88(s,1H),7.91(d,J=8.4Hz,1H),7.75(br s,1H),7.71(d,J=7.8Hz,1H),7.39(d,J=8Hz,1H),7.02(t,J=9.6Hz,1H),5 .73-5.64(m,1H),5.19(s,1H),5.01(d,J=10Hz,1H),4.89(d,J=17.2Hz,1H ),4.72-4.61(m,2H),3.02-2.96(m,5H),2.84-2.76(m,1H),2.51-2.47(m, 4H),2.22(s,3H),2.16(t,J=6.6Hz,2H),1.45(s,3H);MS(ESI)531.4[M+H] + Example 11B: 1H NMR(300MHz,DMSO-d6)δ 10.25(br s,1H),8.88(s,1H),7.91(d,J=8.4Hz,1H),7.75(br s,1H),7.71(d,J=7.8Hz,1H),7.39(d,J=8Hz,1H),7.02(t,J=9.6Hz,1H),5.73-5. 64(m,1H),5.19(s,1H),5.01(d,J=10Hz,1H),4.89(d,J=17.2Hz,1H),4.72-4.61(m ,2H),3.02-2.96(m,5H),2.84-2.76(m,1H),2.51-2.47(m,4H),2.22(s,3H),2.16 (t,J=6.6Hz,2H),1.45(s,3H);MS(ESI)531.4.Absolute stereochemistry arbitrarily assigned to Example 11A and Example 11B Ta.

[0195] Example 12A (S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 12B (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 12A and 12B were prepared using Intermediate 17 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg). The enantiomers were separated by SFC chromatography (Chiral Pak AD-H, 35% (0.5% DEA in MeOH)) to give Peak 1 (Example 12A, 169 mg) and Peak 2 (Example 12B, 166 mg). Example 12A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.05(br s,1H),8.83(s,1H),7.89(d,J=8Hz,1H),7.71(d,J=8Hz,1H),7.65(br s,1H),7.42(dd,J=8.4Hz,J=8.4Hz 1H),6.98(d,J=8.8Hz,1H),5.70-5.63(m,1H),5.04(s,1H),4.99(d,J=10.4H z,1H),4.85(d,J=16.8Hz,1H),4.77-4.74(m,1H),4.56(dd,J=16.4Hz,J=6.4 Hz,1H)3.09-2.93(m,1H)2.81-2.74(m,4H),2.5-2.49(m,4H),2.32-2.17(m, 7H),2.05-1.98(m,1H),1.92-1.80(m,1H),1.73-1.69(m,1H),1.91-1.86(m, 1H),0.87(t,J=7.6Hz,3H);MS(ESI)541.3[M+H] + Example 12B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.05(br s,1H),8.83(s,1H),7.89(d,J=8Hz,1H),7.71(d,J=8Hz,1H),7.65(br s,1H),7.42(dd,J=8.4Hz,J=8.4Hz 1H),6.98(d,J=8.8Hz,1H),5.70-5.63(m,1H),5.04(s,1H),4.99(d,J=10.4Hz,1H),4.85 (d,J=16.8Hz,1H),4.77-4.74(m,1H),4.56(dd,J=16.4Hz,J=6.4Hz,1H)3.09-2.93(m,1H) )2.81-2.74(m,4H),2.5-2.49(m,4H),2.32-2.17(m,7H),2.05-1.98(m,1H),1.91-1.80( m,1H),1.73-1.67(m,1H),1.91-1.86(m,1H),0.86(t,J=7.6Hz,3H);MS(ESI)541.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 12A and 12B.

[0196] Example 13A (S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 13B (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Using intermediate 17 and 1-(4-(4-amino-2-methylphenyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one, 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure described for Examples 9A and 9B. Prepared. MS(ESI) 623.2 [M+H] + .

[0197] Step 2: To a stirred solution of 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (900 mg, 1.45 mmol) in methanol (15 mL) was added KCO (399 mg, 2.89 mmol). The reaction was stirred at room temperature for 4 hours. After completion by TLC, the solvent was evaporated. The reaction was diluted with water (30 mL) and the solid compound was filtered to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg, 86%) as a pale yellow solid. The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 40% (0.5% DEA in MeOH)) to give peak 1 (Example 13A, 162 mg) and peak 2 (Example 13B, 108 mg). Example 13A: yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.12(brs,1H),8.84(s,1H),7.89(d,J=8.4Hz,1H),7.71(d,J=8.1Hz,1H),7.67(brs,1H),7.41(d,J=8.4Hz,1H) ,6.96(d,J=8.4Hz,1H),5.67-5.66(m,1H),5.05(s,1H),4.99(d,J=10.5Hz,1H),4.85(d,J=18Hz,1H),4.77-4.74( m,1H),4.56(dd,J=6.3,6.6Hz,1H),3.39-3.32(m,1H),2.84-2.83(m,1H),2.79-2.71(m,9H),2.24(s,3H),2.22- 2.19(m,1H),2.02-2.01(m,1H),1.89-1.86(m,1H),1.73-1.69(m,1H),0.86(t,J=7.2Hz,3H);MS(ESI)527.2[M+H] + Example 13B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.12(brs,1H),8.84(s,1H),7.89(d,J=8.4Hz,1H),7.71(d,J=8.1Hz,1H),7.67(brs,1H),7.41(d,J=8.4Hz,1H) ,6.96(d,J=8.4Hz,1H),5.67-5.66(m,1H),5.05(s,1H),4.99(d,J=10.5Hz,1H),4.85(d,J=18Hz,1H),4.77-4.74( m,1H),4.56(dd,J=6.3,6.6Hz,1H),3.39-3.32(m,1H),2.84-2.83(m,1H),2.79-2.71(m,9H),2.24(s,3H),2.22- 2.19(m,1H),2.02-2.01(m,1H),1.89-1.86(m,1H),1.73-1.69(m,1H),0.86(t,J=7.2Hz,3H);MS(ESI)527.4[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 13A and 13B.

[0198] Intermediate 18 (S)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] Intermediate 19 (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] Racemic intermediate 16 (6 g, 24.79 mmol) was purified by SFC purification (Lux Cellulose-2, 10% ethanol). Intermediate 18 (1.9 g, 7.88 mmol) and intermediate 19 (1.8 g, 7.47 mmol). Intermediate 18: colorless oil; [α] D 25 (c=0.5, CHCl3)-27.31 o MS(ESI) 242.3 [M+H] + Intermediate 19: Colorless oil; [α] D 25 (c=0.5,CHCl3)-35.53 o MS(ESI) 242.3 [M+H] + .

[0199] Intermediate 20 (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 20 was prepared using Intermediate 1 and Intermediate 19 following the procedure described for Intermediate 3. [α] D 25 (c=0.1,CHCl3)+17.84 o MS (LCMS) 384.5 [M+H] + .

[0200] Example 14 (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Using intermediate 20, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure described for Examples 9A and 9B. MS (ESI) 609.6 [ M+H] + .

[0201] Step 2: To a stirred solution of (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (350 mg, 0.575 mmol) in MeOH (6 mL) was added K2CO3 (238 mg, 1.72 mmol) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was concentrated under reduced pressure. Water (15 mL) was added and the mixture was stirred for 10 min. The mixture was diluted with saturated NaHCO3 and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (water / CH3CN) to give Example 14 (220 mg, 74%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)10.25(brs,1H),8.81(s,1H),7.90(d,J=7.2Hz,1H),7.69(d,J=8.4Hz,1H),7.5 7(brs,2H),6.90(d,J=8.8Hz,2H),5.70-5.63(m,1H),5.04(s,1H),4.99(d,J=9.2Hz,1H),4.85(d,J=1 7.2Hz,1H),4.74(brs,1H),4.57-4.54(m,1H),3.02-2.93(m,5H),2.86-2.74(m,5H),2.22-2.06(m,1H) ),2.05-1.99(m,1H),1.91-1.86(m,1H),1.73-1.67(m,1H),0.8(t,J=7.2Hz,3H);MS(ESI)513.3[M+H] + .

[0202] Intermediate 21 2-Bromo-7-(difluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol [ka] To a stirred solution of MeSiCFH (1.175 g, 9.48 mmol) in 1,2-DME (10 mL) was added 18-crown-6 (625 mg, 2.37 mmol) and CsF (715 mg, 4.739 mmol) at 0 °C, and the reaction was stirred for 15 minutes. To the reaction was added 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1 g, 4.74 mmol) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 hours. The reaction was judged complete by TLC, and the reaction was diluted with water (30 mL) and extracted with EtOAc (2 × 50 mL). The separated organic layer was washed with brine, dried (NaSO), filtered, and concentrated under reduced pressure to give the crude compound. The above reaction was repeated on a 4 × 1 g scale. The residue was purified by flash chromatography (SiO2, EtOAc / petroleum ether) to give Intermediate 21 (470 mg) as an off-white solid. MS (ESI) 266.3 [M+H] + .

[0203] Intermediate 22 2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 22 was prepared using Intermediate 1 and Intermediate 21 following the procedure described for Intermediate 3; MS(ESI) 406.3 [M+H] + .

[0204] Example 15A (S)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 15B (R)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 15A and 15B were prepared using Intermediate 22 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (120 mg). The enantiomers were separated by SFC chromatography (Chiral Pak AD-H, 30.0% (0.5% DEA in methanol)) to give Peak 1 (Example 15A, 35 mg) and Peak 2 (Example 15B, 35 mg). Example 15A: Yellow solid; 1 H NMR (400MHz,DMSO-d6)δ 10.2(br s,1H),8.83(s,1H),8.02(br s,1H),7.82(d,J=8.4Hz,1H),7.57(br s,2H),6.93(d,J=8.7Hz,2H),6.26(t,J=59.1Hz,1H),6.22(s,1H),5.68-5.61(m,1H),4.97(d,J=9.9Hz,1H),4.82(d,J=17.4Hz,1H),4.74(br MS(ESI)549.2[M+H] + Example 15B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.2(br s,1H),8.83(s,1H),8.02(br s,1H),7.82(d,J=8.4Hz,1H),7.57(br s,2H),6.93(d,J=8.7Hz,2H),6.26(t,J=59.1Hz,1H),6.22(s,1H),5.68-5.61(m,1H),4.97(d,J=9.9Hz,1H),4.82(d,J=17.4Hz,1H),4.74(br MS(ESI)549.2[M+H]+ Absolute stereochemistry has been arbitrarily assigned to Example 15A and Example 15B.

[0205] Intermediate 23 [ka] To a solution of 2-bromo-5H-cyclopenta[b]pyridin-7(6H)-one (4 g, 18.80 mmol) in THF (50 mL) at 0 °C was added a 3 M solution of cyclopropylmagnesium bromide in THF (31 mL, 94.3 mmol). The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was quenched with aqueous NH4Cl (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 30% EtOAc / petroleum ether) to give 2-intermediate 23 (3 g, 63%) as a colorless oil. MS (ESI) 255.9 [M+H] + .

[0206] Intermediate 24 2-Allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 24 was prepared using Intermediate 1 and Intermediate 23 according to the procedure described for Intermediate 3. MS (ESI) 396.5 [M+H] + .

[0207] Example 16A (R)-2-Allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 16B (S)-2-Allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 16A and 16B were prepared using Intermediate 24 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 45% (0.5% DEA in methanol)) to give Peak 1 (Example 16A, 159 mg) and Peak 2 (Example 16B, 111 mg). Example 16A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.13(br s,1H),8.82(s,1H),7.92(m,1H),7.71(d,J=7.6Hz,1H),7.58(m,2H),6.92(J= 7.6Hz,2H),5.70-5.64(m,1H),5.04(s,1H),4.98(d,J=10Hz,1H),4.87-4.77( m,2H),4.65(m,1H),3.09(s,4H),2.93-2.79(m,2H),2.46(m,4H),2.22(s,3H) ,2.09-1.99(m,2H),1.22-1.21(m,1H),0.44-0.30(m,4H);MS(ESI)539.5[M+H] + Example 16B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.13(br s,1H),8.82(s,1H),7.92(m,1H),7.71(d,J=8.4Hz,1H),7.58(m,2H),6.92(J=8.7Hz,2H),5.70-5.64(m,1H),5.04(s,1H), 4.98(d,J=9.6Hz,1H),4.87-4.77(m,2H),4.65(m,1H),3.09(s,4H),2.93-2.79(m,2H),2.46(m, 4H),2.22(s,3H),2.09-1.99(m,2H),1.22-1.21(m,1H),0.44-0.30(m,4H);MS(ESI)539.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 16A and Example 16B.

[0208] Example 17A 2-Allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 17B 2-Allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 17A and 17B were prepared according to the procedure described for Examples 9A and 9B using Intermediate 5 and (S)-4-(3,4-dimethylpiperazin-1-yl)aniline to give a mixture of diastereomers, 2-allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg). The diastereomers were separated by chiral SFC chromatography (Chiral Pak IG, (0.5% DEA in methanol:hexane (80:20))) to give peak 1 (Example 17A, 130 mg) and peak 2 (Example 17B, 75 mg). Example 17A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.92(d,J=6.8Hz,1H),7.69(d,J=8.0Hz,1H),7.57(br s,2H),6.91(d,J=8.8Hz, 2H),5.71-5.63(m,1H),5.17(s,1H),4.99(d,J=10.0Hz,1H),4.86(d,J=17.6Hz,1H),4.78-4.71(m,1H),4.65-4.57(m,1H),3.47(t,J=10.8Hz) ,2H),3.00-2.93(m,1H),2.83-2.67(m,3H),2.34-2.22(m,5H),2.13(t,J=6.8Hz,3H),1.45(s,3H),1.05(d,J=6.0Hz,3H);MS(ESI)527.3[M+H] + Example 17B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.93(d,J=7.2Hz,1H),7.68(d,J=8.8Hz,1H),7.57(br s,2H),6.91(d,J=8.8Hz,2H),5.71-5.63(m,1H),5.17(s,1H),4.99(d,J=10.0Hz,1H),4.86(d,J=17.2Hz,1H),4.76-4.70(m,1H),4.65-4.57 (m,1H),3.52-3.47(m,2H),3.01-2.93(m,1H),2.83-2.67(m,3H),2.36-2.11(m,8H),1.45(s,3H),1.05(d,J=6.0Hz,3H);MS(ESI)527.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 17A and 17B.

[0209] Example 18A 2-Allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 18B 2-Allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Using intermediate 5 and (R)-4-(3,4-dimethylpiperazin-1-yl)aniline Examples 18A and 18B were prepared according to the procedures described for Examples 9A and 9B to give a mixture of diastereomers, 2-allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. The diastereomers were separated by chiral SFC chromatography (Chiralpak AD-H, 20.0% (0.5% DEA in methanol)) to give peak 1 (Example 18A, 94 mg) and peak 2 (Example 18B, 85 mg). Example 18A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.09(br s,1H),8.81(s,1H),7.92(d,J=6.8Hz,1H),7.68(d,J=8.0Hz,1H),7.57(m,2H),6.91 (d,J=8.8Hz,2H),5.71-5.62(m,1H),5.16(s,1H),4.99(d,J=10.0Hz,1H),4.86(d,J= 16.8Hz,1H),4.78-4.55(m,2H),3.47(t,J=10.4Hz,2H),3.31-2.93(m,1H),2.83-2.6 7(m,3H),2.36-2.11(m,8H),1.45(s,3H),1.05(d,J=5.6Hz,3H);MS(ESI)527.3[M+H] + Example 18B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.10(br s,1H),8.82(s,1H),7.92(d,J=6.8Hz,1H),7.68(d,J=8.0Hz,1H),7.57(m,2H),6.91 (d,J=9.2Hz,2H),5.72-5.62(m,1H),5.16(s,1H),4.99(d,J=10.0Hz,1H),4.86(d,J= 16.8Hz,1H),4.76-4.70(m,1H),4.61-4.58(m,1H),3.48(m,2H),3.01-2.93(m,1H), 2.83-2.71(m,3H),2.32-2.11(m,8H),1.45(s,3H),1.07(m,3H);MS(ESI)527.3[M+H]+ The absolute stereochemistry at the tertiary alcohol has been arbitrarily assigned in Examples 18A and 18B.

[0210] Example 19A 2-Allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 19B 2-Allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 19A and 19B were prepared using Intermediate 5 and (S)-4-(2,4-dimethylpiperazin-1-yl)aniline according to the procedure described for Examples 9A and 9B to give a mixture of diastereomers, 2-allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). The diastereomers were separated by chiral SFC chromatography (Chiralpak AD-H, 25.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 19A, 158 mg) and Peak 2 (Example 19B, 103 mg). Example 19A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.92(d,J=7.6Hz,1H),7.69(d,J=8.4Hz,1H),7.57(br s,2H),6.88(d,J=9.2Hz,2H),5.71-5.63(m,1H),5.18(s,1H),4.99(d,J=10.4 Hz,1H),4.86(d,J=17.2Hz,1H),4.78-4.71(m,1H),4.65-4.57(m,1H),3.87(br s,1H),3.21-3.16(m,1H),3.00-2.93(m,2H),2.83-2.72(m,2H),2.58-2.51(m,1H),2.34-2.28(m ,1H),2.20(s,3H),2.12(t,J=6.8Hz,3H),1.45(s,3H),0.97(d,J=6.4Hz,3H);MS(ESI)527.3[M+H] + .Example 19B: yellow solid matter; 1 H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.92(d,J=7.2Hz,1H),7.69(d,J=8.0Hz,1H),7.57(br s,2H),6.88(d,J=8.0Hz,2H),5.71-5.64(m,1H),5.18(s,1H),4.99(d,J=10.4 Hz,1H),4.86(d,J=17.2Hz,1H),4.78-4.71(m,1H),4.65-4.57(m,1H),3.87(br s,1H),3.21-3.16(m,1H),3.00-2.92(m,2H),2.83-2.72(m,2H),2.58-2.51(m,1H),2.34-2.28(m ,1H),2.20(s,3H),2.13(t,J=7.2Hz,3H),1.45(s,3H),0.96(d,J=6.4Hz,3H);MS(ESI)527.2[M+H] + .Third-level chemical stereochemistry, Example 19A, and Example 19B can be used as an arbitrary cutter.

[0211] Example 20A 2-Allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 20B 2-Allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 20A and 20B were prepared according to the procedure described for Examples 9A and 9B using Intermediate 5 and (R)-4-(2,4-dimethylpiperazin-1-yl)aniline to give a mixture of diastereomers, 2-allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). The diastereomers were separated by chiral SFC chromatography (Chiralpak AD-H, 20.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 20A, 170 mg) and Peak 2 (Example 20B, 170 mg). Example 20A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.92(d,J=7.6Hz,1H),7.69(d,J=8.4Hz,1H),7.57(br s,2H),6.88(d,J=8.8Hz,2H),5.71-5.63(m,1H),5.18(s,1H),4.99(d,J=10.4 Hz,1H),4.86(d,J=17.2Hz,1H),4.78-4.71(m,1H),4.65-4.57(m,1H),3.87(br s,1H),3.21-3.16(m,1H),3.00-2.93(m,2H),2.83-2.72(m,2H),2.59-2.52(m,1H),2.34-2.28(m ,1H),2.20(s,3H),2.12(t,J=7.2Hz,3H),1.45(s,3H),0.96(d,J=6.4Hz,3H);MS(ESI)527.2[M+H] + .Example 20B: yellow solid matter; 1 H NMR(400MHz,DMSO-d6)δ 10.1(br s,1H),8.82(s,1H),7.92(d,J=7.6Hz,1H),7.69(d,J=8.4Hz,1H),7.57(br s,2H),6.88(d,J=8.8Hz,2H),5.71-5.63(m,1H),5.18(s,1H),4.99(d,J=10H z,1H),4.86(d,J=17.2Hz,1H),4.78-4.71(m,1H),4.65-4.57(m,1H),3.87(br s,1H),3.21- 3.16(m,1H),3.00-2.93(m,2H),2.83-2.72(m,2H),2.59-2.51(m,1H),2.34-2.28(m,1H),2 .20(s,3H),2.12(t,J=7.2Hz,3H),1.45(s,3H),0.96(d,J=6.4Hz,3H);MS(ESI)527.3[M+H] + .Third-level chemical stereochemistry, Example 20A, and Example 20B can be used as an arbitrary cutter.

[0212] Intermediate 25 6-ブロモ-1-メチル-2,3-ジヒドロ-1H-インデン-1-オール [ka] A suspension of anhydrous CeCl3 (17.5 g, 71.08 mmol) in THF (100 mL) was stirred at room temperature for 1 hour and cooled to -78 °C. 1.6 M MeLi (44 mL, 71.08 mmol) in DEE was added at -78 °C, and the reaction was stirred for 30 minutes. To this was added a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (10 g, 47.39 mmol) in THF (100 mL) at -78 °C. The ice bath was removed, and the reaction was stirred at room temperature for 2 hours. After completion by TLC, the reaction was quenched with aqueous NH4Cl (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , 30% EtOAc / petroleum ether) to give Intermediate 25 (6 g, 55%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.43(d,J=2.0Hz,1H),7.35(dd,J=8.0,2.0Hz,1H),7.16(d,J=8.0Hz,1H),5.14( s,1H)2.89-2.81(m,1H),2.75-2.66(m,1H),2.07(t,J=4.4Hz,2H),1.40(s,3H).

[0213] Intermediate 26 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 26 was prepared using Intermediate 1 and Intermediate 25 according to the procedure described for Intermediate 3. MS (ESI) 369.4 [M+H] + .

[0214] Example 21A (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 21B (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 21A and 21B were prepared using Intermediate 26 according to the procedures described for Examples 2A and 2B to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (350 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak IG, 40.0% (0.5% DEA in methanol)) to give Peak 1 (Example 21A, 70 mg) and Peak 2 (Example 21B, 71 mg). Example 21A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.03(br s,1H),8.79(s,1H),7.54(br s,2H),7.38-7.34(m,2H),7.27(dd,J=8.0,2.0Hz,1H),6.86(d,J=9.2Hz,2H),5.68 -5.62(m,1H),5.15(s,1H),5.09(d,J=9.6Hz,1H),4.93(d,J=17.6Hz,1H),4.24(br s,2H),3.05(s,4H),2.99-2.92(m,1H),2.85-2.77(m,1H),2.50-2.46(m, 4H),2.22(s,3H),2.11(t,J=6.8Hz,2H),1.43(s,3H);MS(ESI)512.3[M+H] + .Example 21B: yellow solid matter; 1 H NMR(400MHz,DMSO-d6)δ 10.03(br s,1H),8.79(s,1H),7.54(br s,2H),7.38-7.34(m,2H),7.27(dd,J=8.0,2.0Hz,1H),6.86(d,J=9.2Hz,2H),5.68 -5.62(m,1H),5.15(s,1H),5.09(d,J=9.6Hz,1H),4.93(d,J=17.6Hz,1H),4.24(br s,2H),3.05(s,4H),2.99-2.92(m,1H),2.85-2.77(m,1H),2.50-2.46(m, 4H),2.22(s,3H),2.11(t,J=6.8Hz,2H),1.43(s,3H);MS(ESI)512.3[M+H] + .The absolute stereochemistry of Example 21A and Example 21B is arbitrary and the same.

[0215] Intermediate 27 6-ブロモ-1-エチル-2,3-ジヒドロ-1H-インデン-1-オール

change

[0216] Intermediate 28 2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 28 was prepared using Intermediate 1 and Intermediate 27 according to the procedure described for Intermediate 3. MS (ESI) 383.4 [M+H] + .

[0217] Example 22A (S)-2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 22B (R)-2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)a (amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 22A and 22B were prepared using Intermediate 28 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(3-ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (340 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak IG, 35.0% (0.5% DEA in methanol)) to give Peak 1 (Example 22A, 102 mg) and Peak 2 (Example 22B, 91 mg). Example 22A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.01(br s,1H),8.79(s,1H),7.55(br s,2H),7.38(d,J=8.4Hz,1H),7.28(d,J=6.8Hz,2H),6.85(d,J=9.2Hz,2H),5.71-5.62(m,1H ),5.08(d,J=10.4Hz,1H),5.02(s,1H),4.92(d,J=17.2Hz,1H),4.23-4.19(m,2H),3.06-3.04 (m,4H),2.98-2.91(m,1H),2.81-2.75(m,1H),2.44-2.32(m,4H),2.21-2.16(m,4H),2.05-1 .98(m,1H),1.82-1.75(m,1H),1.69-1.62(m,1H),0.86(t,J=7.6Hz,3H);MS(ESI)526.2[M+H] + Example 22B: 1H NMR(400MHz,DMSO-d6)δ 10.01(br s,1H),8.79(s,1H),7.55(br s,2H),7.38(d,J=8.4Hz,1H),7.28(d,J=6.8Hz,2H),6.85(d,J=9.2Hz,2H),5.67-5.63(m,1H ),5.09(d,J=10.4Hz,1H),5.02(s,1H),4.92(d,J=17.2Hz,1H),4.23-4.22(m,2H),3.06-3.04 (m,4H),2.94-2.91(m,1H),2.81-2.77(m,1H),2.45-2.42(m,4H),2.21-2.16(m,4H),2.03-2 .00(m,1H),1.82-1.75(m,1H),1.67-1.64(m,1H),0.86(t,J=7.6Hz,3H);MS(ESI)526.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 22A and 22B.

[0218] Example 23A (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 23B (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 23A and 24b were prepared using Intermediate 26 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (635 mg). The enantiomers were separated by SFC chromatography (Chiral Pak AD-H, 40% (0.5% isopropylamine in isopropyl alcohol)) to give Peak 1 (Example 23A, 223 mg) and Peak 2 (Example 23B, 223 mg). Example 23A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.00(brs,1H),8.81(s,1H),7.47-7.29(m,5H),6.93(d,J=8.4Hz,1H),5. 71-5.64(m,1H),5.14(s,1H),5.09(d,J=10.4Hz,1H),4.93(d,J=17.2Hz,1H ),4.25(brs,2H),2.99-2.91(m,1H),2.85-2.76(m,5H),2.45(brs,4H),2.2 2(s,3H),2.17(s,3H),2.12-2.09(m,2H),1.42(s,3H);MS(ESI)526.3[M+H] + Example 23B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.00(brs,1H),8.81(s,1H),7.47-7.29(m,5H),6.93(d,J=8.4Hz,1H),5. 71-5.64(m,1H),5.14(s,1H),5.09(d,J=10.4Hz,1H),4.93(d,J=17.2Hz,1H ),4.25(brs,2H),2.99-2.91(m,1H),2.85-2.76(m,5H),2.45(brs,4H),2.2 2(s,3H),2.17(s,3H),2.12-2.09(m,2H),1.42(s,3H);MS(ESI)526.7[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 23A and 23B.

[0219] Intermediate 29 6-Bromo-4-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol [ka] Step 1: 6-Bromo-4-fluoro-2,3-dihydro-1H-inden-1-one was prepared according to WO 2005 / 095387. 1 H NMR (400MHz, CDCl3-d6) δ 7.70 (s, 1H), 7.42 (d, J = 9.6 Hz, 1 H), 3.10 (t, J = 6.0 Hz, 2 H), 2.75 (t, J = 6.4 Hz, 2 H).

[0220] Step 2: To a solution of 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (6 g, 26 mmol) in diethyl ether (60 mL) at 0 °C, 3.0 M MeMgBr in DEE (87 mL, 262 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, 10% EtOAc / petroleum ether) to afford 6-bromo-4-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol (3 g, 47%) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ 7.28(d,J=1.6Hz,1H),7.11(dd,J=10.0,4.8Hz,1H),3.03-2.95(m,1H),2.85-2.74(m,1H),2.30-2.18(m,2H),1.58(s,3H).

[0221] Intermediate 30 2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 30 was prepared using Intermediate 1 and Intermediate 29 according to the procedure described for Intermediate 3. MS (ESI) 387.3 [M+H] + .

[0222] Example 24A (S)-2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 24B (R)-2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 24A and 24B were prepared using Intermediate 30 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (165 mg). The enantiomers were separated by SFC chromatography (Chiral Pak AD-H, 30% (0.5% isopropylamine in IPA)) to give peak 1 (Example 24A, 43 mg) and peak 2 (Example 24B, 47 mg). Example 24A: Yellow solid; H NMR (400 MHz, DMSO-d) δ 10.10(brs,1H),8.81(s,1H),7.55(brs,2H),7.21(d,J=9.2Hz,2H),6.86 (d,J=9.2Hz,2H),5.71-5.64(m,1H),5.31(s,1H),5.09(d,J=10.8Hz,1H) ,4.96(d,J=17.2Hz,1H),4.28(brs,2H)),3.05-2.78(m,6H),2.50-2.45( m,4H),2.22(s,3H),2.16-2.13(m,2H),1.44(s,3H);MS(ESI)530.3[M+H] + .Example 24B: Yellow solid; 1H NMR (400MHz, DMSO-d6) δ 10.10(br s,1H),8.81(s,1H),7.55(br s,2H),7.21(d,J=9.6Hz,2H),6.86(d,J=9.2Hz,2H),5.71-5.64(m,1H),5.31(s,1H),5.09(d,J=10.4Hz,1H),4.96(d,J=16.8Hz,1H),4.28(br MS(ESI)530.3[M+H] + .] + Absolute stereochemistry has been arbitrarily assigned to Examples 24A and 24B.

[0223] Intermediate 31 2-Bromo-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol [ka] Step 1: To a stirred solution of 2-chloro-6,7-dihydroquinolin-8(5H)-one (1.7 g, 9.39 mmol) in CHCN (30 mL) was added TMS-Br (2.86 g, 18.78 mmol), and the reaction was heated in a CEM-microwave at 150 °C for 20 min. After completion by TLC, the reaction was diluted with DCM (100 mL) and washed with aqueous NaHCO (50 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO, 20% EtOAc / petroleum ether) to give 2-bromo-6,7-dihydroquinolin-8(5H)-one (1.2 g, 57%) as a brown oil. MS (ESI) 226.3 [M+H].

[0224] Step 2: To a solution of 2-bromo-6,7-dihydroquinolin-8(5H)-one (1.20 g, 5.33 mmol) in DEE (30 mL) at 0 °C, 3.0 M CHMgI in DEE (8.88 mL, 26.65 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 h. After completion by TLC, the reaction was quenched with water (25 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO, 20% EtOAc / petroleum ether) to give Intermediate 31 (900 mg, 70%) as an off-white solid. MS (ESI) 241.9 [M+H] + .

[0225] Intermediate 32 2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 32 was prepared using Intermediate 1 and Intermediate 31 according to the procedure described for Intermediate 3. MS (ESI) 384.1 [M+H] + .

[0226] Example 25A (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 25B (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 25A and 25B were prepared using Intermediate 32 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (450 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 45% (0.5% DEA in methanol)) to give Peak 1 (Example 25A, 160 mg) and Peak 2 (Example 25B, 165 mg). Example 25A: Yellow solid; 11H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.81 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.72 - 5.61 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.89 (s, 1H), 4.84 (s, 1H), 4.81 (br s, 1H), 4.65 (dd, J = 16.0, 5.2 Hz, 1H), 3.14 - 3.07 (m, 4H), 2.83 - 2.75 (m, 2H), 2.49 - 2.43 (m, 4H), 2.23 (s, 3H), 1.98 - 1.87 (m, 2H), 1.82 (d, J = 10.8 Hz, 1H), 1.77 - 1.68 (m, 1H), 1.49 (s, 3H); MS (ESI) 527.3 [M + H] + . Example 25B: Yellow solid; 1 1H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.81 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.71 - 5.61 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.89 (s, 1H), 4.84 (s, 1H), 4.81 (s, 1H), 4.66 (dd, J = 15.6, 5.2 Hz, 1H), 3.09 (s, 4H), 2.86 - 2.72 (m, 2H), 2.47 - 2.44 (m, 4H), 2.22 (s, 3H), 1.96 - 1.93 (m, 2H), 1.83 - 177 (m, 1H), 1.73 - 1.70 (m, 1H), 1.49 (s, 3H); MS (ESI) 527.3 [M + H] + . The absolute stereochemistry was arbitrarily assigned to Example 25A and Example 25B. It was arbitrarily assigned to Example 25A and Example 25B.

[0227] Intermediate 33 2-Bromo-8-ethyl-5,6,7,8-tetrahydroquinolin-8-ol [Chemical formula] To a solution of 2-bromo-6,7-dihydroquinolin-8(5H)-one (2.00 g, 8.88 mmol) in diethyl ether (40 mL) at 0 °C was added 3.0 M MeMgBr in DEE (14.82 mL, 44.44 mmol) dropwise. The ice bath was removed, and the mixture was allowed to warm to room temperature and stirred for 16 h. After completion by TLC, the reaction was quenched with water (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water, brine, (Na SO ), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO , 10% EtOAc / petroleum ether) to give Intermediate 33 (900 mg, 40%) as a pale yellow oil. MS (ESI) 256.2 [M+H] + .

[0228] Intermediate 34 2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 34 was prepared using Intermediate 1 and Intermediate 33 according to the procedure described for Intermediate 3. MS (ESI) 398.0 [M+H] + .

[0229] Example 26A (S)-2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 26B (R)-2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 26A and 26B were prepared using Intermediate 34 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (600 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 35% (0.5% DEA in methanol)) to give Peak 1 (Example 26A, 160 mg) and Peak 2 (Example 26B, 136 mg). Example 26A: Yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.11(br s,1H),8.81(s,1H),7.78(d,J=8.4Hz,1H),7.69(d,J=7.8Hz,1H),7.60-754(m,2H),6.93( d,J=8.8Hz,2H),5.70-5.61(m,1H),4.99(d,J=9.6Hz,1H),4.86(d,J=17.2Hz,1H),4.81(br s,1H),4.73(s,1H),4.59(dd,J=16,5.6Hz,1H),3.12-3.06(m,4H),2.85-2.67(m,2H),2.49-2.4 0(m,4H),2.22(s,3H),1.96-1.71(m,6H),0.78(t,J=7.6Hz,3H);MS(ESI)541.3 Example 26B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.11(br s,1H),8.81(s,1H),7.78(d,J=8.4Hz,1H),7.69(d,J=7.8Hz,1H),7.60-754(m,2H),6.93( d,J=8.8Hz,2H),5.70-5.61(m,1H),4.99(d,J=9.6Hz,1H),4.86(d,J=17.2Hz,1H),4.81(br s,1H),4.73(s,1H),4.59(dd,J=16,5.6Hz,1H),3.12-3.06(m,4H),2.85-2.67(m,2H),2.4 9-2.40(m,4H),2.22(s,3H),1.96-1.71(m,6H),0.78(t,J=7.6Hz,3H).MS(ESI)541.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 26A and Example 26B.

[0230] Example 27A (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 27B (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 27A and 27B were prepared using Intermediate 32 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (800 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 50% (0.5% DEA in methanol)) to give Peak 1 (Example 27A, 69 mg) and Peak 2 (Example 27B, 68 mg). Example 27A: Yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.12(brs,1H),8.84(s,1H),7.75-7.67(m,3H),7.39(d,J=8.8Hz,1H),6.99(d ,J=8.8Hz,1H),5.71-5.61(m,1H),4.98(d,J=10Hz,1H),4.89(d,J=8.4Hz,2H),4 .84-4.80(m,1H),4.67-4.61(m,1H),2.85-2.67(m,6H),2.52-2.48(m,4H)2.47 (s,6H),1.96-1.92(m,2H),1.83-1.70(m,2H),1.49(s,3H);MS(ESI)541.2[M+H] + Example 27B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.12(brs,1H),8.84(s,1H),7.75-7.67(m,3H),7.39(d,J=8.8Hz,1H),6.99(d,J =8.8Hz,1H),5.71-5.61(m,1H),4.98(d,J=10Hz,1H),4.89(d,J=8.4Hz,2H),4.84 -4.80(m,1H),4.67-4.61(m,1H),2.85-2.67(m,6H),2.52-2.48(m,4H),2.25-2.2 4(m,6H),1.96-1.92(m,2H),1.83-1.70(m,2H),1.49(s,3H);MS(ESI)541.2[M+H] +Absolute stereochemistry has been arbitrarily assigned to Examples 27A and 27B.

[0231] Example 28A (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 28B (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Intermediate 32 was used to synthesize 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one using the procedure described for Example 9A and Example 9B. MS (ESI) 609.5 [M+H] + .

[0232] Step 2: To a 0 °C solution of 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (400 mg, 0.66 mmol) in MeOH (6 mL) was added K2CO3 (272 mg, 1.97 mmol). The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was concentrated under reduced pressure. Water (10 mL) was added and the mixture was stirred for 10 min. The resulting solid was filtered and dried under vacuum to give racemic 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(piperazin-1-yl)phenyl)-amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (260 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-n, 40% (0.5% DEA in methanol)) to give peak 1 (Example 28A, 39 mg) and peak 2 (Example 28B, 33 mg). Example 28A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.10(br s,1H),8.81(s,1H),7.76(d,J=8.4Hz,1H),7.69(d ,J=8.4Hz,1H),7.56(brs,2H),6.90(d,J=8.8Hz,2H),5.69-5.62(m,1H),4.98(d,J=10.0Hz,1H),4.88(s,1H),4.84-4.80(m,2H), 4.67-4.61(m,1H),3.00-2.99(m,4H),2.83-2.76(m,6H),1.96-1.91(m,2H),1.83-1.70(m,2H),1.49(s,3H);MS(ESI)513.3[M+H] + Example 28B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.09(br s,1H),8.81(s,1H),7.77(d,J=8.4Hz,1H),7.69(d,J=8.0Hz,1H),7.57(d,J=7. 2Hz,2H),6.90(d,J=8.8Hz,2H),5.71-5.621(m,1H),4.98(d,J=9.2Hz,1H),4.8 8(s,1H),4.84-4.81(m,2H),4.67-4.62(s,1H),3.01-2.99(m,4H),2.84-2.74( m,6H),1.96-1.92(m,2H),1.83-1.70(m,2H),1.49(s,3H);MS(ESI)513.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 28A and Example 28B.

[0233] Intermediate 35 1-(7'-amino-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethan-1-one [ka] Step 1: 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] was prepared according to US Pat. No. 7,507,748.

[0234] Step 2: To a stirred solution of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (2.5 g, 12.25 mmol) in DCM (40 mL) was added TEA (3.69 g, 36.75 mmol) and trifluoroacetic anhydride (3.08 g, 14.70 mmol) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was diluted with DCM (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 10% EtOAc / petroleum ether) to give 2,2,2-trifluoro-1-(7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)ethan-1-one (1.7 g, 46%) as a yellow oil. 1 H NMR(300 MHz,DMSO-d6)δ 8.26(dd,J=20.7Hz,2.4Hz,1H),8.05-8.00(m,1H),7.13(d,J=8.7Hz,1H),5.04(d,J=12.3Hz,2H),3.74(d,J=6.9Hz,2H),1.24-1.15(m,4H).

[0235] Step 3: To a stirred solution of 2,2,2-trifluoro-1-(7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)ethan-1-one (1.7 g, 5.66 mmol) in EtOH (17 mL) was added SnCl (6.44 g, 33.99 mmol) and NH Cl (1.81 g, 33.99 mmol). The reaction was heated at 80 °C for 2 h. After completion by TLC, the reaction was concentrated under reduced pressure, and the residue was dissolved in water (50 mL), basified to pH -8 using saturated NaHCO and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na SO ), filtered and concentrated under reduced pressure to give Intermediate 35 (1.4 g, 91%) as a pale yellow solid. MS (ESI) 270.9 [M+H] + .

[0236] Example 29A (S)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 29B (R)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Using Intermediate 5 and Intermediate 35, 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((2'-(2,2,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure described for Examples 9A and 9B. MS (ESI) 592.4 [M+H] + .

[0237] Step 2: To a solution of 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((2'-(2,2,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (135 mg, 0.23 mmol) in MeOH (6 mL) at 0 °C was added K2CO3 (94 mg, 0.68 mmol). The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was concentrated under reduced pressure. Water (10 mL) was added to the crude compound and stirred for 10 min. The precipitate was filtered and dried under vacuum to give racemic 2-allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (85 mg) off-white. The enantiomers were separated by chiral SFC chromatography (Chiral Pak IA, 45% (0.5% DEA in methanol)) to give peak 1 (Example 29A, 30 mg) and peak 2 (Example 29B, 25 mg). Example 29A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)10.16(brs,1H),8.85(s,1H),7.90(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.55(br s,1H),7.32(d,J=8.0Hz,1H),6.66(d,J=8.4Hz,1H),5.71-5.63(m,1H),5.18(s,1H),4.99(d,J=9.6Hz,1H), 4.85(d,J=17.6Hz,1H),4.74(d,J=10.0Hz,1H),4.60(dd,J=16.4Hz,6.0Hz,1H),3.91(s,2H),3.03-2.94(m ,1H),2.87-2.72(m,3H),2.13(t,J=6.8Hz,2H),1.45(s,3H),0.88(s,2H),0.77(s,2H).MS(ESI)496.2[M+H]+ Example 29B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)10.16(brs,1H),8.85(s,1H),7.90(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.55(b rs,1H),7.32(d,J=8.8Hz,1H),6.66(d,J=8.4Hz,1H),5.71-5.63(m,1H),5.18(s,1H),4.99(d,J=10.4Hz, 1H),4.85(d,J=18Hz,1H),4.74(d,J=14Hz,1H),4.60(dd,J=16Hz,5.2Hz,1H),3.91(s,2H),3.01-2.96(m, 1H),2.84-2.67(m,3H),2.13(t,J=6.8Hz,2H),1.45(s,3H),0.88(s,2H),0.77(s,2H).MS(ESI)496.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Examples 29A and 29B.

[0238] Intermediate 36 tert-Butyl 7'-amino-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate [ka] Step 1: To a stirred solution of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (3 g, 14.63 mmol) in 1,4-dioxane:HO (45 mL, 2:1) was added 1 N NaOH (15 mL) at 0 °C. After 5 min, di-tert-butyl dicarbonate (3.7 mL, 16.91 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 2 h. The reaction was acidified with KHSO (pH: 2-3), and then the mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (25 mL), dried over NaSO, and concentrated. The resulting crude mixture was purified by column chromatography (SiO2, 20% EA / pet. ether) to give tert-butyl 7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (2.5 g, 56%) as a pale yellow solid. MS (LCMS) 249.0 [M-C4H 10 ] + .

[0239] Step 2: To a stirred solution of tert-butyl 7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (1.0 g, 3.28 mmol) in EtOH (50 mL) was added SnCl2 (3.74 g, 19.67 mmol) followed by NH4Cl (1.04 g, 19.67 mmol) at room temperature. The reaction was stirred at 70 °C for 1 h. After completion by LCMS, the crude reaction was concentrated under reduced pressure to give water ( The mixture was diluted with 50 mL of HCl and basified with saturated NaHCO3 (pH: 8-9). The mixture was then filtered through a pad of Celite and extracted with 30% MeOH:DCM (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated to give Intermediate 36 (615 mg, 93%) as an off-white solid. MS (LCMS) 275.4 [M+H] + .

[0240] Intermediate 37A tert-Butyl (S)-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate [ka] Intermediate 37B tert-Butyl (R)-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate [ka] Intermediates 37A and 37B were prepared using Intermediate 7 and Intermediate 36 according to the procedure described for Examples 2A and 2B to give racemic tert-butyl-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]-pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1'H-spiro-[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (364 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak IC, 35% methanol) to give Peak 1 (Intermediate 37A, 140 mg) and Peak 2 (Intermediate 37B, 135 mg). Intermediate 37A: Yellow solid; MS(ESI)650.5[M+H] + .Intermediate 37B: Yellow solid; MS(ESI)650.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to intermediate 37A and intermediate 37B.

[0241] Example 30A (S)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropanediol 1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] To a stirred solution of Intermediate 37A (140 mg, 0.22 mmol) in DCM (4 mL) was added 2 M HCl in EtO (1 mL) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure and triturated with diethyl ether to give Example 30A (60 mg, 50%) as the HCl salt after drying under high vacuum. 1 H NMR(400MHz,DMSO-d6)δ 10.38(brs,1H),9.39(s,2H),8.91(s,1H),8.08(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,1H), 7.73(s,1H),7.47(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,2H),5.70-5.60(m,1H),4.97(d,J= 15.4Hz,1H),4.81-4.77(m,2H),4.60-4.55(m,1H),4.43-4.33(m,2H),3.26(brs,1H),3. 13-2.94(m,2H),2.67-2.56(m,2H),2.33-2.23(s,1H),1.09(s,4H);MS(ESI)550.5[M+H] + .

[0242] Example 30B [ka] Example 30B was prepared according to the procedure of Example 30A as the hydrochloride salt. 1H NMR(400MHz,DMSO-d6)δ 10.38(brs,1H),9.4(s,2H),8.91(s,1H),8.08(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,1H), 7.73(s,1H),7.47(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,2H),5.70-5.60(m,1H),4.97(d,J= 15.4Hz,1H),4.81-4.77(m,2H),4.60-4.55(m,1H),4.43-4.33(m,2H),3.26(brs,1H),3. 13-2.94(m,2H),2.67-2.56(m,2H),2.33-2.23(s,1H),1.09(s,4H);MS(ESI)550.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 30A and Example 30B.

[0243] Example 31A (S)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinone-2-yl)-1,2-dihydro-3H-pi Lazolo[3,4-d]pyrimidin-3-one [ka] Example 31B (R)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinone-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Using Intermediate 32 and Intermediate 35, 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinone-2-yl)-6-((2'-(2,2,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (364 mg, 26%) was prepared according to the procedure described for Examples 2A and 2B. MS (ESI) 606.4 [M+H] + .

[0244] Step 2: To a stirred solution of 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((2'-(2,2,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg, 0.66 mmol) in MeOH (12 mL) was added K2CO3 (183 mg, 1.32 mmol) and the reaction was stirred at room temperature for 16 h. After completion by TLC, the solvent was evaporated. The reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure to give racemic 2-allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)amino)-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (310 mg) as a pale yellow solid. The enantiomers were separated by chiral SFC chromatography (Chiralpak AD-H, (0.5% isopropylamine in IPA)) to give peak 1 (Example 31A, 120 mg) and peak 2 (Example 31B, 123 mg). Example 31A: yellow solid; 1 H NMR (400 MHz, DMSO-d 6)δ 10.15(br s,1H),8.85(s,1H),7.75-7.69(m,2H),7.56(br s,1H),7.30(d,J=8.0Hz,1H),6.67(d,J=8.8Hz,1H),5.71-5.61(m,1H),4.99(d,J=9.2Hz,1H),4.90-4.81(m,3H),4.67-4.62(dd,J=16Hz,J=6 .0Hz,1H),3.92(s,2H),2.86-2.66(m,4H),1.96-1.92(m,2H),1.84-1.71(m,2H),1.49(s,3H),0.88(s,2H),0.78(s,2H);MS(ESI)510.2[M+H] + Example 31B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.15(br s,1H),8.85(s,1H),7.75-7.69(m,2H),7.56(br s,1H),7.30(d,J=7.6Hz,1H),6.67(d,J=8.4Hz,1H),5.70-5.63(m,1H),4.9 9(d,J=9.2Hz,1H),4.89-4.80(m,3H),4.67-4.62(dd,J=16Hz,J=5.6Hz,1H) ,3.92(s,2H),2.86-2.74(m,4H),1.96-1.92(m,2H),1.84-1.78(m,1H),1.7 3-1.71(m,1H),1.49(s,3H),0.88(s,2H),0.78(s,2H);MS(ESI)510.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 31A and Example 31B.

[0245] Intermediate 38 2-Bromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine [ka] Step 1: 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine was synthesized according to the procedure in WO2016138821.

[0246] Step 2: To a stirred solution of 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (3 g, 24.16 mmol) in CH3CN (30 mL) was added NBS (9.04 g, 50.80 mmol) portionwise at 0 °C. The reaction was stirred at 0 °C for 2 h. After completion by TLC, the reaction was concentrated. The crude mixture was triturated with CCl4 (5 × 30 mL), filtered, and the filtrate was concentrated under vacuum to give 2,3-dibromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (3 g, 44%) as a white solid. MS (ESI) 281.1 [M+H] + .

[0247] Step 3: To a stirred solution of 2,3-dibromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (500 mg, 1.76 mmol) in dry THF was added 1.6 M iPrMgCl (1.65 mL, 2.85 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h. After completion by TLC, the reaction was quenched with water (25 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (Na SO ) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO , 3% MeOH / DCM) to give intermediate 38 (280 mg, 77%) as an off-white solid. MS (ESI) m / z 203.3 [M+H] + .

[0248] Intermediate 39 2-Allyl-1-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 39 was prepared using Intermediate 1 and Intermediate 38 according to the procedure described for Intermediate 3. The mixture was degassed for 20 minutes and then heated in a microwave at 100° C. for 2 hours. MS (ESI) 345.5 [M+H] + .

[0249] Example 32 2-Allyl-1-(5,6-dihydro-8-imidazo[2,1-c][1,4]oxazin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 32 (5 mg) was prepared using Intermediate 39 following the procedures described for Examples 2A and 2B. 1 H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),8.77(s,1H),7.53-7.48(m,3H),6.86(d,J=8.8Hz,1H),5.76(s,1H),5.73-5.71(m,1H),5.11(d,J=10.8Hz,1H),5.03( d,J=17.6Hz,1H),4.71(s,2H),4.24(s,2H),4.10-4.05(m,4H),3.06(t,J=4.4Hz,4H),2.50-2.42(m,4H),2.21(s,3H);MS(ESI)m / z 488.2[M+H] + .

[0250] Intermediate 40 2-Iodo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka] Step 1: To a stirred solution of 6-chloro-3-methylpicolinate (10 g, 54 mmol) in CHCN (50 mL) was added NaI (40 g, 270 mmol) followed by TMS-Cl (36 mL, 270 mmol) at room temperature. The reaction was refluxed for 8 hours. After completion by TLC, the solvent was evaporated and the residue was diluted with water (100 mL) and EtOAc (3 × 100 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 50% EtOAc / petroleum ether) to afford 6-iodo-3-methylpicolinic acid (8 g, 57%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 13.50 (br s, 1H), 7.72 (d, J = 3Hz, 2H), 2.41 (s, 3H).

[0251] Step 2: To a stirred solution of 6-iodo-3-methylpicolinic acid (8 g, 30 mmol) in MeOH (80 mL) was added H2SO4 (4.8 mL, 91 mmol) dropwise at 0 °C. The ice bath was removed, and the mixture was stirred under reflux for 12 h. After completion by TLC, the solvent was evaporated and the residue was diluted with water (100 mL). The pH was adjusted to 9 using saturated NaHCO3, and the reaction was extracted with EtOAc (3 x 50 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% EtOAc / petroleum ether) to give methyl 6-iodo-3-methylpicolinate (7 g, 83%) as a pale yellow solid. MS (ESI) 278.3 [M+H] + .

[0252] Step 3: To a stirred solution of methyl 6-iodo-3-methylpicolinate (8.5 g, 30 mmol) in CCl4 (100 mL) was added NBS (7.1 g, 39 mmol) and AIBN (492 mg, 3 mmol). The reaction was heated at 65 °C for 16 h. After completion by TLC, the solvent was evaporated and the residue was suspended in water (100 mL). The mixture was extracted with DCM (3 × 50 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 15% EtOAc / petroleum ether) to give methyl 3-(bromomethyl)-6-iodopicolinate (4.31 g, 40%) as a brown liquid. MS (ESI) 356.1 [M+H] + .

[0253] Step 4: To a stirred, room temperature solution of methyl 3-(bromomethyl)-6-iodopicolinate (3 g, 8.4 mmol) in THF (10 mL) was added 2.0 M methylamine in THF (42 mL, 84 mmol). The reaction was stirred at room temperature for 24 hours. After completion by TLC, the solvent was evaporated and the residue was diluted with water (30 mL). The resulting precipitate was filtered and dried to give Intermediate 40 (1.3 g, 56%) as an off-white solid. MS (ESI) 275.2 [M+H] + .

[0254] Intermediate 41 2-Allyl-1-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 41 was prepared using Intermediate 1 and Intermediate 40 according to the procedure described for Intermediate 3. The mixture was degassed for 20 minutes and then heated in a microwave at 100° C. for 2 hours. MS(ESI) 369.4 [M+H] + .

[0255] Example 33 2-Allyl-1-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 33 (150 mg) was prepared using Intermediate 41 following the procedures described for Examples 2A and 2B. 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.85(s,1H),8.33(d,J=7.2Hz,1H),8.06(d,J=8Hz,1H),7.58(br s,2H),6.94(d,J=8.8Hz,2H),5.73-5.66(m,1H),5.00(d,J=10Hz,1H),4.86(d,J=17.2Hz,1H),4.63-4.61 (m,2H),4.55(s,2H),3.13(s,3H),3.11-3.09(m,4H),2.47-2.44(m,4H),2.22(s,3H);MS(ESI)512.3[M+H] + .

[0256] Intermediate 42 6-(tert-butyl)-2-iodo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka] To a stirred room temperature solution of methyl 3-(bromomethyl)-6-iodopicolinate (500 mg, 1.4 mmol) in THF (5 mL) was added tert-butylamine (256 mg, 3.50 mmol). The reaction was stirred at room temperature for 16 hours. After completion by TLC, the solvent was evaporated and the residue was diluted with water (30 mL). The precipitated solid was filtered and dried to give Intermediate 42 (220 mg, 49%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ 7.96 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 1.49 (s, 9H).

[0257] Intermediate 43 2-Allyl-1-(6-(tert-butyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 43 was prepared using Intermediate 1 and Intermediate 42 according to the procedure described for Intermediate 3. The mixture was degassed for 20 minutes and then heated in a microwave at 100° C. for 2 hours. MS (ESI) 411.14 [M+H] + .

[0258] Example 34 2-Allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Step 1: Using intermediate 43, 2-allyl-1-(6-(tert-butyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (150 mg) was prepared according to the procedure described for Examples 2A and 2B. MS (ESI) 554.0 [M+H] + .

[0259] Step 2: To a stirred solution of 2-allyl-1-(6-(tert-butyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (150 mg, 7.05 mmol) was added trifluoromethanesulfonic acid (0.7 mL) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 2 h. After completion by TLC, the reaction was neutralized with NaHCO and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (H0 / CHCN gradient) to give Example 34 (10 mg) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ 10.20(br s,1H),9.09(br s,1H),8.85(s,1H),8.32(d,J=7.2Hz,1H),8.07(d,J=8.4Hz,1H),7.58(br s,2H),6.94(d,J=8.4Hz,2H),5.74-5.67(m,1H),5.01(d,J=10.0Hz,1H),4.80(d,J=18.0Hz,1H),4.63(br s,2H),4.46(br s,2H),3.10(s,4H),2.47-2.45(m,4H),2.22(s ,3H); MS(ESI) 498.2 [M+H] + .

[0260] Intermediate 44 5-Bromo-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-3-ol [ka] Step 1: To a stirred solution of ethyl 2-hydroxyacetate (27.67 g, 266.14 mmol) in DME (200 mL) was added 60% NaH (8.744 g, 380.2 mmol) portionwise at 0 °C. The ice bath was removed and the reaction was stirred for 30 minutes. Ethyl 5-bromo-2-chloronicotinate (20 g, 76.04 mmol) was added and the reaction was refluxed for 16 hours. After completion by TLC, the reaction was concentrated under reduced pressure and the residue was dissolved in water (150 mL). The mixture was adjusted to pH 4 using acetic acid. The mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 30% EtOAc / petroleum ether) to give ethyl 5-bromo-3-oxo-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate (8.5 g, 30%) as an off-white solid. MS(ESI) 285.9 [M+H] + .

[0261] Step 2: A mixture of ethyl 5-bromo-3-oxo-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate (9 g, 31.57 mmol) and 50% aqueous HSO (90 mL) was heated to 60 °C and stirred for 16 h. After completion by TLC, the reaction mixture was diluted with ice-cold water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (150 mL), brine (200 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give 5-bromofuro[2,3-b]pyridin-3(2H)-one (4.5 g, 66%) as a light brown solid. MS (ESI) 213.8 [M+H] + .

[0262] Step 3: To a stirred solution of 5-bromofuro[2,3-b]pyridin-3(2H)-one (4 g, 18.77 mmol) in diethyl ether (40 mL) was added 3.0 M CH3MgI in DEE (31 mL, 93.85 mmol) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% EtOAc / petroleum ether) to give intermediate 44 (2.0 g, 46%) as a brown solid. MS (ESI) 229.9 [M+H] + .

[0263] Intermediate 45 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 45 was prepared using Intermediate 1 and Intermediate 44 according to the procedure described for Intermediate 3. The mixture was degassed for 20 minutes and then heated in a microwave at 100° C. for 6 hours. MS (ESI) 372.4 [M+H] + .

[0264] Example 35A 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 35B (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 35A and 35B were prepared using Intermediate 45 according to the procedure described for Examples 2A and 2B to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (150 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, (35.0% (0.5% isopropylamine in IPA)) to give peak 1 (Example 35A, 48 mg) and peak 2 (Example 35B, 150 mg). Compound 2 (Example 35B, 46 mg) was obtained. Example 35A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ10.30(br s,1H),8.81(s,1H),8.18(d,J=2.4Hz,1H),7.83(br s,1H),7.49(d,J=8.4Hz,2H),6.84(d,J=8.8Hz,2H),5.83(s,1H),5.73-5.64 (m,1H),5.11(d,J=10.4Hz,1H),4.97(d,J=17.2Hz,1H),4.44(s,2H),4.23(br MS(ESI)515.2[M+H] + Example 35B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.04(br s,1H),8.81(s,1H),8.17(d,J=2.4Hz,1H),7.83(br s,1H),7.49(d,J=8.4Hz,2H),6.83(d,J=8.4Hz,2H),5.83(s,1H),5.74-5.65 (m,1H),5.11(d,J=10.4Hz,1H),4.97(d,J=17.2Hz,1H),4.44(s,2H),4.23(br MS(ESI)515.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 35A and Example 35B.

[0265] Intermediate 46 2-Bromo-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol [ka] Step 1: 5,6-dihydro-7H-pyrrolo[1,2-a]imidazol-7-one was prepared according to US Patent Application Publication No. 2012 / 0214762.

[0266] Step 2: To a 0°C solution of 5,6-dihydro-7H-pyrrolo[1,2-a]imidazol-7-one (15 g, 123.0 mmol) in THF (150 mL) was added 3 M MeMgBr (49 mL, 147.0 mmol) dropwise. The ice bath was removed and the reaction was stirred at room temperature for 5 h. After completion by TLC, the reaction was quenched with saturated NH4Cl solution at 0°C. The mixture was extracted with 10% MeOH / DCM (2 x 200 mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, 3% MeOH / DCM) to give 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (5.1 g, 30%) as a yellow solid. MS (ESI) 139.1 [M+H] + .

[0267] Step 3: To a solution of 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (14 g, 0.101 mol) in DCM (140 mL) at 0 °C, NaHCO (0.111 mmol) and NBS (37.7 g, 0.212 mol) were added portionwise over 10 min. The ice bath was removed and the reaction was stirred at room temperature for 3 h. After completion by TLC, the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 3% MeOH / DCM) to give 2,3-dibromo-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (7 g, 23%) as a yellow solid. MS (ESI) 296.8 [M+H] + .

[0268] Step 4: 2,3-Dibromo-7-methyl-6,7-dihydro in THF (70 mL) To 5H-pyrrolo[1,2-a]imidazol-7-ol (7 g, 23.7 mmol) at 0 °C was added 1.3 M i-PrMgCl in THF (29 mL, 37.9 mmol) dropwise. The ice bath was removed and the reaction was stirred at room temperature for 2 h. After completion by TLC, the reaction was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, 3% MeOH / DCM) to give intermediate 46 (3.5 g, 68%) as an off-white solid. MS (ESI) 217.3 [M+H] + .

[0269] Intermediate 47 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 47 was prepared using Intermediate 1 and Intermediate 46 following the procedure described for Intermediate 3. MS (ESI) 359.1 [M+H] + .

[0270] Example 36A (S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 36B (R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 36A and 36B were prepared using Intermediate 47 according to the procedures described for Examples 2A and 2B to give racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (250 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak OJ-H, 10.0% (0.5% DEA in ethanol) to give Peak 1 (Example 36A, 53 mg) and Peak 2 (Example 36B, 66 mg). Example 36A: yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 9.92(br s,1H),8.77(s,2H),7.50(d,J=8.4Hz,2H),7.45(s,1H),6.85(d,J=7.2Hz,2H),5.75-5.68(m,1H),5.55(s,1H),5.10(d,J=10.0Hz,1H),5. 02(d,J=17.2Hz,1H),4.24(s,2H),4.12-4.02(m,2H)3.05(s,4H),2.44(s,1H)2.43(s,4H),2.21(s,3H),1.49(s,3H);MS(ESI)502.2[M+H] + Example 36B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 9.92(br s,1H),8.77(s,2H),7.50(d,J=8.4Hz,2H),7.45(s,1H),6.85(d,J=7.2Hz,2H),5.75-5.68(m,1H),5.55(s,1H),5.10(d,J=10.0Hz,1H),5.0 2(d,J=17.2Hz,1H),4.24(s,2H),4.12-4.02(m,2H),3.06(s,4H),2.46(s,1H),2.45(s,4H),2.21(s,3H),1.50(s,3H);MS(ESI)502.3[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 36A and Example 36B.

[0271] Intermediate 48 3-Bromo-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol [ka] Step 1: 3-Amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one was prepared according to Sakairi, M., Arzneimittel Forschung, 62(11), 537-544; 2012.

[0272] Step 2: To a solution of 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (200 mg, 1.34 mmol) in dibromomethane (2 mL) at 0 °C, CuBr (0.149 g, 0.668 mmol) was added portionwise. Isoamyl (0.179 g, 1.49 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction was quenched with water (50 mL), basified with saturated NaHCO3, and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30% EtOAc / petroleum ether) to give 3-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (60 mg, 21%) as a brown solid. MS (ESI) 212.3 [M+H] + .

[0273] Step 3: To a solution of 3-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (50 mg, 0.23 mmol) in EtO (2 mL) at 0 °C, 3.0 M MeMgBr in EtO (0.4 mL, 1.15 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 16 h. After completion by TLC, the reaction was poured into ice water (15 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was dried (NaSO) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 30% EtOAc / petroleum ether) to give intermediate 48 (15 mg, 28%) as a brown solid. MS (ESI) 228.4 [M+H] + .

[0274] Intermediate 49 2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 49 was prepared using Intermediate 1 and Intermediate 48 following the procedure described for Intermediate 3. MS (ESI) 370.4 [M+H] + .

[0275] Example 37A (S)-2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 37B (R)-2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H- Cyclopenta[c]pyridin-3-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 37A and 37B were prepared using Intermediate 49 according to the procedures described for Examples 9A and 9B to give racemic 2-allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (25 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak AD-H 20.0% (0.5% DEA in methanol)) to give Peak 1 (Example 37A, 10 mg) and Peak 2 (Example 37B, 10 mg). Example 37A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.14(br s,1H),8.81(s,1H),8.37(s,1H),7.75(br s,1H),7.58(br s,2H),6.93(d,J=8.8Hz,2H),5.70-5.61(m,1H),5.49(s,1H),5.02(d,J=10Hz,1H),4.86(d,J=17.2Hz,1H),4.65-4.45(m,2H), 3.07-3.03(m,4H),3.02-2.81(m,2H),2.46-2.43(m,4H),2.22(s,3H),2.16(t,J=7.6Hz,2H),1.45(s,3H);MS(ESI)513.4[M+H] + .Example 37B: yellow solid matter; 1 H NMR(400MHz,DMSO-d6)δ 10.14(br s,1H),8.81(s,1H),8.37(s,1H),7.75(br s,1H),7.58(br s,2H),6.93(d,J=12.4Hz,2H),5.70-5.61(m,1H),5.49(s,1H),5.02(d,J=9.6Hz,1H),4.86(d,J=17.2Hz,1H),4.65-4.45(m,2H) ,3.08-3.06(m,4H),3.04-2.81(m,2H),2.46-2.43(m,4H),2.22(s,3H),2.16(t,J=7.6Hz,2H),1.45(s,3H);MS(ESI)513.7[M+H] + .The absolute stereochemistry of Example 37A and Example 37B is arbitrary and the same as that of Example 37B.

[0276] Intermediate 50 2-ブロモ-7-(1,1-ジフルオロエチル)-6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-7-オール

change

[0277] Step 2: To a solution of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (2.5 g, 9.82 mmol) in THF (25 mL) was added 60% NaH (590 mg, 14.76 mmol) at 0 °C. The mixture was stirred for 30 minutes, and acetic anhydride (1.39 mL, 14.76 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 16 hours. After completion by TLC, the reaction was quenched with ice-water and extracted with EtOAc (2 × 100 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried (NaSO), and evaporated to dryness. The residue was purified by flash chromatography (neutral alumina, 10% EtOAc / petroleum ether) to give 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (1.7 g, 58%) as a yellow liquid. MS(ESI) 296.0 [M+H] + .

[0278] Step 3: A stirred solution of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (3.4 g, 11.5 mmol) in MeOH (40 mL) was purged with ozone gas at −78° C. for 30 minutes. Upon completion by TLC, the reaction was quenched with 1 mL of dimethyl sulfide at −78° C. and stirred at room temperature for 1 hour. The reaction mixture was concentrated and diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (NaSO), and evaporated under reduced pressure to give 7-acetyl-2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (2.1 g, 61%) as a white solid. MS (ESI) m / z 298.1[M+H] + .

[0279] Step 4: To 7-acetyl-2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (800 mg, 2.69 mmol) in a sealed tube was added DAST (8.9 mL, 67.34 mmol), and the reaction was stirred at room temperature for 2 days. Upon completion, the reaction mixture was added dropwise to crushed ice and extracted with EtOAc (2 × 100 mL). The organic layer was separated, washed with water (2 × 50 mL), dried (NaSO), and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO, 10% EtOAc / hexanes) to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenta-[b]pyridin-7-yl acetate (85 mg, 10%) as a brown oil. MS (ESI) 320.1 [M+H] + .

[0280] Step 5: To a stirred solution of 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (300 mg, 0.937 mmol) in MeOH (5 mL) was added K2CO3 (259 mg, 1.88 mmol) at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 3 h. Upon completion by TLC, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried (NaSO) and evaporated under reduced pressure to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (230 mg, 0.83 mmol, 88%) as a brown liquid. MS (ESI) 278.0 [M+H] + .

[0281] Intermediate 51 2-Allyl-1-(7-(1,1-difluoroethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Intermediate 51 was prepared using Intermediate 1 and Intermediate 50 according to the procedure described for Intermediate 3. MS (ESI) 420.2 [M+H] + .

[0282] Example 38A (S)-2-Allyl-1-(7-(1,1-difluoroethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 38B (R)-2-Allyl-1-(7-(1,1-difluoroethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 38A and 38B were prepared using Intermediate 51 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-(1,1-difluoroethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (105 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 38A, 10 mg) and Peak 2 (Example 38B, 20 mg). Example 38A: 1 H NMR(400MHz,DMSO-d6)δ 10.03(br s,1H),8.82(s ,1H),8.01(br s,1H),7.81(d,J=8.0Hz,1H),7.57(br s,2H),6.92(d,J=8.8Hz,2H),6.12(s,1H),5.6-5.62(m,1H),4.99(d,J=9.6Hz,1H),4.86-4.77(m,2H),4.5(m,1H),3.09(s,5H),3. 01-2.99(m,1H),2.98-2.89(m,1H),2.50-2.46(m,4H),2.22(s,3H),2.20-2.10(m,1H),1.92(t,J=19.6Hz,3H);MS(ESI)563.5[M+H] + Example 38B: 1H NMR(400MHz,DMSO-d6)δ 10.03(br s,1H),8.82(s,1H),8.01(br s,1H),7.81(d,J=8.0Hz,1H),7.57(br s,2H),6.92(d,J=8.8Hz,2H),6.12(s,1H),5.66-5.64(m,1H),5.00-4.97(d,J=9.6Hz,1H),4.85-4.81(m,2H),4.57(m,1H),3.09 -2.86(m,5H),2.89-2.88(m,1H),2.57-2.50(m,5H),2.22(s,3H),2.15-2.05(m,1H)1.92(t,J=19.6Hz,3H);MS(ESI)563.5[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 38A and Example 38B.

[0283] Intermediate 52 1-(1-methylpiperidin-4-yl)-1H-indol-5-amine [ka] Intermediate 52 was prepared according to the procedure described in EP 2141163. MS (ESI) 230.6 [M+H] + .

[0284] Example 39A (S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4-yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 39B (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4-yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 39A and 39B were prepared using Intermediate 17 and Intermediate 52 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4-yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (240 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 39A, 69 mg) and Peak 2 (Example 39B, 67 mg). Example 39A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.21(br s,1H),8.84(s,1H),8.09(br s,1H),7.90(d,J=7.6Hz,1H),7.77(d,J=8.0Hz,1H),7.49-7.46(m,2H),7.40-7.30(m,1H),6.43(d,J =3.2Hz,1H),5.73-5.63(m,1H),5.06(s,1H),4.99(d,J=10.4Hz,1H),4.86(d,J=16.4Hz,1H),4.83-4 .70(m,1H),4.60-4.50(m,1H),4.35-4.25(m,1H),3.01-2.89(m,3H),2.82-2.75(m,1H),2.24(s,3H) ,2.24-2.12(m,3H),2.03-1.86(m,6H),1.73-1.68(m,1H),0.87(t,J=7.4Hz,3H);MS(ESI)565.5[M+H] + Example 39B: Yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.21(br s,1H),8.84(s,1H),8.09(br s,1H),7.90(d,J=7.6Hz,1H),7.77(d,J=8.4Hz,1H),7.49-7.46(m,2H),7.40-7.30(m,1H),6.43(d,J =3.2Hz,1H),5.71-5.63(m,1H),5.06(s,1H),4.99(d,J=10.4Hz,1H),4.86(d,J=17.6Hz,1H),4.83-4 .70(m,1H),4.60-4.55(m,1H),4.35-4.25(m,1H),3.00-2.89(m,3H),2.82-2.75(m,1H),2.24(s,3H) ,2.24-2.12(m,6H),2.03-1.86(m,6H),1.73-1.68(m,1H),0.87(t,J=7.4Hz,3H);MS(ESI)565.4[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 39A and Example 39B.

[0285] Intermediate 53 3-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline [ka] Intermediate 53 was prepared according to the procedure described in WO 2014 / 134308. MS(ESI) 203.4 [M+H] + .

[0286] Example 40A S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Example 40B (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] Examples 40A and 40B were prepared using Intermediate 17 and Intermediate 53 according to the procedure described for Examples 9A and 9B to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (217 mg). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 40A, 35 mg) and Peak 2 (Example 40B, 33 mg). Example 40A: Yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.20(br s,1H),8.88(s,1H),7.90(d,J=8.4Hz,1H),7.72(d,J=8.0Hz,1H),7.65(brs,1H),7.45(dd,J=8. 4Hz,2.0Hz,1H),7.01(d,J=8.4Hz,1H),5.51-5.50(m,1H),5.50(s,1H),5.05(s,1H),4.99(d,J= 10Hz,1H),4.85(d,J=17.2Hz,1H),4.74-4.59(m,2H),2.97-2.95(m,3H),2.82-2.80(m,1H),2.5 6-2.50(m,2H),2.28-2.19(m,9H),2.01-1.69(m,3H),0.86(t,J=7.6Hz,3H);MS(ESI)538.2[M+H] + Example 40B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.20(br s,1H),8.88(s,1H),7.90(d,J=8.4Hz,1H),7.72(d,J=8.0Hz,1H),7.65(brs,1H),7. 45(dd,J=8.4Hz,2.0Hz,1H),7.01(d,J=8.4Hz,1H),5.51-5.50(m,1H),5.50(s,1H), 5.05(s,1H),4.99(d,J=10Hz,1H),4.85(d,J=17.2Hz,1H),4.74-4.59(m,2H),2.97-2.95(m,3H),2.82-2.80 (m,1H),2.56-2.50(m,2H),2.28-2.19(m,9H),2.01-1.69(m,3H),0.86(t,J=7.6Hz,3H);MS(ESI)538.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 40A and Example 40B.

[0287] Intermediate 54 N-(2-bromo-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide [ka] To a stirred solution of Intermediate 31 (250 mg, 1.037 mmol) in acetonitrile (6 mL) was added chlorosulfonic acid (0.2 mL) at room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure, diluted with water (10 mL), extracted with EtOAc (2 × 10 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The above reaction was repeated on a 3 × 250 mg scale. The combined residues were purified by flash chromatography (SiO, 40% EtOAc / petroleum ether) to give Intermediate 54 (480 mg, 41%) as an off-white solid. MS (ESI) 283.1 [M+1] + .

[0288] Intermediate 55 [ka] Intermediate 55 was prepared using Intermediate 1 and Intermediate 54 following the procedure described for Intermediate 3. MS (ESI) 425.1 [M+H] + .

[0289] Example 41A (S)—N-(2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide [ka] Example 41B (R)-N-(2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide [ka] Examples 41A and 41B were prepared using Intermediate 17 and Intermediate 55 according to the procedure described for Examples 9A and 9B to give racemic N-(2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (220 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak IC, (40.0% (0.5% DEA in MeOH)) to give Peak 1 (Example 41A, 70 mg) and Peak 2 (Example 41B, 50 mg). Example 41A: yellow solid; 1H NMR(400MHz,DMSO-d6)δ 10.12(brs,1H),8.80(s,1H),8.18(s,1H),7.71(d,J=7.6Hz,1H),7.60(d,J=8.0H z,3H),6.96(d,J=8.8Hz,2H),5.60-5.55(m,1H),4.97(d,J=10.0Hz,1H),4.87(d, J=17.2Hz,1H),4.75-4.70(m,1H),4.53-4.51(m,1H),3.30-3.10(m,4H),2.93-2. 76(m,6H),2.68-2.58(m,4H),1.86-1.68(m,6H),1.40(s,3H);MS(ESI)568.2[M+H] + Example 41B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ 10.12(brs,1H),8.79(s,1H),8.17(s,1H),7.71(d,J=7.6Hz,1H),7.60(d,J=8.0Hz,3H ),6.92(d,J=8.8Hz,2H),5.60-5.55(m,1H),4.97(d,J=10.4Hz,1H),4.87(d,J=17.2Hz, 1H),4.73-4.69(m,1H),4.53-4.48(m,1H),3.10(s,4H),2.79(m,2H),2.63-2.58(m,1H ),2.47-2.44(m,4H),2.22(s,3H),1.84-1.68(m,6H),1.40(s,3H);MS(ESI)568.2[M+H] + Absolute stereochemistry has been arbitrarily assigned to Example 41A and Example 41B.

[0290] Example 42 2-Allyl-1-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ka] To a stirred solution of N-(2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (500 mg, 0.881 mmol) in a pressure tube was added 1,4-dioxane (10 mL) and 6 M HCl (10 mL). The reaction was heated at 100° C. for 16 h. The reaction was concentrated under reduced pressure and the pH was adjusted to 8 with 1 M NaOH. The mixture was extracted with 10% MeOH / DCM (3×50 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by HPLC chromatography (C18, water / CH3CN) to give Example 42 (90 mg, 19%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.15(brs,1H),8.81(s,1H),7.74(d,J=8.1Hz,1H),7.65-7.52(m,3H),6.9 2(d,J=9.3Hz,2H),5.76-5.60(m,1H),5.00(d,J=10.2Hz,1H),4.86(d,J=17. 1Hz,1H),4.74-4.60(m,2H),3.15-3.05(m,4H),2.85-2.75(m,2H),2.48-2. 43(m,4H),2.25(s,3H),1.90-1.75(m,6H),1.35(s,3H);MS(ESI)526.2[M+H] + .

[0291] Step A Wee1 binding assay Fluorescence Resonance Energy Transfer (FRET) assay Wee1 kinase was measured by using a 384-well plate assay. Wee1 kinase (final concentration 2 nM) was incubated with AlexaFluor-labeled tracer 178 (final concentration 50 nM, K dThe Eu anti-GST antibody (final concentration 2 nM), Eu anti-GST antibody (final concentration 2 nM), and then inhibitors (0.003-10 micromolar concentrations) were mixed in a final volume of 16 µL of kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ®-35, 10 mM MgCl, 1 mM EGTA). The plate was shaken for 30 s, incubated at room temperature for 60 min, and recorded on a fluorescent plate reader. The results are shown in Table 1.

[0292] Step B H23 cell proliferation assay H23 [ATCC (CRL-5800™)] cells were grown and maintained in RPMI-1640 medium containing 10% FBS and 1% penicillin-streptomycin. Cells were treated with compounds diluted in DMSO using 9-point, 5-fold serial dilutions. Plates were placed at 37°C in 5% CO2 and incubated for 4 days. Plates were briefly shaken (2 min) and incubated at room temperature for 10 min before being developed by adding 100 μL of CellTiter-Glo reagent (Promega) to the assay plate. Plates were read on an M5e plate reader according to the CellTiter-Glo protocol. IC was determined using GraphPad Prism software. 50 The results are shown in Table 1. show.

[0293] [Table 1-1]

[0294] [Table 1-2] IC of Wee1 enzyme 50 For A = single IC 50 ≤10nM; B = single IC 50 >10 nM and <100 nM; C = single IC 50 ≥ 100 nM. IC of H23 50 For A = single IC 50 ≤100nM; B = single IC 50>100 nM and <1000 nM; C = single IC 50 ≧1000 nM.

[0295] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made thereto without departing from the spirit of the present disclosure. It should therefore 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 encompass all modifications and alternatives consistent with the true scope and spirit of the present invention.

Claims

1. A compound of formula (I) having the structure: 【Chemical 1】 (In the formula, R １ represents hydrogen, halogen, and substituted or unsubstituted C １ ~C ６ is selected from the group consisting of alkyl, Ring A is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; Ring B is selected from the group consisting of substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R ２ teeth, 【Chemistry 2】 is selected from the group consisting of m is 0, 1, 2, or 3; R ３ represents halogen and substituted or unsubstituted C １ ~C ６ is selected from the group consisting of alkyl, X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl, substituted or unsubstituted amine (C １ ~C ６ alkyl), substituted or unsubstituted —NH—(CH ２ ) １－６ -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C １ ~C ６ Alkoxy, substituted or unsubstituted C ３ ~C ６ cycloalkoxy, substituted or unsubstituted (C １ ~C ６ alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y is CH or N; Y １ is CR ４Ａ or N, Y ２ is CR ４Ｂ or N, Ring C is a substituted or unsubstituted C ６ ~C １０ selected from the group consisting of aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R ４Ａ and R ４Ｂ are independently hydrogen, halogen, and unsubstituted C １－４ is selected from the group consisting of alkyl, R ５ is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl).

2. R １ The compound of claim 1 , wherein is hydrogen.

3. The compound according to claim 1 or 2, wherein ring A is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl.

4. 3. The compound of claim 1 or 2, wherein Ring A is selected from the group consisting of substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyridazine.

5. The compound according to any one of claims 1 to 4, wherein ring B is a substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl. 【Request 6】 【Chemical 3】 【Chemistry 4】 3. The compound of claim 1 or 2, wherein each of said groups is substituted or unsubstituted.

7. The compound of any one of claims 1 to 6, wherein ring A is unsubstituted.

8. The compound of any one of claims 1 to 7, wherein Ring B is substituted.

9. Ring B is fluoro, hydroxy, amino, unsubstituted —NHC(O)C １ ~C ６ Alkyl, unsubstituted C １ ~C ６ Haloalkyl, and unsubstituted C １ ~C ６ 9. The compound of claim 8, substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

10. R ２ but, 【Chemistry 5】 and The compound of any one of claims 1 to 9, wherein Y is CH.

11. The compound of claim 10, wherein X is a substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl.

12. 11. The compound of claim 10, wherein X is selected from the group consisting of substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted diazetidine, substituted or unsubstituted azaoxetane, substituted or unsubstituted pyrrolidine, substituted or unsubstituted tetrahydrofuran, substituted or unsubstituted imidazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted piperazine, substituted or unsubstituted morpholine, and substituted or unsubstituted dioxane.

13. The compound of any one of claims 10 to 12, wherein X is substituted.

14. X is halogen, substituted or unsubstituted C １ ~C ６ Alkyl, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted amine (C １ ~C ６ alkyl), and substituted or unsubstituted (C １ ~C ６ 14. The compound of claim 13, substituted with one or two substituents independently selected from the group consisting of: alkyl)acyl.

15. The compound according to any one of claims 1 to 14, wherein m is 0.

16. 【Chemical 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 or a pharmaceutically acceptable salt of any of the foregoing.

17. A pharmaceutical composition for ameliorating or treating cancer, malignant growth, and / or tumor replication, comprising an effective amount of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the cancer is brain cancer, cervicocerebral cancer, or the like. a pharmaceutical composition for treating a cancer selected from the group consisting of esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, Wilms' carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

18. 18. The pharmaceutical composition of claim 17, wherein the cancer is resistant to one or more anti-cancer agents.

19. 19. A pharmaceutical composition for inhibiting malignant growth or tumor replication, comprising an effective amount of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the malignant growth or tumor is caused by a cancer selected from brain cancer, cerebral cervical cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, Wilms' carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. composition.

20. A pharmaceutical composition for inhibiting the activity of WEE1 in a cell, comprising an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

21. 21. The pharmaceutical composition of claim 20, wherein the cell is a TP53 mutant cell.

22. A method for preparing a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, comprising: a compound of formula (A) having the structure: 【Chemistry 10】 (In the formula, R ２ is as defined above) with a compound of formula (B) having the structure: 【Chemistry 11】 (In the formula, R １ , ring A, and ring B are as defined above).

23. Has the following structure: 【Chemistry 12】 or having the following structure: 【Chemistry 13】 , a compound of formula (B) or a pharmaceutically acceptable salt thereof (In the formula, R １ represents hydrogen, halogen, and substituted or unsubstituted C １ ~C ６ is selected from the group consisting of alkyl, Ring A is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; Ring B is selected from the group consisting of substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

24. A compound having the following structure: or a pharmaceutically acceptable salt thereof: 【Chemistry 14】 。

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