substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-one

Abstract

Provided herein are compounds of Formula (I). Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful in the treatment of diseases or conditions, including conditions characterized by excessive cell proliferation, such as breast cancer.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980021575.2, filed on February 26, 2019, entitled “Substituted 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one”.

[0002] Incorporate any priority claim by reference

[0003] Any or all patent applications that identify a foreign or domestic priority claim against it in, for example, a patent application data sheet or request filed with this patent application are hereby incorporated by reference under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Patent Application No. 62 / 641149, filed March 9, 2018, and No. 62 / 755163, filed November 2, 2018. Technical Field

[0004] This patent application relates to compounds as WEE1 inhibitors and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer.

[0005] describe

[0006] WEE1 kinase plays a role in G2-M cell cycle checkpoint arrest, which is crucial for DNA repair, prior to mitosis. Normal cells repair damaged DNA during G1 arrest. Cancer cells typically have a defective 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

[0007] Some implementation schemes provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] Some embodiments disclosed herein relate to pharmaceutical compositions that may comprise an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0009] Some embodiments described herein relate to methods for alleviating and / or treating the cancers described herein, which may include administering 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 containing 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 the cancer described herein. Other embodiments described herein relate 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 containing 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 an agent for alleviating and / or treating the cancers described herein. Other embodiments described herein relate 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for alleviating and / or treating the cancers described herein.

[0010] Some embodiments described herein relate to methods for inhibiting the replication of malignant growths or tumors, which may include contacting the 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 containing 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 caused by the cancer described herein. Other embodiments described herein relate 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 containing 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 an agent for inhibiting the replication of malignant growths or tumors, wherein the malignant growth or tumor is caused by the cancer described herein. Other embodiments described herein relate 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 containing 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 growths or tumors, wherein the malignant growth or tumor is caused by the cancer described herein.

[0011] Some embodiments described herein relate to methods for alleviating or treating the cancer described herein, which may include contacting a subject having the 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition containing 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 an agent for alleviating or treating the cancer described herein, which may include contact with a malignant growth or tumor, wherein the malignant growth or tumor is caused by the cancer described herein. Other embodiments described herein relate to an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for alleviating or treating the cancer described herein, and the alleviation or treatment of the cancer described herein may include contact with a malignant growth or tumor, wherein the malignant growth or tumor is caused by the cancer described herein.

[0012] Some embodiments described herein relate to methods for inhibiting the activity of WEE1 in cells (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 WEE1 p53-deficient cells, and / or reducing the overexpression of WEE1 in cells), which may include providing an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to cancer cells from the cancer described herein or a pharmaceutical composition comprising an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition containing an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of an agent 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 WEE1 p53-deficient cells, and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition containing an effective amount of the 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 WEE1 p53-deficient cells, and / or reducing the overexpression of WEE1 in cells).

[0013] Some embodiments described herein relate to methods for alleviating or treating the cancers described herein, which may include 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to the use of a pharmaceutical composition comprising an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for alleviating or treating the cancers 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to effective amounts of the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) or pharmaceutical compositions comprising effective amounts of the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), for the purpose of alleviating or treating the cancers 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Detailed Implementation

[0014] WEE1 is a tyrosine kinase, a key component of ATR-mediated G2 cell cycle checkpoint control, which prevents cells from entering mitosis in response to DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1, leading to 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 entering mitosis. Inhibition of WEE1 eliminates the G2 checkpoint, promoting unplanned mitosis in cancer cells with DNA damage and leading to cell death via mitotic barrier. Therefore, WEE1 inhibition has the potential to sensitize tumors to DNA-damaging agents such as cisplatin and induce tumor cell death.

[0015] definition

[0016] 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, publications, and other publications cited herein are incorporated herein by reference in their entirety unless otherwise stated. Where multiple definitions exist for terms herein, the terminology used in that section shall prevail unless otherwise stated.

[0017] Whenever a group is described as “optionally substituted,” the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as “unsubstituted or substituted,” if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated “optionally substituted” or “substituted” group may be substituted by one or more groups selected individually and independently from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclic(alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, nitro, thionyl, thionyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amino group, disubstituted amino group and amine (C1-C6 alkyl).

[0018] As used in this article, "C" a To C b The term “C1 to C4 alkyl” indicates the number of carbon atoms in the group. The indicated group may contain “a” to “b” carbon atoms (inclusive). Therefore, for example, “C1 to C4 alkyl” refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If “a” and “b” are not specified, the widest range described in these definitions is assumed.

[0019] If two "R" groups are described as "joined together," then the R groups and the atoms they are attached to can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic compounds. For example, but not limited to, if NR a R b R of the group a and R b When indicated as "together," it means that they are covalently bonded to each other to form a ring:

[0020]

[0021] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. An alkyl group can have 1 to 30 carbon atoms (wherever it appears herein, a numerical range such as "1 to 30" refers to each integer within a given range; for example, "1 to 30 carbon atoms" means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, but the definition of this invention also covers the term "alkyl" when no numerical range is specified). An alkyl group can also be a medium-sized alkyl group having 1 to 12 carbon atoms. An alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. The aryl group can be substituted or unsubstituted.

[0022] As used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group having two to twenty carbon atoms, containing one or more carbon double bonds, 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.

[0023] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group having two to twenty carbon atoms and containing one or more carbon triple bonds, including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, etc. The alkynyl group may be unsubstituted or substituted.

[0024] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings may be joined together in a fused, bridged, or helical manner. As used herein, the term “fused” refers to two rings sharing two atoms and one bond. As used herein, the term “bridged cycloalkyl” refers to a compound in which the cycloalkyl group contains a bond connecting one or more atoms that are not adjacent atoms. As used herein, the term “spiral” refers to two rings sharing one atom and said two rings not connected by a bridge. Cycloalkyl groups may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. Cycloalkyl groups may be unsubstituted or substituted. Examples of monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-benzothiophene, and tetradecahydroanthrayl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantyl, and norbornyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0025] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bond cannot form a fully delocalized π-electron system throughout all rings (otherwise the group would be “aryl” as defined herein). A cycloalkenyl group may contain 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. When the ring consists of two or more rings, these rings may be connected together in a fused, bridged, or helical manner. The cycloalkenyl group may be unsubstituted or substituted.

[0026] As used herein, “carbocyclic” refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. As described herein, when the ring consists of two or more rings, these rings can be joined together in a fused, bridged, or helical manner. A carbocyclic group may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. The carbocyclic group may be unsubstituted or substituted. Examples of carbocyclic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups as defined herein, and the non-aromatic portions of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-cyclopenten[b]pyridine.

[0027] As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a chemical bond) with a fully delocalized π-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C. 14 aryl group, C6-C 10 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 can be substituted or unsubstituted.

[0028] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), the heteroatoms being elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in one or more rings, 5 to 10 atoms in one or more rings, or 5 to 6 atoms in one or more rings, such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused-ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazolidone, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, borazine, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0029] As used herein, "heterocyclic group" or "heterocyclic group" refers to a ternary, quaternary, pentaneary, hexanal, heptanal, octaneary, nonanal, decanal, or up to 18-membered monocyclic, bicyclic, and tricyclic ring system in which a carbon atom, together with one to five heteroatoms, constitutes the ring system. The heterocycle may optionally contain one or more unsaturated bonds positioned in such a manner that a fully delocalized π-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. The heterocycle may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, these rings may be joined together in a fused, bridged, or helical manner. As used herein, the term "fused" refers to two rings sharing two atoms and one bond. As used herein, the term "bridged heterocyclic group" or "bridged alicyclic group" refers to a compound in which the heterocyclic group or alicyclic group comprises a bond connecting one or more atoms that are not adjacent atoms. As used herein, the term "spiral" refers to two rings that share a common atom and are not connected by a bridge. The heterocyclic group or alicyclic group may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogen in the alicyclic ring may be quaternized. The heterocyclic group or alicyclic group may be unsubstituted or substituted.Examples of such "heterocyclic" or "heterocyclic" groups include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxopentane, 1,3-dioxopentane, 1,4-dioxopentane, 1,3-oxothiocyclohexane, 1,4-oxothiocyclohexadiene, 1,3-oxothiocyclopentane, 1,3-dithiocyclopentadiene, 1,3-dithiopentane, 1,4-oxothiocyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, and dioxane. Hydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazolidinone, thiazoline, thiazoline, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, aziridine, pyrrolidone, pyrrolidone, 4-piperidinone, pyrazoline, pyrazole, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and their benzo[a]-fused analogues (e.g., benzimidazolinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spirochetal 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.

[0030] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and aryl group of an aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0031] As used herein, “heteroarylalkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and heteroaryl group of a heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furanylalkyl, thienylalkyl, pyrroliylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzofused analogs.

[0032] "Heterocyclic (alkyl)" and "heterocyclic (alkyl)" refer to heterocyclic or heterocyclic groups that are substituents connected via a lower alkylene group. The lower alkylene group and heterocyclic group of the (heterocyclic)alkyl group can 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-thiaran-4-yl (methyl), and 1,3-thiazin-4-yl (methyl).

[0033] As used herein, a “lower alkylene group” is a straight-chain -CH2-chain group that forms a bond to connect a molecular segment via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group may be replaced by one or more hydrogen atoms and / or by a cycloalkyl group (e.g., It replaces two hydrogen atoms on the same carbon atom.

[0034] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0035] As used herein, “alkoxy” refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0036] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), and heterocyclic(alkyl) group connected as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl groups can be substituted or unsubstituted.

[0037] The "cyano" group refers to the "-CN" group.

[0038] As used herein, the term "halogen atom" or "halogen" refers to any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0039] A "thiocarbonyl" group is one in which R can be the same "-C(=S)R" group as defined relative to the O-carboxyl group. Thiocarbonyl groups can be substituted or unsubstituted.

[0040] The "O-carbamoyl" group refers to the R group in the carbamoyl group. A and R B "-OC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The O-carbamoyl group can be substituted or unsubstituted.

[0041] The "N-carbamoyl" group refers to the combination of R and R... A "ROC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-carbamoyl group can be substituted or unsubstituted.

[0042] The "O-thiocarbamoyl" group refers to the R group in the R group. A and R B "-OC(=S)-N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The O-thiocarbamoyl group can be substituted or unsubstituted.

[0043] The "N-thiocarbamoyl" group refers to the group containing R and R. A "ROC(=S)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-thiocarbamoyl group can be substituted or unsubstituted.

[0044] The "C-acylamino" group refers to the R group within it. A and R B "-C(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The C-amide group can be substituted or unsubstituted.

[0045] The "N-acylamino" group refers to the combination of R and R... A "RC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-amino group can be substituted or unsubstituted.

[0046] The "S-sulfonamide" group refers to the R group within it. A and R B"-SO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The S-sulfonamide group can be substituted or unsubstituted.

[0047] The "N-sulfonamide" group refers to the combination of R and R... A "RSO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-sulfonamide group can be substituted or unsubstituted.

[0048] The “O-carboxyl” group refers to an “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0049] The terms "ester" and "C-carboxyl" refer to esters where the R group can be the same "-C(=O)OR" group as defined relative to the O-carboxyl group. Esters and C-carboxyl groups can be substituted or unsubstituted.

[0050] The "nitro" group refers to the "-NO2" group.

[0051] The "sulfonyl" group refers to a "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The sulfonyl group can be substituted or unsubstituted.

[0052] The "sulfinyl" group refers to a group in which R can be the same "-S(=O)-R" group as defined relative to the sulfoxide group. The sulfinyl group can be substituted or unsubstituted.

[0053] A "sulfonyl" group is one in which R can be the same "SO2R" group as defined relative to the sulfoxide group. The sulfonyl group can be substituted or unsubstituted.

[0054] As used herein, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups may be substituted or unsubstituted.

[0055] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy groups may be substituted or unsubstituted.

[0056] As used in this article, the term "amino" refers to the -NH2 group.

[0057] A "monosubstituted amine" group refers to the group in which R... A "-NHR" can be any of the following as defined herein: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A "group. R" A It can be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH (methyl), -NH (phenyl), etc.

[0058] The "disubstituted amine" group refers to the group in which R... A and R B "-NR" can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) as defined herein. A R B "group. R" A and R B It can be substituted or unsubstituted independently. Examples of disubstituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), etc.

[0059] As used herein, the "amine (alkyl)" group refers to the -(alkylene)-NR'R" group, wherein R' and R" are independently hydrogen or alkyl as defined herein. The amine (alkyl) group may be substituted or unsubstituted. Examples of amine (alkyl) groups include, but are not limited to, -CH2NH (methyl), -CH2NH (phenyl), -CH2CH2NH (methyl), -CH2CH2NH (phenyl), -CH2N (methyl)2, -CH2N (phenyl)(methyl), -NCH2 (ethyl)(methyl), -CH2CH2N (methyl)2, -CH2CH2N (phenyl)(methyl), -NCH2CH2 (ethyl)(methyl), etc.

[0060] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens. As another example, "C1 to C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two, or three atoms.

[0061] As used herein, a free radical refers to a substance having a single unpaired electron, allowing the free radical-containing substance to covalently bond to another substance. Therefore, in this context, a free radical is not necessarily a free radical in the sense of a free radical. Rather, a free radical refers to a specific part of a larger molecule. The term "free radical" is used interchangeably with the term "group".

[0062] The term "pharmaceutically acceptable salt" refers to a salt of a compound that will not cause significant irritation to the organism to which it is applied and will not eliminate 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 the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrophosphate). Pharmaceutical salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids (e.g., 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-oxoglutaric acid, or naphthalenesulfonic acid). Pharmaceutical salts can also be obtained by reacting the compound with a base to form a salt, such as ammonium salts, alkali metal salts (e.g., sodium, potassium, or lithium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), carbonates, bicarbonates, organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tri(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reacting with amino acids (e.g., arginine and lysine). For compounds of formula (I), those skilled in the art will understand that when the salt is formed by the protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group can associate with a positive charge (e.g., NH2 can become NH3).+ And this positive charge can be generated by negatively charged counterions (such as Cl-). - )balance.

[0063] It should be understood that in any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly specified, each center may independently be an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds presented herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, or diastereomeric pure, diastereomeric enriched stereoisomers. Furthermore, it should be understood that in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond may independently be E or Z, or a mixture thereof. Likewise, it should be understood that all tautomeric forms are intended to be included in any of the compounds described herein.

[0064] It should be understood that in cases where the compounds disclosed herein have unfilled valences, they are filled with hydrogen or its isotopes (e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0065] It should be understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to increased metabolic stability, such as, for example, an increased in vivo half-life or a reduced dose requirement. Each chemical element represented in the compound structure may include any isotope of that element. For example, in the compound structure, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless the context clearly specifies otherwise, the compounds mentioned herein encompass all possible isotopic forms.

[0066] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which comprise different crystalline arrangements of the same elemental composition of the compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein are present in a solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). In other embodiments, the compounds described herein are present in a non-solvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during crystallization with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcohols are formed when the solvent is an alcohol. Furthermore, the compounds provided herein can exist in both non-solvated and solvated forms. Generally, a solvated form is considered equivalent to a non-solvated form used for the purposes of the compounds and methods provided herein.

[0067] Regarding the range values ​​provided, it should be understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are covered within the implementation scheme.

[0068] The terms and phrases and their variations used in this application, particularly in the appended claims, should be understood as open-ended rather than restrictive, unless otherwise expressly stated. For the foregoing examples, the term "comprising" should be understood as "including but not limited to," "including but not limited to," etc.; as used herein, the term "comprising" is synonymous with "including," "containing," or "characterized as" and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term "having" should be interpreted as "having at least"; the term "comprising" should be interpreted as "including but not limited to"; the term "example" is used to provide exemplary instances of the items under discussion, not an exhaustive or restrictive list thereof; and the use of terms such as "preferred," "ideal," "desired," and "expected" and similar semantically similar words should not be construed as implying that certain features are critical, necessary, or even important to the structure or function, but are merely intended to highlight alternative or additional features that may or may not be used in a particular embodiment. Furthermore, the term "comprising" should be interpreted as synonymous with the phrase "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 stated features or components, but may also include additional features or components.

[0069] For virtually any plural and / or singular term used herein, those skilled in the art can convert from plural to singular and / or from singular to plural, as appropriate to the context and / or application. For clarity, various singular / plural substitutions may be explicitly stated herein. The indefinite article “a” or “an” does not exclude multiple. The fact that certain measures are referred to in mutually different dependent claims does not indicate that a combination of these measures cannot be used to make the advantages more pronounced. Any reference marks in the claims should not be construed as limiting their scope.

[0070] compound

[0071] Some embodiments disclosed herein relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, having the following structure:

[0072]

[0073] Where: R 1The ring can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl groups; ring A can be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups; ring B can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups; R 2 Optional m can be 0, 1, 2, or 3; R 3 X can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups; X can be selected from hydrogen, halogens, hydroxyl groups, cyano groups, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and 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-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl, and substituted or unsubstituted N-carbamoyl; Y can be CH or N (nitrogen); Y 1 CR 4A Or N (nitrogen); Y 2 CR 4B Or N (nitrogen); the ring C can be self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic and substituted or unsubstituted 7-10 membered bicyclic heterocyclic; R 4A and R 4B It can be independently selected from hydrogen, halogens, and unsubstituted C. 1-4 Alkyl; and R 5 It can be a substituted or unsubstituted 5-7 member monocyclic heterocyclic group.

[0074] Some embodiments disclosed herein relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein: R 1 The ring can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl groups; ring A can be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups; ring B can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups; R 2 Optional m can be 0, 1, 2, or 3; R 3X can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups; X can be selected from hydrogen, halogens, hydroxyl groups, cyano groups, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and 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-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl, and substituted or unsubstituted N-carbamoyl; Y can be CH or N (nitrogen); Y 1 CR 4A Or N (nitrogen); Y 2 CR 4B Or N (nitrogen); the ring C can be self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic and substituted or unsubstituted 7-10 membered bicyclic heterocyclic; and R 4A and R 4B It can be independently selected from hydrogen, halogens, and unsubstituted C. 1-4 alkyl.

[0075] In some implementation schemes, R 1 The ring can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, ring A can be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups. In some embodiments, ring B can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups. In some embodiments, R... 2 Optional In some implementations, m can be 0, 1, 2, or 3. In some implementations, R 3 X can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, X can be selected from hydrogen, halogens, hydroxyl groups, cyano groups, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and 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-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl, and substituted or unsubstituted N-carbamoyl. In some embodiments, Y may be CH or N. In some embodiments, Y 1 CR 4A Or N. In some implementations, Y 2 CR 4B Or N. In some embodiments, the ring C may be self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic, and substituted or unsubstituted 7-10 membered bicyclic heterocyclic. In some embodiments, R 4A and R 4B Independently selected from hydrogen, halogens and unsubstituted C 1-4 alkyl.

[0076] In some implementation schemes, R 1 It can be selected from hydrogen, halogen, and C1-C6 alkyl. In some embodiments, R 1 It can be hydrogen. In other embodiments, R 1 It can be halogen. In some implementations, R 1 It can be fluorine. In other embodiments, R 1 It can be an unsubstituted C1-C6 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight-chain or branched) or hexyl (straight-chain or branched)). In some embodiments, R 1 It can be an unsubstituted methyl group. In some embodiments, R 1 It can be a substituted C1-C6 alkyl group, such as those described herein. In some embodiments, R 1 It can be an unsubstituted C1-C6 haloalkyl (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, R 1 It can be -CHF2, -CF3, -CF2CH3 or -CH2CF3.

[0077] In some embodiments, ring A may be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups.

[0078] In some embodiments, ring A may be a substituted phenyl group. In other embodiments, ring A may be an unsubstituted phenyl group.

[0079] In some embodiments, ring A may be a substituted 5-6 membered monocyclic heteroaryl group. In some embodiments, ring A may be an unsubstituted 5-6 membered monocyclic heteroaryl group. In some embodiments, ring A may 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.

[0080] When the ring is substituted, ring A can be substituted by one or more substituents selected from halogens, unsubstituted C1-C4 haloalkyls, and unsubstituted C1-C4 alkyls. In some embodiments, ring A is monosubstituted by a halogen (e.g., fluorine).

[0081] In some implementation schemes, Optional Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Can be replaced or not replaced In some implementation schemes, Can be replaced or not replaced Ring A is unsubstituted. In other embodiments, Optional self-replacement or non-replacement Replaced or not replaced and replaced or unreplaced As described in this article, The ring A portion may not have been replaced.

[0082] In some embodiments, ring B may be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups.

[0083] In some embodiments, ring B may be a substituted or unsubstituted 5- to 7-membered monocyclic carbocyclic group. In some embodiments, ring B may be a substituted or unsubstituted 5-membered monocyclic carbocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 6-membered monocyclic carbocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 7-membered monocyclic carbocyclic group.

[0084] In some implementation schemes, Optional from: Each of the aforementioned groups may be substituted or unsubstituted.

[0085] In some embodiments, ring B may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclic group. In some embodiments, ring B may be a substituted or unsubstituted 5-membered monocyclic heterocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 6-membered monocyclic heterocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 7-membered monocyclic heterocyclic group.

[0086] In some implementation schemes, Optional from: Each of the above groups may be substituted or unsubstituted, including any -NH group.

[0087] In some implementation schemes, ring B can be selected from... Each of the aforementioned groups may be substituted or unsubstituted, including any -NH group. In some embodiments, ring B may be substituted or unsubstituted.

[0088] In some embodiments, when ring B is substituted, ring B may be substituted by one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, amino groups, and unsubstituted N-linked amide groups (e.g., -NHC(O)C). 1- 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, ring B may be substituted by one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, amino groups, unsubstituted N-linked amide groups (e.g., -NHC(O)C). 1- C6 alkyl groups and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, ring B may be substituted with one, two, or three substituents, which are independently selected from fluorine, hydroxyl, amino, unsubstituted -NHC(O)C 1- C6 alkyl, unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring B may be substituted with one or two substituents, which are independently selected from fluorine, hydroxyl, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0089] In some implementation schemes, Optional from: Each of the above groups may be substituted or unsubstituted, including any -NH group.

[0090] In some implementation schemes, Optional from: Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Optional from: Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Can be replaced or not replaced In some implementation schemes Can be replaced or

[0091] Both ring A and ring B may be substituted or not substituted. In some embodiments, Rings A and B may be substituted independently or not. In some embodiments, Neither ring A nor ring B may be replaced. In some implementations, Rings A and B can both be replaced independently. In some implementations, Ring A can be replaced, and Ring B may not be replaced. In some implementations, Ring A may not have been replaced, and Ring B can be replaced. In some implementations, Ring A may not have been replaced, and The ring B can be substituted with one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, Ring A may not have been replaced, and The ring B can be substituted with one, two, or three substituents, which are independently selected from fluorine, hydroxyl, amino, unsubstituted N-linked amide (e.g., -NHC(O)C). 1- C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Ring A may not have been replaced, and The ring B can be substituted by one or two substituents, which are independently selected from fluorine, hydroxyl, amino, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl and -NHC(O)CH3.

[0092] In some implementation schemes, R 2 Optional In some implementation schemes, R 2 Can be In some implementation schemes, R 2 Can be

[0093] In some embodiments, Y may be CH or N (nitrogen). In some embodiments, Y may be CH. In some embodiments, Y may be N (nitrogen).

[0094] In some implementation schemes, R 3 It can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, R 3 It can be halogen. In some implementations, R 3 It can be a substituted C1-C6 alkyl group (such as those described herein). In some embodiments, R 3 It can be an unsubstituted C1-C6 alkyl group (such as those described herein).

[0095] In some implementations, m can be 0, 1, 2, or 3. In some implementations, m can be 0. In some implementations, m can be 1. In some implementations, m can be 2. In some implementations, m can be 3. When m is 2 or 3, R 3 The groups can be the same as or different from each other.

[0096] In some embodiments, X may be selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl), or 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, tert-butoxy, pentoxy (straight or branched) or hexoxy (straight or branched)), substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy), substituted or unsubstituted (C1-C6 alkyl) acyl, substituted or unsubstituted C-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl and substituted or unsubstituted N-carbamoyl.

[0097] In some embodiments, X may be hydrogen. In other embodiments, X may be a halogen. In some embodiments, X may be fluorine. In some embodiments, X may be chlorine. In other embodiments, X may be a hydroxyl group. In still other embodiments, X may be a cyano group. In some embodiments, X may be an amino group.

[0098] In some embodiments, X may be an unsubstituted C1-C6 alkyl group (such as those described herein). In some embodiments, X may be an unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl group. In some embodiments, X may be a substituted C1-C6 alkyl group (such as those described herein). In some embodiments, X may be an unsubstituted C1-C6 haloalkyl group (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, X may be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, X may be an unsubstituted C1-C6 hydroxyalkyl group (such as C1-C6 monohydroxyalkyl or C1-C6 dihydroxyalkyl). In some embodiments, X may be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3)2. In some embodiments, X may be an unsubstituted C1-C6 cyanoalkyl (such as a C1-C6 monocyanoalkyl or a C1-C6 dicyanoalkyl). In some embodiments, X may be selected from... In some embodiments, X may be an unsubstituted C1-C6 alkoxyalkyl group (such as a C1-C6 monoalkoxyalkyl group or a C1-C6 dialkoxyalkyl group). In some embodiments, X may be selected from... In some implementations, X may be selected from... Substituted C1-C6 alkyl groups.

[0099] In some embodiments, X may be an unsubstituted C1-C6 alkoxy group (such as those described herein). In some embodiments, X may be an unsubstituted methoxy group, an unsubstituted ethoxy group, or an unsubstituted isopropoxy group. In some embodiments, X may be a substituted C1-C6 alkoxy group (such as those described herein). In some embodiments, X may be a C1-C6 alkoxy group substituted with one, two, or three substituents, which are independently selected from halogens, amino groups, monosubstituted amines (such as those described herein), and disubstituted amines (such as those described herein). In some embodiments, X may be a C1-C6 alkoxy group substituted with one substituent, which is selected from halogens, amino groups, monosubstituted amines (such as those described herein), and disubstituted amines (such as those described herein).

[0100] In some implementations, X can be selected from...

[0101] In some embodiments, X may be a substituted C3-C6 cycloalkoxy group (such as those described herein). In some embodiments, X may be an unsubstituted C3-C6 cycloalkoxy group (such as those described herein).

[0102] In some embodiments, X may be a substituted (C1-C6 alkyl)acyl group, such as a substituted -(CO)-CH3. In some embodiments, X may be an unsubstituted (C1-C6 alkyl)acyl group, such as an unsubstituted -(CO)-CH3.

[0103] In some embodiments, X may be a substituted 4-6 membered monocyclic heterocyclic group. In some embodiments, X may be an unsubstituted 4-6 membered monocyclic heterocyclic group. In some embodiments, X may be selected from aziridine, oxacyclobutane, diaziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, and dioxacyclohexane; wherein each of the above groups is substituted or unsubstituted, including any -NH group. In some embodiments, X may be selected from... Each of the above groups may be substituted or unsubstituted, including any -NH group.

[0104] In some embodiments, X may be a 4-6 membered monocyclic heterocyclic group (such as those described herein) substituted with one or two substituents, wherein these substituents are independently selected from halogens, substituted or unsubstituted C1-C6 alkyl groups (such as those described herein), monosubstituted amines (such as those described herein), disubstituted amines (such as those described herein), amino groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and substituted or unsubstituted (C1-C6 alkyl) acyl groups. In some embodiments, X may be a 4-6 membered monocyclic heterocyclic group substituted with one or two substituents, wherein these substituents are independently selected from fluorine, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, -CH2OH, and -N(CH3)2. In some embodiments, X may be selected from...

[0105] In some embodiments, X may be a substituted amine (C1-C6 alkyl). In some embodiments, X may be an unsubstituted amine (C1-C6 alkyl). In some embodiments, X may be selected from... Each of the above groups may be substituted or unsubstituted, including any -NH group.

[0106] In some implementations, X may be a substituted -NH-(CH2). 1-6 -amine. In some embodiments, X may be unsubstituted -NH-(CH2).1-6 -amine. In some embodiments, X may be selected from... Each of the above groups may be substituted or unsubstituted, including any -NH group.

[0107] In some embodiments, X may 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).

[0108] In some embodiments, X may be a disubstituted amine. In some embodiments, the two substituents of the disubstituted amine are independently selected from unsubstituted C1-C6 alkyl groups (such as those described herein) and unsubstituted C3-C6 cycloalkyl groups (such as those described herein).

[0109] In some implementations, X can be selected from...

[0110] In some embodiments, X may be a substituted or unsubstituted C-amide. In some embodiments, X may be a substituted or unsubstituted N-amide. In some embodiments, X may be a substituted or unsubstituted C-carboxyl group. In some embodiments, X may be a substituted or unsubstituted O-carboxyl group. In some embodiments, X may be a substituted or unsubstituted O-carbamoyl group. In some embodiments, X may be a substituted or unsubstituted N-carbamoyl group. In some embodiments, X may be monosubstituted with an unsubstituted C1-C6 hydroxyalkyl group (such as those described herein).

[0111] In some implementation schemes, Y 1 CR 4A Or N (nitrogen). In some implementations, Y 1 CR 4A In some implementation schemes, Y 1 It can be N (nitrogen).

[0112] In some implementation schemes, Y 2 CR 4B Or N (nitrogen). In some implementations, Y 2 For CR 4B In some implementation schemes, Y 2 It can be N (nitrogen).

[0113] In some implementation schemes, Y 1 and Y 2 Each can be N (nitrogen). In some implementations, Y 1 CR 4A And Y2 CR 4B In some implementation schemes, Y 1 CR 4A And Y 2 It can be N (nitrogen). In some implementations, Y 1 It can be N (nitrogen), and Y 2 CR 4B .

[0114] In some implementation schemes, R 4A It can be hydrogen. In some implementations, R 4A It can be halogen. In some implementations, R 4A Can be unreplaced C 1-4 Alkyl groups (such as those described herein).

[0115] In some implementation schemes, R 4B It can be hydrogen. In some implementations, R 4B It can be halogen. In some implementations, R 4B Can be unreplaced C 1-4 Alkyl groups (such as those described herein).

[0116] In some implementation schemes, R 4A and R 4B Each can be hydrogen. In some implementations, R 4A and R 4B Each can be a halogen (wherein the halogens may be the same or different from each other). In some embodiments, R 4A and R 4B Each can be an unreplaced C 1-4 Alkyl groups (such as those described herein, and wherein C...) 1-4 Alkyl groups may be the same as or different from each other. In some embodiments, R 4A and R 4B One of them can be hydrogen, and R 4A and R 4B The other component can be a halogen. In some implementations, R 4A and R 4B One of them can be hydrogen, and R 4A and R 4B The other one could be the unsubstituted C. 1-4 Alkyl groups (such as those described herein). In some embodiments, R 4A and R 4B One of them can be a halogen, and R 4A and R 4B The other one could be the unsubstituted C. 1-4 Alkyl groups (such as those described herein).

[0117] In some implementation schemes, R 2 Can be For example, R 2 Can be In some implementations, when R 2 for R 5 It can be a substituted 5-7 member monocyclic heterocyclic group. In other embodiments, R 5 It can be an unsubstituted 5-7 member monocyclic heterocyclic group. R 5 Examples of groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azaheptanyl. When R is substituted... 5 When the group is used, possible substituents include unsubstituted C. 1-4 Alkyl, halogen, hydroxyl and unsubstituted C 1-4 Halogenated alkyl groups.

[0118] In some implementations, the ring C may be either self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic and substituted or unsubstituted 7-10 membered bicyclic heterocyclic.

[0119] In some implementations, ring C may be replaced by C6-C. 10 Aryl. In some embodiments, the ring C may be an unsubstituted C6-C. 10 Aryl group. In some embodiments, the ring C may be a substituted C6 aryl group. In some embodiments, the ring C may be an unsubstituted C6 aryl group.

[0120] In some embodiments, ring C may be a substituted 5-10-membered heteroaryl group. In some embodiments, ring C may be an unsubstituted 5-10-membered heteroaryl group. In some embodiments, ring C may be a substituted 5-6-membered heteroaryl group. In some embodiments, ring C may be an unsubstituted 5-6-membered heteroaryl group. In some embodiments, ring C may be selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, benzimidazole, indole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, quinoline, isoquinoline, quinazoline, and quinoxaline; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0121] In some embodiments, ring C may be a substituted or unsubstituted 5-membered monocyclic carbocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 6-membered monocyclic carbocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 7-membered monocyclic carbocyclic group.

[0122] In some embodiments, ring C may be a substituted or unsubstituted 5-membered monocyclic heterocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 6-membered monocyclic heterocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 7-membered monocyclic heterocyclic group. In some embodiments, ring C may be selected from imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline, oxazoline, thiazoline, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidinone, pyrzoline, pyrazole, tetrahydropyran, azepine, oxazepine, and diazepine; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0123] In some embodiments, ring C may be a substituted or unsubstituted 7-membered bicyclic heterocyclic group (e.g., fused, bridged, or helical heterocyclic group). In some embodiments, ring C may be a substituted or unsubstituted 8-membered bicyclic heterocyclic group, such as a fused, bridged, or helical heterocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 9-membered bicyclic heterocyclic group (e.g., fused, bridged, or helical heterocyclic group). In some embodiments, ring C may be a substituted or unsubstituted 10-membered bicyclic heterocyclic group, such as a fused, bridged, or helical heterocyclic group. In some embodiments, the ring C may be selected from pyrrolidine, dihydroindole, 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; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0124] In some embodiments, the ring C may be substituted with one or more substituents, which are independently selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl groups. In some embodiments, the ring C may be substituted with one substituent, which is selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl groups.

[0125] In some implementation schemes, R 2 Optional from: Each of the above groups may be substituted or not substituted.

[0126] Examples of compounds of formula (I) include the following:

[0127]

[0128]

[0129] Or a pharmaceutically acceptable salt of any of the above.

[0130] synthesis

[0131] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be prepared by those skilled in the art in various ways using known techniques, as directed by the detailed teachings provided herein. For example, in one embodiment, a compound of formula (I) is prepared according to general scheme 1 as shown herein.

[0132] Generally, the coupling reaction between compounds of general formula A and B used to form a compound of formula (I) as shown in General Scheme 1 can be carried out in a manner similar to the reactions described herein in the examples, by appropriately adjusting the reagents and conditions described in the examples. Any preliminary reaction steps required for the starting compounds or other precursors used to form general formulas A and B can be performed by those skilled in the art. In General Scheme 1, ring A, ring B, and R... 1 and R 2 As described in this article.

[0133] General Scheme 1

[0134]

[0135] Pharmaceutical Composition

[0136] Some embodiments described herein relate to pharmaceutical compositions that may comprise effective amounts of one or more compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof.

[0137] 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 the administration of compounds to living organisms. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are typically formulated according to a specific intended route of administration.

[0138] The term "physiologically acceptable" is defined as a carrier, diluent, or excipient that does not eliminate the biological activity and properties of the compound and does not cause significant harm or injury to the animal to which the composition is intended to be delivered.

[0139] As used herein, "carrier" refers to a compound that facilitates the binding of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0140] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that does not have significant pharmaceutical activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of a potent pharmaceutical product whose mass is too small to manufacture and / or administer. It can also be a liquid used to dissolve a pharmaceutical product intended for administration by injection, ingestion, or inhalation. Common forms of diluents in the art are buffered aqueous solutions, such as, but not limited to, phosphate-buffered saline solutions with pH and isotonicity that mimic human blood.

[0141] As used herein, "excipient" refers to a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelator. "Diluent" is a type of excipient.

[0142] The pharmaceutical compositions described herein may be administered to human patients themselves or to compositions wherein the pharmaceutical composition is mixed with other active ingredients (as in combination therapy), or with carriers, diluents, excipients, or combinations thereof. The appropriate formulation depends on the chosen route of administration. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0143] The pharmaceutical compositions disclosed herein can be manufactured in ways known per se, such as by conventional mixing, dissolving, granulation, pill preparation, grinding, emulsification, encapsulation, embedding, or tableting processes. Furthermore, they contain an active ingredient in an amount effective to achieve their intended use. Many compounds used in the pharmaceutical compositions disclosed herein can be provided as salts having pharmaceutically compatible counterions.

[0144] Various techniques exist in the art for administering compounds, salts, and / or compositions, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery (including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, and intraocular injection). In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered orally.

[0145] Compounds, salts, and / or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound into the affected area in the form of a reservoir or sustained-release formulation. Furthermore, compounds can be administered in targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. The liposomes will target the organ and be selectively taken up by it. For example, intranasal or pulmonary delivery to target respiratory diseases or conditions may be desirable.

[0146] The composition may (if desired) be present in a packaging or dispenser device that may include one or more unit dose forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification associated with the container form as prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the form of the drug for human or veterinary use. For example, such notification may be a label or approved product insert approved by the U.S. Food and Drug Administration for prescription drugs. Compositions that may contain the compounds and / or salts described herein formulated in a compatible drug carrier may also be prepared, placed, and labeled for the treatment of the indicated condition in a suitable container.

[0147] Uses and treatments

[0148] Some embodiments described herein relate to methods for alleviating and / or treating the cancers described herein, which may include administering 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 containing 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 the cancer described herein. Other embodiments described herein relate 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 containing 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 an agent for alleviating and / or treating the cancers described herein. Other embodiments described herein relate 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for alleviating and / or treating the cancers described herein.

[0149] Some embodiments described herein relate to methods for inhibiting the replication of malignant growths or tumors, which may include contacting the 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 containing 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 caused by the cancer described herein. Other embodiments described herein relate 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 containing 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 an agent for inhibiting the replication of malignant growths or tumors, wherein the malignant growth or tumor is caused by the cancer described herein. Other embodiments described herein relate 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 containing 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 growths or tumors, wherein the malignant growth or tumor is caused by the cancer described herein.

[0150] Some embodiments described herein relate to methods for alleviating or treating the cancer described herein, which may include contacting a subject having the 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition containing 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 alleviating or treating cancer, which may include contact with a malignant growth or tumor, wherein the malignant growth or tumor is caused by the cancer described herein. Other embodiments described herein relate to an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for alleviating or treating cancer, or a pharmaceutical composition comprising an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the alleviation or treatment of cancer may include contact with a malignant growth or tumor, wherein the malignant growth or tumor is caused by the cancer described herein.

[0151] Some embodiments described herein relate to methods 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 WEE1 p53-deficient cells, and / or reducing the 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) to cancer cells from the cancer described herein 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). Other embodiments described herein relate to the use of a pharmaceutical composition comprising an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of an agent 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 WEE1 p53-deficient cells, and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to a pharmaceutical composition comprising an effective amount of the 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 WEE1 p53-deficient cells, and / or reducing the overexpression of WEE1 in cells). Some embodiments described herein relate to methods 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 WEE1 p53-deficient cells, and / or reducing the 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) to cancer cells from the cancer described herein 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).Other embodiments described herein relate to methods for inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutant cells, inhibiting WEE1 activity in TP53 wild-type cells, inhibiting WEE1 activity in WEE1 p53-deficient cells, and / or reducing WEE1 overexpression in cells), which may include contacting cancer cells of the 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit WEE1 activity.

[0152] Some embodiments described herein relate to methods for alleviating or treating the cancers described herein, which may include 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to the use of a pharmaceutical composition comprising an effective amount of the compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for alleviating or treating the cancers 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Other embodiments described herein relate to effective amounts of the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) or pharmaceutical compositions comprising effective amounts of the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), for the purpose of alleviating or treating the cancers 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 WEE1 p53-deficient cells and / or reducing the overexpression of WEE1 in cells). Some embodiments described herein relate to methods for alleviating or treating the cancers described herein, which may include contacting cancer cells 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the compound 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 WEE1 p53-deficient cells and / or reduces the overexpression of WEE1 in cells).

[0153] Some embodiments disclosed herein relate to methods for inhibiting the activity of WEE1, which may include providing to a subject suffering from or having cancer cells derived from the 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 containing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Some embodiments disclosed herein relate 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 containing 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 an agent for inhibiting the activity of WEE1. Other embodiments disclosed herein relate to a pharmaceutical composition containing 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.

[0154] Suitable examples of cancers include, but are not limited to: brain cancer, cervical 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 / choleduct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrial cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0155] As described herein, cancers can be resistant to one or more anticancer agents. In some embodiments, the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) or pharmaceutical compositions comprising an effective amount of the compounds described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) may be used to treat and / or alleviate cancers that have become resistant to one or more anticancer agents (such as one or more WEE1 inhibitors). Examples of anticancer agents to which a subject may have developed resistance include, but are not limited to, WEE1 inhibitors (such as AZD1775). In some embodiments, cancers that have become resistant to one or more anticancer agents may be the cancers described herein.

[0156] Several known WEE1 inhibitors can 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, the compound of formula (I) or a pharmaceutically acceptable salt thereof may result in a 25% reduction in the severity of side effects (such as those described herein) compared to the severity of the same side effects experienced by subjects receiving a known WEE1 inhibitor (such as AZD1775, formally known as MK1775 (CAS No.: 955365-80-7, 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof results in a 25% reduction in the number of side effects experienced by subjects receiving a known WEE1 inhibitor (e.g., AZD1775). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof results in a side effect severity (such as one of those described herein) that is about 10% to about 30% less severe than the same side effect experienced by a subject receiving a known WEE1 inhibitor (such as AZD1775). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof results in a side effect number that is 10% to about 30% less than the number of side effects experienced by a subject receiving a known WEE1 inhibitor (e.g., AZD1775).

[0157] In any of the embodiments described in paragraphs

[0064] -

[0112] under the heading “Compounds”, one or more compounds of formula (I) or pharmaceutically acceptable salts thereof are provided, which may be used to treat, alleviate and / or inhibit the growth of cancer, wherein inhibition of WEE1 activity is beneficial.

[0158] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles, and especially mammals. "Mammalian" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates (e.g., monkeys, chimpanzees, and apes), and especially 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 feverish child or infant. In other embodiments, the subject may be an adult.

[0159] As used herein, the terms “treat,” “treating,” “treatment,” and “therapeutic” do not necessarily mean the complete cure or elimination of a disease or condition. Any degree of relief from any undesirable sign or symptom of a disease or condition may be considered a treatment and / or therapy. Furthermore, treatment may include behaviors that may worsen a subject’s overall feeling of health or appearance.

[0160] The terms “therapeutic effective amount” and “effective amount” are used to indicate the amount of an active compound or agent that elicits the indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound, salt, or composition may be the amount required to prevent, alleviate, or improve symptoms of a disease or condition, or to prolong the survival of a treated subject. This response may occur in tissues, systems, animals, or humans and includes the reduction of signs or symptoms of the treated disease or condition. Based on the disclosure provided herein, the determination of an effective amount is entirely within the capabilities of those skilled in the art. Therapeutic effective amounts (referred to as doses) of the compounds disclosed herein will depend on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal under consideration. The dose may be modulated to achieve the desired effect, but the dose will depend on factors such as body weight, diet, concomitant drug treatments, and other factors that a person skilled in the medical field will recognize.

[0161] For example, an effective amount of a compound or radiation is an amount that results in: (a) a reduction, alleviation, or disappearance of one or more symptoms caused by cancer; (b) a 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 (such as non-small cell lung cancer), a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and / or pain. Similarly, an effective or therapeutically effective amount of a WEE1 inhibitor is an amount that results in a reduction in WEE1 activity and / or phosphorylation (such as phosphorylation of CDC2). A reduction in WEE1 activity is known to those skilled in the art and can be determined by analyzing the intrinsic kinase activity of WEE1 and the phosphorylation of downstream substrates.

[0162] The amount of the compound of formula (I) or its pharmaceutically acceptable salt used for treatment will vary not only from the specific compound or salt chosen, but also from the route of administration, the nature and / or symptoms of the disease or condition being treated, and the patient's age and condition, and will ultimately be determined by the attending physician or clinician. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated using the free base. As those skilled in the art will understand, in some cases it may be necessary to administer the compounds disclosed herein in amounts exceeding or even far exceeding the dosage range described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.

[0163] However, generally speaking, suitable doses will typically be in the range of about 0.05 mg / kg to about 10 mg / kg. For example, suitable doses may be in the range of about 0.10 mg / kg body weight / day to about 7.5 mg / kg body weight / day, such as about 0.15 mg / kg body weight / day to about 5.0 mg / kg body weight / day, about 0.2 mg / kg body weight / day to 4.0 mg / kg body weight / day, or any amount between these ranges. The compound may be administered in unit dosage forms; for example, containing 1 mg to 500 mg, 10 mg to 100 mg, 5 mg to 50 mg, or any amount between these ranges of active ingredient / unit dosage form.

[0164] The required dose can be conveniently provided as a single dose or as fractional doses administered at appropriate intervals (e.g., as sub-dose twice, three, four, or more times daily). The sub-dose itself can be further divided into, for example, multiple discrete, loosely spaced administrations.

[0165] As will be apparent to those skilled in the art, the available in vivo dose and specific administration method will vary depending on age, weight, severity of pain, species of the mammal receiving treatment, the specific compound used, and the specific purpose for which the compound is used. The determination of the effective dose level (i.e., the dose level necessary to achieve the desired outcome) can be performed by those skilled in the art using conventional methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, the available dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing its in vitro and in vivo activities in animal models. Such comparisons can be made by comparing it with established drugs such as cisplatin and / or gemcitabine.

[0166] The dosage and interval can be individually adjusted to provide plasma levels sufficient to maintain the modulating effect or minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated based on in vivo and / or in vitro data. The dosage necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or bioassays can be used to determine plasma concentrations. The MEC value can also be used to determine the dosing interval. The composition should be administered using a regimen that maintains plasma levels at 10% to 90% above the MEC, preferably between 30% and 90%, and most preferably between 50% and 90%. In cases of local application or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0167] It should be noted that in cases of toxicity or organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust administration. Conversely, in cases of insufficient clinical response (excluding toxicity), the attending physician will also know to adjust treatment to a higher level. The dosage administered in the management of the disorder of interest will vary depending on the severity of the disease or condition being treated and the route of administration. For example, the severity of the disease or condition can be assessed in part by standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on age, weight, and individual patient response. Procedures equivalent to those discussed above are available in veterinary medicine.

[0168] The efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subset of such compounds (sharing certain chemical components) can be established by determining its in vitro toxicity to cell lines, such as mammalian and preferably human cell lines. Results of such studies typically predict toxicity in animals, such as mammals or more specifically humans. Alternatively, the toxicity of a particular compound in animal models, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. Several recognized methods, such as in vitro methods, animal models, or human clinical trials, can be used to establish the efficacy of a particular compound. When selecting a model to determine efficacy, a person skilled in the art can follow existing techniques to select an appropriate model, dosage, route of administration, and / or regimen.

[0169] Example

[0170] Further embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0171] Intermediate 1

[0172] 2-Allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0173]

[0174] Intermediate 1 was prepared according to the steps described by Matheson et al. in ACS Chem. Biol., (2016), Vol. 11, pp. 2066-2067. MS (LCMS) 223.0 [M+H] + .

[0175] Intermediate 2

[0176] 2-Bromo-6,7-dihydro-5 H -cyclopenten[ b ]Pyridine-7-ol

[0177]

[0178] Step 1: An aqueous solution (2.25 L) of a mixture of propionamide (62 g, 898.55 mmol), ethyl 2-oxocyclopentylcarboxylate (140.35 g, 898.55 mmol), and Na₂CO₃ (94.3 g, 898.55 mmol) was stirred at room temperature for 18 h. The mixture was extracted with EtOAc (3 × 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-oxocyclopentylcarboxylate (40 g, 20%) as a grayish-white solid. MS (LCMS) 226.3 [M+H] + .

[0179] Step 2: A concentrated HCl solution (390 mL) of ethyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentylcarboxylate (39 g, 173.33 mmol) was stirred in a sealed tube at 110 °C for 18 h. The solvent was removed, and the pH was adjusted to 8-9 by adding an aqueous solution of NaHCO3 at 0 °C. The resulting solid was filtered and washed with Et2O (2 × 100 mL) to give 15 g (64% yield) of 6,7-dihydro-1H-cyclopenten[b]pyridin-2(5H)-one as a grayish-white solid. MS (LCMS) 135.9 [M+H] + .

[0180] Step 3: A PBr3 solution (180 mL) of 6,7-dihydro-1H-cyclopenten[b]pyridin-2(5H)-one (18 g, 133.33 mmol) was heated at 180 °C for 18 h. The reaction was then cooled to room temperature and the reaction mixture was poured into ice-cold water. The pH was adjusted to 8-9 with saturated NaHCO3. The resulting solution was filtered through a diatomaceous earth filter. The filtrate was extracted with EtOAc (2 × 500 mL). The organic extracts were combined, dried (Na2SO4), and concentrated to give 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridinium (7 g, 26%) as a grayish-white solid. MS (LCMS) 197.8 [M+H] + .

[0181] Step 4: Add m-CPBA (10.5 g, 61.22 mmol) to a stirred solution (120 mL) of 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridine (4 g, 20.41 mmol) in DCM. Heat the mixture under reflux for 16 h, quench the reaction with saturated NaHCO3, and extract the reaction mixture with 5% methanol / DCM (2 × 100 mL). Combine the organic layers, dry (Na2SO4), and concentrate to give 1-oxide of 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridine as a grayish-white solid (3.3 g, 76% yield). MS (LCMS) 213.8 [M+H] + .

[0182] Step 5: A solution (30 mL) of 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridine-1-oxide (3.2 g, 15.09 mmol) in Ac₂O was heated at 100 °C for 16 h. Ac₂O was removed under reduced pressure. The residue was purified by rapid chromatography (SiO₂, 7% EtOAc / petroleum ether) to obtain ethyl 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridine-7-acetate (2 g, 52%) as an oil. MS (LCMS) 255.9 [M+H] + .

[0183] Step 6: LiOH·H2O (0.755 g, 31.49 mmol) was added to a THF / H2O stirred solution (20 mL, 1:1) of ethyl 2-bromo-6,7-dihydro-5H-cyclopenteno[b]pyridine-7-ethyl acetate (2 g, 7.84 mmol) at room temperature. The reaction was stirred for 3 h, then diluted with water and extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography (SiO2, 40% EtOAc / petroleum ether) to give intermediate 2 (1.2 g, 71%) as a brown solid. MS (LCMS) 214.1 [M+H] +.

[0184] Intermediate 3

[0185] 2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methylthio)-1H-pyridyl Azo[3,4-d]pyrimidin-3(2H)-one

[0186]

[0187] N,N'-dimethylethylenediamine (0.43 mL, 4.02 mmol) was added to a 1,4-dioxane solution (30 mL) of intermediate 1 (450 mg, 2.02 mmol), intermediate 2 (558 mg, 2.62 mmol), CuI (384 mg, 2.02 mmol), and K₂CO₃ (390 mg, 2.83 mmol) at 80 °C. The suspension was heated at 95 °C for 18 h. The mixture was cooled to room temperature, diluted with an aqueous solution of NH₄OH (30 mL), and extracted with EtOAc (2 × 50 mL). The organic extracts were combined, washed with brine (20 mL), dried (Na₂SO₄), and evaporated to dryness. The residue was purified by rapid chromatography (SiO₂, 40% EtOAc / petroleum ether) to give intermediate 3 (280 mg, 38%) as a pale yellow oil. MS (ESI) 356.4 [M+H] + .

[0188] Example 1A

[0189] (S)-2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-((4-(4-methyl) (Pyropiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0190]

[0191] Example 1B

[0192] (R)-2-Allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-((4-(4-methyl) (1,2-dihydro-3-ylpiperazine)phenyl)amino)- ... H -pyrazolo[3,4- d Pyrimidine-3-one

[0193]

[0194] To a solution of intermediate 3 (280 mg, 0.79 mmol) in toluene (20 mL), m-CPBA (201 mg, 1.17 mmol) was added, and the mixture was stirred at room temperature for 1 h. DIPEA (0.69 mL, 3.94 mmol) and 4-(4-methylpiperazin-1-yl)aniline (178 mg, 0.93 mmol) were added, and the mixture was stirred at room temperature for 18 h. Saturated NaHCO3 (25 mL) was added, and the mixture was extracted with EtOAc (2 × 30 mL). The organic extracts were combined, washed with brine (20 mL), dried (Na2SO4), and concentrated. The residue was purified by reversed-phase HPLC (acetonitrile / water) to give a yellow solid racemic 2-allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (87 mg, 30% yield). 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; 1 H NMR(DMSO-d6,400MHz)δ10.08(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; 1H NMR(DMSO-d6,400MHz)δ10.05(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] + The absolute configurations of Examples 1A and 1B can be arbitrarily specified.

[0195] Intermediate 4

[0196] 2-Bromo-7-methyl-6,7-dihydro-5 H -cyclopenten[ b ]Pyridine-7-ol

[0197]

[0198] Step 1: Dess-Martin periodide (3.0 g, 7.26 mmol) was added to a DCM stirred solution (15 mL) of racemic 2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridin-7-ol (1.4 g, 6.60 mmol). The mixture was stirred at room temperature for 16 h, the reaction was quenched with a saturated NaHCO3 aqueous solution, and the reaction solution was extracted with DCM (2 × 30 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 40% EtOAc / petroleum ether) to give 2-bromo-5H-cyclopenten[b]pyridin-7(6H)-one (780 mg, 60%) as a grayish-white solid. MS (LCMS) 212.0 [M+H] + .

[0199] Step 2: Magnesium methyl iodide (2M THF, 7.5mL) was added to a stirred THF solution (400mg, 1.90mmol) of 2-bromo-5H-cyclopenteno[b]pyridin-7(6H)-one (10mL) at 0°C. The reaction was stirred at 0°C to room temperature for 16h, quenched with saturated NH4Cl aqueous solution, and the reaction mixture was extracted with EtOAc (2×40mL). The organic layers were combined, concentrated under reduced pressure, and the residue was purified by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to give intermediate 4 (200mg, 46%) as a grayish-white solid. MS (LCMS) 227.9 [M+H] + .

[0200] Intermediate 5

[0201] 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methylthio) 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0202]

[0203] Intermediate 5 was prepared using intermediates 1 and 4 following the same steps as described for intermediate 3. MS (LCMS) 370.1 [M+H] + .

[0204] Example 2A

[0205] (S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0206]

[0207] Example 2B

[0208] (R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0209]

[0210] Oxone (673 mg, 2.68 mmol) was added to a stirred solution of intermediate 5 (330 mg, 0.89 mmol) in THF / H₂O (20 mL, 1:1), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated under reduced pressure to give a semi-solid mixture of sulfoxide and sulfone (330 mg, 0.822 mmol). DIPEA (0.43 mL, 2.46 mmol) was added to a toluene mixture of sulfoxide and sulfone (330 mg, 0.82 mmol) (10 mL), 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 diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (neutral alumina, 5% methanol / DCM) to give a racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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 a grayish-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) δ10.16(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: Yellow solid; 1H NMR (400MHz, DMSO-d6) δ10.16(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] + For Examples 2A and 2B, any absolute configuration can be specified.

[0211] Intermediate 6

[0212] 2-Bromo-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0213]

[0214] TMSCF3 (3.2 mL, 21.23 mmol) was added to a THF stirred solution (20 mL) of 1.5 g (7.08 mmol) of 2-bromo-5,6-dihydro-7H-cyclopenteno[b]pyridin-7-one (3.5 g, 7.08 mmol) at 0 °C, followed by the addition of TBAF (1 M THF solution) (0.7 mL, 0.71 mmol). The reaction was stirred at 0 °C to room temperature for 12 h, quenched with 6 N HCl, and the reaction mixture was extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to give intermediate 6 (825 mg, 41%) as a brown solid. MS (LCMS) 281.9 [M+H] + .

[0215] Intermediate 7

[0216] 2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- (methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0217]

[0218] Intermediate 7 was prepared using intermediates 1 and 6 following the same steps as described for intermediate 3. MS (LCMS) 424.3 [M+H] + .

[0219] Example 3A

[0220] (S)-2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine-2- )-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0221]

[0222] Example 3B

[0223] (R)-2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine-2- )-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0224]

[0225] Examples 3A and 3B were prepared using intermediate 7 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[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(400MHz,DMSO-d6)δ10.20(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; 1HNMR(400MHz,DMSO-d6)δ10.20(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] + The absolute configurations of Examples 3A and 3B can be arbitrarily specified.

[0226] Intermediate 8

[0227] 5-Bromo-3-methyl-2,3-dihydrofurano[3,2-] b ]Pyridine-3-ol

[0228]

[0229] Step 1: Prepare 2,3-dihydrofurano[3,2-b]pyridine-5-amine according to WO Publication No. 2008 / 069311. MS (LCMS) 137.1 [M+H] + .

[0230] Step 2: CuBr2 (7.303 g, 33.08 mmol) was added to a stirred CH2Br2 solution (200 mL) of 2,3-dihydrofurano[3,2-b]pyridine-5-amine (9.0 g, 66.17 mmol), followed by dropwise addition of isoamyl nitrite (8.515 g, 72.78 mmol). The reaction was stirred at room temperature for 2 h, quenched with a saturated aqueous solution of NaHCO3 (50 mL), and the reaction mixture was filtered through a diatomaceous earth mat. The filtrate was extracted with DCM (3 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid chromatography (SiO2, EtOAc / petroleum ether) to give 5-bromo-2,3-dihydrofurano[3,2-b]pyridine (6.0 g, 45%) as a brown solid. MS (ESI) 200.2 [M+H] + .

[0231] Step 3: m-CPBA (6.27 g, 36.18 mmol) was added to a stirred solution of 5-bromo-2,3-dihydrofurano[3,2-b]pyridine (6.0 g, 30.15 mmol) in DCM (100 mL) 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 ground with n-pentane and dried to give crude 5-bromo-2,3-dihydrofurano[3,2-b]pyridine 4-oxide (9.5 g) as a grayish-white solid. MS(ESI) 216.2[M+H + Acetic anhydride (100 mL) was added to 9.5 g of 5-bromo-2,3-dihydrofurano[3,2-b]pyridine 4-oxide, and the mixture was heated at 90 °C for 1 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with 100 mL of saturated NaHCO3 aqueous solution and extracted with EtOAc (3 × 60 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, EtOAc / petroleum ether) to give 5-bromo-2,3-dihydrofurano[3,2-b]pyridine-3-yl acetate (5.0 g, 65%) as a brown solid. MS (ESI) 258.2 [M+H] + .

[0232] Step 4: LiOH·H₂O (2.45 g, 58.35 mmol) was added to a THF / H₂O stirred solution (1:1, 30 mL) of 5-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-yl acetate (5.0 g, 19.45 mmol) and stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 100 mL), and the organic layers were combined and washed with water (100 mL) and brine (100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give 5-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-ol (2.5 g, 59%) as a grayish-white solid. MS (ESI) 216.1 [M+H] + .

[0233] Step 5: Freshly prepared Jones' reagent (25 mL, CrO3 (3 equivalents) and H2SO4 (3 equivalents)) was added to a stirred acetone solution (30 mL) of 5-bromo-2,3-dihydrofurano[3,2-b]pyridin-3-ol (2.6 g, 12.09 mmol) at 0 °C, and the reaction was stirred at 0 °C for 30 min. The reaction solution was diluted with EtOAc (60 mL) and washed with ice-cold water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 1.2 g (46% yield) of 5-bromofurano[3,2-b]pyridin-3(2H)-one as a brown solid. MS (ESI) 214.4 [M+H] + .

[0234] Step 6: Add methyl magnesium iodide (8.6 mL, 3.0 M Et2O, 25.80 mmol) to a 0 °C solution of 1.1 g (5.16 mmol) of 5-bromofurano[3,2-b]pyridin-3(2H)-one in Et2O solution (15 mL). Stir the reaction at 0 °C for 1 h, quench the reaction with NH4Cl aqueous solution (30 mL), and extract the reaction solution with EtOAc (2 × 30 mL). Combine the organic layers, dry (Na2SO4), filter, and concentrate under reduced pressure. Purify the residue by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to intermediate 8 (510 mg, 43% yield) as a brown solid. MS (ESI) 230.3 [M+H + .

[0235] Intermediate 9

[0236] 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[3,2-b]pyridin-5-yl)-6-(methylthio)- 1,2-Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0237]

[0238] Intermediate 9 was prepared using intermediates 1 and 8 following the steps described for intermediate 3; MS (ESI) 372.6 [M+H] + .

[0239] Example 4A

[0240] (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[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

[0241]

[0242] Example 4B

[0243] (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[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

[0244]

[0245] Examples 4A and 4B were prepared using intermediate 9 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[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)δ10.10(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, J=17.2Hz,1H),4.50-4.43(m,4H),3.07(t,J=4.4Hz,4H),2.44(t,J=4.4Hz,4H),2.21(s,3H),1.55(s,3H); MS(ESI)515.6[M+H] + Example 4B: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ10.10(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, J=17.2Hz,1H),4.50-4.43(m,4H),3.07(t,J=4.4Hz,4H),2.44(t,J=4.4Hz,4H),2.21(s,3H),1.55(s,3H); MS(ESI)515.5[M+H] + The absolute configurations of Examples 4A and 4B can be arbitrarily specified.

[0246] Intermediate 10

[0247] 3-Ethyl-5-iodo-2,3-dihydrobenzofuran-3-ol

[0248]

[0249] Step 1: Prepare 5-iodobenzofuran-3(2H)-one according to WO Publication No. 2008 / 068974. MS (ESI) m / z 260.9 [M+H] + .

[0250] Step 2: 3.0 M EtMgBr (12.82 mL, 38.46 mmol) was added dropwise to a 20 mL toluene-toluene stirred solution of 5-iodobenzofuran-3(2H)-one (2 g, 7.69 mmol) at 0 °C. The mixture was allowed to reach room temperature and stirred for 16 h. After TLC showed the reaction was complete, the reaction was quenched with water (50 mL) and the reaction mixture was extracted with EtOAc (2 × 100 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO₂, 20% EtOAc / petroleum ether) to give intermediate 10 (1.5 g, 67%) as a yellow solid. MS (ESI) 272.9 [M + H - H₂O] + .

[0251] Intermediate 11

[0252] 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

[0253]

[0254] Intermediate 11 was prepared using intermediates 1 and 10 following the steps described for intermediate 3. MS (ESI) 385.1 [M+H] + .

[0255] Example 5A

[0256] (R)-2-Allyl-1-(3-Ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((4-(4-methylpiperyl) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0257]

[0258] Example 5B

[0259] (S)-2-Allyl-1-(3-Ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((4-(4-methylpiperyl) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0260]

[0261] Examples 5A and 5B were prepared using intermediate 11 following the steps described for Examples 2A and 2B, yielding 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)δ9.95(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) δ9.95 (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,4 H),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] + The absolute configurations of Examples 5A and 5B can be arbitrarily specified.

[0262] Intermediate 12

[0263] 5-Bromo-3-(trifluoromethyl)-2,3-dihydrofurano[3,2-b]pyridine-3-ol

[0264]

[0265] Finely grind a 1 / 1 by weight mixture of KOH and diatomaceous earth. Fill a glass dropper with the KOH / diatomaceous earth mixture (720 mg). Dissolve 5-bromofurano[3,2-b]pyridin-3(2H)-one (500 mg, 2.35 mmol) and Me3SiCF3 (666 mg, 4.69 mmol) in DMF (2.0 mL). Add the solution to the glass dropper using a syringe. Elute the product with 4.0 mL of DMF. Repeat the reaction at a scale of 4 × 500 mg. Combine the reaction mixtures and quench the reaction with saturated NH4Cl (50 mL). Extract the aqueous layer with Et2O (2 × 75 mL), and combine the organic layers, wash with brine (2 × 100 mL), dry (Na2SO4), filter, and concentrate under reduced pressure. The residue was purified by rapid chromatography (SiO2, 20% EtOAc / petroleum ether) to give intermediate 12 (530 mg, 16%) as a grayish-white solid. MS (ESI) 284.2 [M+H] + .

[0266] Intermediate 13

[0267] 2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofurano[3,2-b]pyridin-5-yl)-6-(methyl) Thio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0268]

[0269] Intermediate 13 was prepared using intermediates 1 and 12 following the same steps as described for intermediate 3. MS(ESI) 426.4 [M+H] + .

[0270] Example 6A

[0271] (R)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofurano[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

[0272]

[0273] Example 6B

[0274] (S)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofurano[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

[0275]

[0276] Examples 6A and 6B were prepared using intermediate 13 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofurano[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 methanol)) 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)δ10.2(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; 1 H NMR(400MHz,DMSO-d6)δ10.2(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] + Any absolute configuration can be specified for Examples 6A and 6B.

[0277] Intermediate 14

[0278] 2-Bromo-7,7-difluoro-6,7-dihydro-5 H -cyclopenten[ b ]Pyridine

[0279]

[0280] DAST (3.7 mL, 28.30 mmol) was added to a 50 mL solution of 2-bromo-5,6-dihydro-7H-cyclopenteno[b]pyridin-7-one (2.0 g, 9.43 mmol) stirred in DCM at room temperature, and the mixture was stirred at room temperature for 4 days. The reaction was quenched with an aqueous solution of NaHCO3 (25 mL) at 0 °C, and the reaction mixture was extracted with DCM (3 × 30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 3% EtOAc / petroleum ether) to give intermediate 14 (0.8 g, 36% yield) as a grayish-white solid. MS (ESI) 233.9 [M+H] + .

[0281] Intermediate 15

[0282] 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methylthio)-1, 2-Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0283]

[0284] Intermediate 15 was prepared using intermediates 1 and 14 following the steps described for intermediate 3; MS (ESI) 376.4 [M+H] + .

[0285] Example 7

[0286] 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-((4-(piperazine-1- (B-)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0287]

[0288] Step 1: Following the steps described for Examples 2A and 2B, tert-butyl piperazine-1-carboxylate was prepared using 4-(4-((2-allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate tert-butyl (120 mg, 19% yield) + .

[0289] Step 2: At 0°C, a solution of 2M HCl in Et2O (5 mL) was added to a stirred Et2O solution (10 mL) of 250 mg (0.41 mmol) of 4-(4-((2-allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.41 mmol). The mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, and ground with Et2O to give Example 7 (94 mg, 42%) as a pale yellow solid in the form of hydrochloride. 1 H NMR (400MHz, DMSO-d6) δ10.28(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] + .

[0290] Example 8

[0291] 2-Allyl-1-(7,7-difluoro-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-((4-(4-methyl) Piperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0292]

[0293] Example 8 (120 mg, 19%) was prepared as a yellow solid using 4-(4-methylpiperazin-1-yl)aniline and intermediate 15, following the steps described for Examples 2A and 2B. 1H NMR(400MHz,DMSO-d6)δ10.24(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 s,6H),2.78-2.62(m,2H),2.52-2.42(m,4H),2.22(s,3H); MS(ESI)519.3[M+H] + .

[0294] Intermediate 16

[0295] 2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0296]

[0297] To a 20 mL solution of 2-bromo-5,6-dihydro-7H-cyclopenteno[b]pyridin-7-one (2 g, 9.43 mmol) in a 0 °C PhMe solution, 3 M EtMgBr DEE solution (9.4 mL, 28.29 mmol) was added dropwise. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. After TLC showed the reaction was complete, the reaction was cooled to 0 °C, quenched with a saturated NH4Cl solution (30 mL), and the reaction mixture was extracted with EtOAc (2 × 50 mL). The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 30% EtOAc / hexane) to give intermediate 16 (860 mg, 38%) as an oil. MS (ESI) 244.2 [M+H] + .

[0298] Intermediate 17

[0299] 2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methylthio) 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0300]

[0301] Intermediate 17 was prepared using intermediates 1 and 16 following the steps described for intermediate 3. MS (LCMS) 384.5 [M+H] + .

[0302] Example 9A

[0303] (S)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0304]

[0305] Example 9B

[0306] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0307]

[0308] To a 90 mL solution of intermediate 17 (4.5 g, 11.7 mmol) in toluene at 0 °C, m-CPBA (3.7 g, 12.9 mmol) was added. The ice bath was removed, and the reaction was stirred for 30 min. TLC showed that the reaction was complete. Then, 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 h. TLC confirmed the reaction was complete, and water (100 mL) was added to the reaction mixture, followed by extraction with EtOAc (3 × 100 mL). The organic layers were combined, washed with saturated NaHCO3 solution (250 mL) and brine (300 mL), dried (Na2SO4), and evaporated under reduced pressure. The crude product was ground with 30% Et2O / pentane to obtain racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 compound (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; 1H NMR (400MHz, DMSO-d6) δ10.05(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; 1 H NMR (400MHz, DMSO-d6) δ10.05(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] + Any absolute configuration may be specified for Examples 9A and 9B.

[0309] Example 10A

[0310] (S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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

[0311]

[0312] Example 10B

[0313] (R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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

[0314]

[0315] Examples 10A and 10B were prepared using intermediate 5 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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; 1 H NMR (400MHz, DMSO-d6) δ10.13(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; 1H NMR (400MHz, DMSO-d6) δ10.13(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] + The absolute configurations of Examples 10A and 10B can be arbitrarily specified.

[0316] Example 11A

[0317] (S)-2-Allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl- 6,7-Dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0318]

[0319] Example 11B

[0320] (R)-2-Allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl- 6,7-Dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0321]

[0322] Examples 11A and 11B were prepared using intermediate 5 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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 ethanol)) to give peak 1 (Example 11A, 90 mg) and peak 2 (Example 11B, 90 mg). Example 11A: Yellow solid; 1H NMR (300MHz, DMSO-d6) δ10.25(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: 1 H NMR (300MHz, DMSO-d6) δ10.25(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. The absolute configuration is arbitrarily specified for Examples 11A and 11B.

[0323] Example 12A

[0324] (S)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0325]

[0326] Example 12B

[0327] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0328]

[0329] Examples 12A and 12B were prepared using intermediate 17 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline following the steps described for Examples 9A and 9B, yielding racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 methanol)) 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) δ10.05(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=8.4Hz1H),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),1.92-1.80(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) δ10.05(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=8.4Hz1H),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] + The absolute configurations of Examples 12A and 12B can be arbitrarily specified.

[0330] Example 13A

[0331] (S)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0332]

[0333] Example 13B

[0334] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0335]

[0336] Step 1: 2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 using intermediate 17 and 1-(4-(4-amino-2-methylphenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one according to the steps described for Examples 9A and 9B. MS(ESI) 623.2 [M+H] + .

[0337] Step 2: K₂CO₃ (399 mg, 2.89 mmol) was added to a 15 mL stirred methanol solution of 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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). The reaction was stirred at room temperature for 4 h. After the reaction was complete as indicated by TLC, the solvent was evaporated. The reaction solution was diluted with water (30 mL), and the solid compound was filtered to give a pale yellow racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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%). The enantiomers were separated by chiral SFC chromatography (Chiral Pak AD-H, 40% (0.5% DEA in methanol)) to give peak 1 (Example 13A, 162 mg) and peak 2 (Example 13B, 108 mg). Example 13A: Yellow solid; 1 H NMR (400MHz, DMSO-d6) δ10.12(brs,1H),8.84(s,1H),7.89(d,J=8.4Hz,1H),7.71(d,J=8.1Hz,1H),7.67(brs,1H),7.4 1(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; 1H NMR (400MHz, DMSO-d6) δ10.12(brs,1H),8.84(s,1H),7.89(d,J=8.4Hz,1H),7.71(d,J=8.1Hz,1H),7.67(brs,1H),7.4 1(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] + The absolute configurations of Examples 13A and 13B can be arbitrarily specified.

[0338] Intermediate 18

[0339] (S)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0340]

[0341] Intermediate 19

[0342] (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0343]

[0344] Racemic intermediate 16 (6 g, 24.79 mmol) was purified by SFC chromatography (Lux Cellulose-2, 10% ethanol). Intermediates 18 (1.9 g, 7.88 mmol) and 19 (1.8 g, 7.47 mmol). Intermediate 18: colorless oil; [α] D 25 (c=0.5,CHCl3)-27.31°; MS(ESI)242.3[M+H] + Intermediate 19: Colorless oil; [α] D 25 (c=0.5,CHCl3)+35.53°; MS(ESI)242.3[M+H] + .

[0345] Intermediate 20

[0346] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methyl) Thio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0347]

[0348] Intermediate 20 is prepared using intermediates 1 and 19 following the steps described for intermediate 3. [α] D 25 (c=0.1,CHCl3)+17.84°; MS(LCMS)384.5[M+H] + .

[0349] Example 14

[0350] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0351]

[0352] Step 1: (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 using intermediate 20 according to the steps described for Examples 9A and 9B. MS(ESI) 609.6 [M+H] + .

[0353] Step 2: K₂CO₃ (238 mg, 1.72 mmol) was added to a methanol stirred solution (6 mL) of (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. After the reaction was complete as indicated by TLC, the reaction mixture 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 organic layers were combined, 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 a grayish-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] + .

[0354] Intermediate 21

[0355] 2-Bromo-7-(difluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0356]

[0357] 18-crown ether-6 (625 mg, 2.37 mmol) and CsF (715 mg, 4.739 mmol) were added to a stirred solution (10 mL) of 1,2-DME containing Me3SiCF2H (1.175 g, 9.48 mmol) at 0 °C, and the reaction was stirred for 15 min. 2-Bromo-5,6-dihydro-7H-cyclopenten[b]pyridin-7-one (1 g, 4.74 mmol) was added to the reaction mixture at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. After TLC confirmed the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 50 mL). The separated organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude compound. The above reaction was repeated on a scale of 4 × 1 g. The residue was purified by rapid chromatography (SiO2, EtOAc / petroleum ether) to give intermediate 21 (470 mg) as a grayish-white solid. MS (ESI) 266.3 [M+H] + .

[0358] Intermediate 22

[0359] 2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- (methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0360]

[0361] Intermediate 22 was prepared using intermediates 1 and 21 following the steps described for intermediate 3; MS (ESI) 406.3 [M+H] + .

[0362] Example 15A

[0363] (S)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridine-2- )-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0364]

[0365] Example 15B

[0366] (R)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridine-2- )-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0367]

[0368] Examples 15A and 15B were prepared using intermediate 22 following the steps described for Examples 9A and 9B, yielding racemic 2-allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[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; ¹H 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 s, 2H), δ 10.2 (br s, 1H), 8.83 (s, 1H), 8.02 (br s, 1H), 7.82 (d, J = 8.4Hz, 1H), δ 4.74 (br s, 2H), δ 4.82 (br s, 2 ... s,1H),4.60-4.54(m,1H),3.10-2.90(m,6H),2.47-2.46(m,5H),2.22(s,3H),2.11-2.04(m,1H); MS(ESI)549.2[M+H] + Example 15B: Yellow solid; 1H NMR (400MHz, DMSO-d6) δ10.2(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 s,1H),4.60-4.54(m,1H),3.10-2.90(m,6H),2.47-2.46(m,5H),2.22(s,3H),2.11-2.04(m,1H); MS(ESI)549.2[M+H] + The absolute configurations of Examples 15A and 15B can be arbitrarily specified.

[0369] Intermediate 23

[0370]

[0371] A 3M THF solution of cyclopropylmagnesium bromide (31 mL, 94.3 mmol) was added to a 50 mL THF solution of 2-bromo-5H-cyclopenteno[b]pyridin-7(6H)-one (4 g, 18.80 mmol) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. TLC showed that the reaction was complete, and the reaction was quenched with an aqueous solution of NH4Cl (200 mL). The mixture was extracted with EtOAc (2 × 200 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by rapid 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] + .

[0372] Intermediate 24

[0373] 2-Allyl-1-(7-Cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6-(methylthio) 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0374]

[0375] Intermediate 24 was prepared using intermediates 1 and 23 following the same steps as described for intermediate 3. MS (ESI) 396.5 [M+H] + .

[0376] Example 16A

[0377] (R)-2-Allyl-1-(7-Cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0378]

[0379] Example 16B

[0380] (S)-2-Allyl-1-(7-Cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0381]

[0382] Examples 16A and 16B were prepared using intermediate 24 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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; 1 H NMR(400MHz,DMSO-d6)δ10.13(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; 1H NMR(400MHz,DMSO-d6)δ10.13(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] + Any absolute configuration may be specified for Examples 16A and 16B.

[0383] Example 17A

[0384] 2-Allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0385]

[0386] Example 17B

[0387] 2-Allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0388]

[0389] Examples 17A and 17B were prepared using intermediate 5 and (S)-4-(3,4-dimethylpiperazin-1-yl)aniline following the steps described for Examples 9A and 9B, yielding a mixture (500 mg) of diastereomeric 2-allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. The diastereomeric compounds were separated by chiral SFC chromatography (Chiral Pak IG, (0.5% DEA in methanol:hexane (80:20) solution)) to give peak 1 (Example 17A, 130 mg) and peak 2 (Example 17B, 75 mg). Example 17A: Yellow solid; 1H NMR (400MHz, DMSO-d6) δ10.1(brs,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; 1 H NMR (400MHz, DMSO-d6) δ10.1(brs,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] + The absolute configurations of Examples 17A and 17B can be arbitrarily specified.

[0390] Example 18A

[0391] 2-Allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0392]

[0393] Example 18B

[0394] 2-Allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0395]

[0396] Examples 18A and 18B were prepared using intermediate 5 and (R)-4-(3,4-dimethylpiperazin-1-yl)aniline, following the steps described for Examples 9A and 9B, to obtain a mixture of diastereomeric 2-allyl-6-((4-(((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. The diastereomeric compounds 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)δ10.09(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)δ10.10(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 configuration of the tertiary alcohol is arbitrarily specified for Examples 18A and 18B.

[0397] Example 19A

[0398] 2-Allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0399]

[0400] Example 19B

[0401] 2-Allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0402]

[0403] Examples 19A and 19B were prepared using intermediate 5 and (S)-4-(2,4-dimethylpiperazin-1-yl)aniline according to the steps described for Examples 9A and 9B, yielding a mixture (400 mg) of diastereomeric 2-allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. The diastereomeric compounds were separated by chiral SFC chromatography (Chiralpak AD-H, 25.0% (0.5% DEA in methanol)) to give peak 1 (Example 19A, 158 mg) and peak 2 (Example 19B, 103 mg). Example 19A: Yellow solid; 1H NMR (400MHz, DMSO-d6) δ10.1(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; 1 H NMR (400MHz, DMSO-d6) δ10.1(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] + The absolute configuration of the tertiary alcohol is arbitrarily specified for Examples 19A and 19B.

[0404] Example 20A

[0405] 2-Allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((S)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0406]

[0407] Example 20B

[0408] 2-Allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-((R)-7-hydroxy-7-methyl) (-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0409]

[0410] Examples 20A and 20B were prepared using intermediate 5 and (R)-4-(2,4-dimethylpiperazin-1-yl)aniline following the steps described for Examples 9A and 9B, to obtain a mixture (400 mg) of diastereomeric 2-allyl-6-((4-(((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. The diastereomeric compounds were separated by chiral SFC chromatography (Chiralpak AD-H, 20.0% (0.5% DEA in methanol)) 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) δ10.1(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; 1H NMR (400MHz, DMSO-d6) δ10.1(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] + The absolute configuration of the tertiary alcohol is arbitrarily specified for Examples 20A and 20B.

[0411] Intermediate 25

[0412] 6-Bromo-1-methyl-2,3-dihydro-1H-inden-1-ol

[0413]

[0414] A THF suspension (100 mL) of anhydrous CeCl3 (17.5 g, 71.08 mmol) was stirred at room temperature for 1 h and cooled to -78 °C. A 1.6 M DEE solution of MeLi (44 mL, 71.08 mmol) was added at -78 °C, and the reaction was stirred for 30 min. A THF solution (100 mL) of 6-bromo-2,3-dihydro-1H-inden-1-one (10 g, 47.39 mmol) was added at -78 °C. The ice bath was removed, and the reaction was stirred at room temperature for 2 h. TLC showed that the reaction was complete, and the reaction was quenched with an aqueous solution of NH4Cl (200 mL). The mixture was extracted with EtOAc (2 × 200 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 30% EtOAc / petroleum ether) to give intermediate 25 (6 g, 55%) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ7.43(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).

[0415] Intermediate 26

[0416] 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

[0417]

[0418] Intermediate 26 was prepared using intermediates 1 and 25 following the same steps as described for intermediate 3. MS(ESI) 369.4 [M+H] + .

[0419] Example 21A

[0420] (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazine- 1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0421]

[0422] Example 21B

[0423] (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazine- 1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0424]

[0425] Examples 21A and 21B were prepared using intermediate 26 following the steps described for Examples 2A and 2B, yielding 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)δ10.03(brs,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; 1 H NMR(400MHz,DMSO-d6)δ10.03(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 configurations of Examples 21A and 21B can be arbitrarily specified.

[0426] Intermediate 27

[0427] 6-Bromo-1-ethyl-2,3-dihydro-1H-inden-1-ol

[0428]

[0429] EtMgBr solution (23.70 mL, 71.07 mmol) was added dropwise to a stirred toluene solution (50 mL) of 6-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 23.68 mmol) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. The reaction was quenched with a saturated aqueous NH4Cl solution (50 mL), and the reaction mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20% EtOAc / petroleum ether) to give intermediate 27 (4 g, 70%) as a colorless liquid. MS (ESI) 223.1 [M + H - H2O] + .

[0430] Intermediate 28

[0431] 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

[0432]

[0433] Intermediate 28 was prepared using intermediates 1 and 27 following the steps described for intermediate 3. MS(ESI) 383.4 [M+H] + .

[0434] Example 22A

[0435] (S)-2-Allyl-1-(3-Ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazine- 1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0436]

[0437] Example 22B

[0438] (R)-2-Allyl-1-(3-Ethyl-3-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazine- 1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0439]

[0440] Examples 22A and 22B were prepared using intermediate 28 following the steps described for Examples 9A and 9B, yielding 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)δ10.01(brs,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)δ10.01(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] + The absolute configurations of Examples 22A and 22B are arbitrarily specified.

[0441] Example 23A

[0442] (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methyl) (Pyropiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0443]

[0444] Example 23B

[0445] (R)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methyl) (Pyropiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0446]

[0447] Examples 23A and 24b were prepared using intermediate 26 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline following the steps described for Examples 9A and 9B, yielding 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 isopropanol solution)) to give peak 1 (Example 23A, 223 mg) and peak 2 (Example 23B, 223 mg). Example 23A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ10.00(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 ),2.22(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)δ10.00(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 ),2.22(s,3H),2.17(s,3H),2.12-2.09(m,2H),1.42(s,3H); MS(ESI)526.7[M+H] + The absolute configurations of Examples 23A and 23B are arbitrarily specified.

[0448] Intermediate 29

[0449] 6-Bromo-4-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol

[0450]

[0451] Step 1: Prepare 6-bromo-4-fluoro-2,3-dihydro-1H-indanone according to WO publication number 2005 / 095387. 1 H NMR (400MHz, CDCl3-d6) δ7.70 (s, 1H), 7.42 (d, J = 9.6Hz, 1H), 3.10 (t, J = 6.0Hz, 2H), 2.75 (t, J = 6.4Hz, 2H).

[0452] Step 2: 3.0 M DEE solution of MeMgBr (87 mL, 262 mmol) was added dropwise to a 0°C solution (60 mL) of 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (6 g, 26 mmol) in diethyl ether at 0°C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. After TLC showed the reaction was complete, the reaction was quenched with water (50 mL), and the reaction mixture was extracted with EtOAc (2 × 100 mL). The organic layers were combined, washed with water (150 mL) and brine (150 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂, 10% EtOAc / petroleum ether) to give 6-bromo-4-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol (3 g, 47%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.28 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 10.0, 4.8 Hz, 1H), 3.03-2.95 (m, 1H), 2.85-2.74 (m, 1H), 2.30-2.18 (m, 2H), 1.58 (s, 3H).

[0453] Intermediate 30

[0454] 2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-(methylthio)-1,2-di Hydrogen-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0455]

[0456] Intermediate 30 was prepared using intermediates 1 and 29 following the steps described for intermediate 3. MS(ESI) 387.3 [M+H] + .

[0457] Example 24A

[0458] (S)-2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methyl) Piperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0459]

[0460] Example 24B

[0461] (R)-2-Allyl-1-(7-fluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((4-(4-methyl) Piperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0462]

[0463] Examples 24A and 24B were prepared using intermediate 30 following the steps described for Examples 9A and 9B, yielding 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 solution)) to give peak 1 (Example 24A, 43 mg) and peak 2 (Example 24B, 47 mg). Example 24A: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ10.10(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 s, 2 ... s,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] + . ] + The absolute configurations of Examples 24A and 24B can be arbitrarily specified.

[0464] Intermediate 31

[0465] 2-Bromo-8-methyl-5,6,7,8-tetrahydroquinoline-8-ol

[0466]

[0467] Step 1: TMS-Br (2.86 g, 18.78 mmol) was added to a CH3CN stirred solution (30 mL) of 2-chloro-6,7-dihydroquinoline-8(5H)-one (1.7 g, 9.39 mmol), and the reaction was heated in a CEM-microwave at 150 °C for 20 min. After the reaction was complete as indicated by TLC, the reaction solution was diluted with DCM (100 mL) and washed with NaHCO3 aqueous solution (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 20% EtOAc / petroleum ether) to give 2-bromo-6,7-dihydroquinoline-8(5H)-one (1.2 g, 57%) as a brown oil. MS (ESI) 226.3 [M+H].

[0468] Step 2: 3.0 M CH3MgI DEE solution (8.88 mL, 26.65 mmol) was added dropwise to a 0°C DEE solution (30 mL) of 2-bromo-6,7-dihydroquinoline-8(5H)-one (1.20 g, 5.33 mmol). The mixture was allowed to reach room temperature and stirred for 16 h. After TLC showed the reaction was complete, the reaction was quenched with water (25 mL) and the reaction mixture was extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (SiO2, 20% EtOAc / petroleum ether) to give intermediate 31 (900 mg, 70%) as a grayish-white solid. MS (ESI) 241.9 [M+H] + .

[0469] Intermediate 32

[0470] 2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-2-yl)-6-(methylthio)-1,2-dihydro- 3H-pyrazolo[3,4-d]pyrimidin-3-one

[0471]

[0472] Intermediate 32 was prepared using intermediates 1 and 31 following the steps described for intermediate 3. MS(ESI) 384.1 [M+H] + .

[0473] Example 25A

[0474] (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperyl) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0475]

[0476] Example 25B

[0477] (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperyl) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0478]

[0479] Examples 25A and 25B were prepared using intermediate 32 following the steps described for Examples 2A and 2B, yielding 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; 1 H NMR(400MHz,DMSO-d6)δ10.04(br s,1H),8.81(s,1H),7.77(d,J=7.2Hz,1H),7.69(d,J=8.4Hz,1H),7.57(d,J=6.8Hz,2H),6.92( d,J=8.8Hz,2H),5.72-5.61(m,1H),4.98(d,J=10.4Hz,1H),4.89(s,1H),4.84(s,1H),4.81(br s,1H),4.65(dd,J=16.0,5.2Hz,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=10.8Hz,1H),1.77-1.68(m,1H),1.49(s,3H); MS(ESI)527.3[M+H] + Example 25B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ10.04(br s,1H),8.81(s,1H),7.77(d,J=8.4Hz,1H),7.69(d,J=7.6Hz,1H),7.56(d,J=6.8Hz,2H),6.92( d,J=8.8Hz,2H),5.71-5.61(m,1H),4.98(d,J=10.4Hz,1H),4.89(s,1H),4.84(s,1H),4.81(s, 1H),4.66(dd,J=15.6,5.2Hz,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 configurations of Examples 25A and 25B can be arbitrarily specified.

[0480] Intermediate 33

[0481] 2-Bromo-8-ethyl-5,6,7,8-tetrahydroquinoline-8-ol

[0482]

[0483] To a 0°C solution of 2-bromo-6,7-dihydroquinoline-8(5H)-one (2.00 g, 8.88 mmol) in diethyl ether (40 mL), 3.0 M EtMgBr in DEE solution (14.82 mL, 44.44 mmol) was added dropwise. The ice bath was removed, and the mixture was allowed to reach room temperature and stirred for 16 h. TLC showed that the reaction was complete. The reaction was quenched with water (50 mL), and the reaction mixture was extracted with EtOAc (2 × 30 mL). The organic layers were combined, washed with water and brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂, 10% EtOAc / petroleum ether) to give intermediate 33 (900 mg, 40%) as a pale yellow oil. MS (ESI) 256.2 [M+H] + .

[0484] Intermediate 34

[0485] 2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinoline-2-yl)-6-(methylthio)-1,2-dihydro- 3H-pyrazolo[3,4-d]pyrimidin-3-one

[0486]

[0487] Intermediate 34 was prepared using intermediates 1 and 33 following the steps described for intermediate 3. MS(ESI) 398.0 [M+H] + .

[0488] Example 26A

[0489] (S)-2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperyl) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0490]

[0491] Example 26B

[0492] (R)-2-Allyl-1-(8-ethyl-8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazine) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0493]

[0494] Examples 26A and 26B were prepared using intermediate 34 following the steps described for Examples 2A and 2B, yielding 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)δ10.11(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, 5.6 Hz, 1H), 3.12-3.06(m, 4H), 2.85-2.67(m, 2H), 2.49-2.40(m, 4H), 2.22(s, 3H), 1.96-1.71(m, 6H), 0.78(t, J = 7.6 Hz, 3H); MS(ESI) 541.3 Example 26B: Yellow solid; 1H NMR(400MHz,DMSO-d6)δ10.11(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),2.49-2.40(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] + Any absolute configuration may be specified for Examples 26A and 26B.

[0495] Example 27A

[0496] (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-) Methylpiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0497]

[0498] Example 27B

[0499] (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-yl) Methylpiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0500]

[0501] Examples 27A and 27B were prepared using intermediate 32 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline according to the steps described for Examples 2A and 2B, yielding 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; 1H NMR(400MHz,DMSO-d6)δ10.12(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) δ10.12(brs,1H),8.84(s,1H),7.75-7.67(m,3H),7.39(d,J=8.8 Hz,1H),6.99(d,J=8.8Hz,1H),5.71-5.61(m,1H),4.98(d,J=10Hz,1H),4.89(d,J=8.4H z,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),2.2 5-2.24(m,6H),1.96-1.92(m,2H),1.83-1.70(m,2H),1.49(s,3H); MS(ESI)541.2[M+H] + The absolute configurations of Examples 27A and 27B are arbitrarily specified.

[0502] Example 28A

[0503] (S)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(piperazine-1- (B-)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0504]

[0505] Example 28B

[0506] (R)-2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(piperazine-1- (B-)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0507]

[0508] Step 1: 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 was synthesized using intermediate 32 according to the steps described for Examples 9A and 9B. MS (ESI) 609.5 [M+H] + .

[0509] Step 2: Add K₂CO₃ (272 mg, 1.97 mmol) to a methanol solution (6 mL) 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) at 0 °C. Remove the ice bath and stir the reaction at room temperature for 16 h. After the reaction was complete as indicated by TLC, concentrate the reaction mixture under reduced pressure. Add water (10 mL) and stir the mixture 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)δ10.10(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)δ10.09(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] + The absolute configurations of Examples 28A and 28B can be arbitrarily specified.

[0510] Intermediate 35

[0511] 1-(7'-amino-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethane-1-one

[0512]

[0513] Step 1: Prepare 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] according to US 7507748.

[0514] Step 2: TEA (3.69 g, 36.75 mmol) and trifluoroacetic anhydride (3.08 g, 14.70 mmol) were added to a stirred DCM solution (40 mL) of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (2.5 g, 12.25 mmol) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. After TLC showed the reaction was complete, the reaction solution 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'-isoquinoline]-2'(3'H)-yl)ethane-1-one (1.7 g, 46%) as a yellow oil. 1H NMR (300MHz, DMSO-d6) δ8.26 (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).

[0515] Step 3: SnCl2 (6.44 g, 33.99 mmol) and NH4Cl (1.81 g, 33.99 mmol) were added to a stirred ethanol solution (17 mL) of 2,2,2-trifluoro-1-(7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)ethane-1-one (1.7 g, 5.66 mmol). The reaction was heated at 80 °C for 2 h. After the reaction was complete as indicated by TLC, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL), alkalized to pH -8 with saturated NaHCO3, and extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na2SO4), 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] + .

[0516] Example 29A

[0517] (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-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine 3-Pyridoxine

[0518]

[0519] Example 29B

[0520] (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-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine 3-Pyridoxine

[0521]

[0522] Step 1: 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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 using intermediates 5 and 35 according to the steps described for Examples 9A and 9B. MS(ESI) 592.4 [M+H] + .

[0523] Step 2: Add K₂CO₃ (94 mg, 0.68 mmol) to a methanol solution (6 mL) of 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenten[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) at 0 °C. Remove the ice bath and stir the reaction at room temperature for 16 h. After the reaction was complete as indicated by TLC, concentrate the reaction solution under reduced pressure. Add water (10 mL) to the crude compound and stir for 10 min. The precipitate was filtered and dried under vacuum to give a 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-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (85 mg). 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),7.5 5(brs,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; 1H 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(brs,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] + The absolute configurations of Examples 29A and 29B can be arbitrarily specified.

[0524] Intermediate 36

[0525] 7'-Amino-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-tert-butyl carboxylate

[0526]

[0527] Step 1: 15 mL of 1 N NaOH was added to a stirred solution (45 mL, 2:1) of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (3 g, 14.63 mmol) in 1,4-dioxane:H₂O at 0 °C. After 5 min, 3.7 mL of ditert-butyl dicarbonate (16.91 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 2 h. The reaction mixture was acidified with KHSO₄ (pH: 2-3), and then the mixture was extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with water (25 mL), dried (Na₂SO₄), and concentrated. The resulting crude mixture was purified by column chromatography (SiO2, 20% EA / petroleum ether) to give tert-butyl 7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylic acid (2.5 g, 56%) as a pale yellow solid. MS (LCMS) 249.0 [M-C4H 10 ] + .

[0528] Step 2: SnCl2 (3.74 g, 19.67 mmol) was added to a stirred ethanol solution (50 mL) of 7'-nitro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-tert-butyl carboxylate (1.0 g, 3.28 mmol) at room temperature, followed by NH4Cl (1.04 g, 19.67 mmol). The reaction was stirred at 70 °C for 1 h. After the reaction was complete as indicated by LCMS, the crude reaction solution was concentrated under reduced pressure, diluted with water (50 mL), and alkalized with saturated NaHCO3 (pH: 8-9). The mixture was then filtered through a diatomaceous earth mat, and the filtrate was extracted with 30% methanol:DCM (3 × 100 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give intermediate 36 (615 mg, 93%) as a grayish-white solid. MS (LCMS) 275.4 [M+H] + .

[0529] Intermediate 37A

[0530] (S)-7'-((2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine- 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)-tert-butyl carboxylate

[0531]

[0532] Intermediate 37B

[0533] (R)-7'-((2-Allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine- 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)-tert-butyl carboxylate

[0534]

[0535] Intermediate 37A and Example 37B were prepared using intermediates 7 and 36 according to the steps described for Examples 2A and 2B, yielding racemic-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[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)-tert-butyl 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] + The absolute configuration can be arbitrarily assigned to intermediates 37A and 37B.

[0536] Example 30A

[0537] (S)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1- (7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3, [4-d]pyrimidin-3-one

[0538]

[0539] A 2M HCl solution of Et₂O (1 mL) was added to a 4 mL stirred solution of intermediate 37A (140 mg, 0.22 mmol) in DCM at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, ground with diethyl ether, and dried under high vacuum to give Example 30A (60 mg, 50%) as an HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (brs, 1H), 9.39 (s, 2H), 8.91 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 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,1 H),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] + .

[0540] Example 30B

[0541]

[0542] Example 30B was prepared in hydrochloride form according to the steps of Example 30A. 1H NMR (400MHz, DMSO-d6) δ10.38(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,1 H),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] + The absolute configurations of Examples 30A and 30B can be arbitrarily specified.

[0543] Example 31A

[0544] (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-tetrahydroquinolin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0545]

[0546] Example 31B

[0547] (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-tetrahydroquinolin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0548]

[0549] Step 1: 2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-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 using intermediates 32 and 35 according to the steps described for Examples 2A and 2B. MS (ESI) 606.4 [M+H] + .

[0550] Step 2: K₂CO₃ (183 mg, 1.32 mmol) was added to a stirred methanol solution (12 mL) of 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-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), and the reaction was stirred at room temperature for 16 h. The solvent was evaporated after TLC showed the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM solution (2 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a pale yellow solid racemic 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-tetrahydroquinoline-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (310 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak AD-H, (0.5% isopropylamine in IPA solution)) to give peak 1 (Example 31A, 120 mg) and peak 2 (Example 31B, 123 mg). Example 31A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ10.15(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; 1H NMR(400MHz,DMSO-d6)δ10.15(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] + The absolute configurations of Examples 31A and 31B can be arbitrarily specified.

[0551] Intermediate 38

[0552] 2-Bromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0553]

[0554] Step 1: Synthesize 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine according to the steps in WO 2016138821.

[0555] Step 2: NBS (9.04 g, 50.80 mmol) was added in portions to a CH3CN stirred solution (30 mL) of 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (3 g, 24.16 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h. After the reaction was complete as indicated by TLC, the reaction solution was concentrated. The crude mixture was ground 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] + .

[0556] Step 3: 1.6 M iPrMgCl (1.65 mL, 2.85 mmol) was added dropwise to an anhydrous THF stirred solution of 2,3-dibromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (500 mg, 1.76 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h. After TLC showed the reaction was complete, the reaction was quenched with water (25 mL) and the reaction mixture was extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried (Na₂SO₄), and evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO₂, 3% methanol / DCM) to give intermediate 38 (280 mg, 77%) as a grayish-white solid. MS (ESI) m / z 203.3 [M+H] + .

[0557] Intermediate 39

[0558] 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

[0559]

[0560] Intermediate 39 was prepared using intermediates 1 and 38 following the steps described for intermediate 3. The mixture was degassed for 20 min and then heated in a microwave at 100 °C for 2 h. MS(ESI) 345.5 [M+H + .

[0561] Example 32

[0562] 2-Allyl-1-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-6-((4-(4-methylpiperazine) (azinyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0563]

[0564] Example 32 (5 mg) was prepared using intermediate 39 following the steps described for Examples 2A and 2B. 1 HNMR(400MHz,DMSO-d6)δ9.94(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=10.8H z,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] + .

[0565] Intermediate 40

[0566] 2-Iodo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0567]

[0568] Step 1: NaI (40 g, 270 mmol) was added to a stirred CH3CN solution of methyl 6-chloro-3-methylpyridinecarboxylate (10 g, 54 mmol) in 50 mL at room temperature, followed by the addition of TMS-Cl solution (36 mL, 270 mmol). The reaction was refluxed for 8 h. After TLC showed the reaction was complete, the solvent was evaporated, the residue was diluted with water (100 mL), and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 50% EtOAc / petroleum ether) to give 6-iodo-3-methylpyridinecarboxylic acid (8 g, 57%) as a grayish-white solid. 1 H NMR (300MHz, DMSO-d6) δ13.50 (br s, 1H), 7.72 (d, J = 3Hz, 2H), 2.41 (s, 3H).

[0569] Step 2: H₂SO₄ (4.8 mL, 91 mmol) was added dropwise to a methanol-stirred solution (80 mL) of 6-iodo-3-methylpyridinecarboxylic acid (8 g, 30 mmol) at 0 °C. The ice bath was removed, and the mixture was refluxed and stirred for 12 h. After TLC showed the reaction was complete, the solvent was evaporated, and the residue was diluted with water (100 mL). The pH was adjusted to 9 using saturated NaHCO₃, and then extracted with EtOAc (3 × 50 mL). The extracts were combined, washed with water (100 mL) and brine (100 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO₂, 20% EtOAc / petroleum ether) to give methyl 6-iodo-3-methylpyridinecarboxylate (7 g, 83%) as a pale yellow solid. MS (ESI) 278.3 [M+H] + .

[0570] Step 3: NBS (7.1 g, 39 mmol) and AIBN (492 mg, 3 mmol) were added to a CCl4 stirred solution of methyl 6-iodo-3-methylpyridinecarboxylate (8.5 g, 30 mmol) (100 mL). The reaction was heated at 65 °C for 16 h. After the reaction was complete as indicated 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 extracts were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 15% EtOAc / petroleum ether) to give methyl 3-(bromomethyl)-6-iodopyridinecarboxylate (4.31 g, 40%) as a brown solid. MS (ESI) 356.1 [M+H] + .

[0571] Step 4: Add 2.0 M THF solution of methylamine (42 mL, 84 mmol) to 10 mL of a stirred THF solution of methyl 3-(bromomethyl)-6-iodopyridinecarboxylate (3 g, 8.4 mmol) at room temperature. Stir the reaction at room temperature for 24 h. After the reaction was complete as indicated by TLC, evaporate the solvent and dilute the residue with water (30 mL). Filter and dry the resulting precipitate to give intermediate 40 (1.3 g, 56%) as a grayish-white solid. MS (ESI) 275.2 [M+H] + .

[0572] Intermediate 41

[0573] 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

[0574]

[0575] Intermediate 41 was prepared using intermediates 1 and 40 following the same steps as described for intermediate 3. The mixture was degassed for 20 min and then heated in a microwave oven at 100 °C for 2 h. MS(ESI) 369.4 [M+H] + .

[0576] Example 33

[0577] 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

[0578]

[0579] Example 33 (150 mg) was prepared using intermediate 41 following the steps described for Examples 2A and 2B. 1H NMR (400MHz, DMSO-d6) δ10.11(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] + .

[0580] Intermediate 42

[0581] 6-(tert-butyl)-2-iodo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0582]

[0583] A solution of tert-butylamine (256 mg, 3.50 mmol) was added to a THF stirred solution (5 mL) of methyl 3-(bromomethyl)-6-iodopyridinecarboxylate (500 mg, 1.4 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. After the reaction was complete as indicated 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 a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 1.49 (s, 9H).

[0584] Intermediate 43

[0585] 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

[0586]

[0587] Intermediate 43 was prepared using intermediates 1 and 42 following the same steps as for intermediate 3. The mixture was degassed for 20 min and then heated in a microwave at 100 °C for 2 h. MS(ESI) 411.14[M+H + .

[0588] Example 34

[0589] 2-Allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(7-oxo-6,7-dihydro-5H-pyrrole) [3,4-b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0590]

[0591] Step 1: 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 using intermediate 43 according to the steps described for Examples 2A and 2B. MS (ESI) 554.0 [M+H] + .

[0592] Step 2: A solution of trifluoromethanesulfonic acid (0.7 mL) was added to a stirred solution (150 mg, 7.05 mmol) 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) at 0 °C. The ice bath was removed, and the reaction was stirred at room temperature for 2 h. After the reaction was complete as indicated by TLC, the reaction mixture was neutralized with NaHCO3 and then extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (H2O / CH3CN gradient) to give Example 34 (10 mg) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ10.20(br s,1H),9.09(brs,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] + .

[0593] Intermediate 44

[0594] 5-Bromo-3-methyl-2,3-dihydrofurano[2,3-b]pyridine-3-ol

[0595]

[0596] Step 1: 60% NaH (8.744 g, 380.2 mmol) was added in portions to a 200 mL DME stirred solution of ethyl 2-hydroxyacetate (27.67 g, 266.14 mmol) at 0 °C. The ice bath was removed, and the reaction was stirred for 30 min. Ethyl 5-bromo-2-chloronicotinate (20 g, 76.04 mmol) was added, and the reaction was refluxed for 16 h. After TLC showed the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (150 mL). The pH of the mixture was adjusted to 4 using acetic acid. The mixture was extracted with EtOAc (3 × 80 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to give ethyl 5-bromo-3-oxo-2,3-dihydrofurano[2,3-b]pyridine-2-carboxylic acid (8.5 g, 30%) as a grayish-white solid.

[0597] MS(ESI) 285.9 [M+H] + .

[0598] Step 2: A mixture of ethyl 5-bromo-3-oxo-2,3-dihydrofurano[2,3-b]pyridine-2-carboxylate (9 g, 31.57 mmol) and 50% aqueous H₂SO₄ solution (90 mL) was heated to 60 °C and stirred for 16 h. After the reaction was complete as indicated by TLC, the reaction mixture was diluted with ice water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (150 mL) and brine (200 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give 4.5 g, 66%, of 5-bromofurano[2,3-b]pyridine-3(2H)-one as a pale brown solid. MS (ESI) 213.8 [M+H] + .

[0599] Step 3: Add 3.0 M DEE solution of CH3MgI (31 mL, 93.85 mmol) to a stirred ether solution (40 mL) of 5-bromofurano[2,3-b]pyridin-3(2H)-one (4 g, 18.77 mmol) at 0 °C. Remove the ice bath and stir the reaction at room temperature for 1 h. Quench the reaction with saturated NH4Cl (50 mL) and extract the reaction mixture with EtOAc (3 × 50 mL). Dry the organic layer (Na2SO4), filter, and concentrate under reduced pressure. Purify the residue by rapid chromatography (SiO2, 20% EtOAc / petroleum ether) to give intermediate 44 (2.0 g, 46%) as a brown solid. MS (ESI) 229.9 [M+H] + .

[0600] Intermediate 45

[0601] 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[2,3-b]pyridin-5-yl)-6-(methylthio)- 1,2-Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0602]

[0603] Intermediate 45 was prepared using intermediates 1 and 44 following the steps described for intermediate 3. The mixture was degassed for 20 min and then heated in a microwave at 100 °C for 6 h. MS(ESI) 372.4 [M+H + .

[0604] Example 35A

[0605] 2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[2,3-b]pyridin-5-yl)-6-((4-(4-methyl) (Pyropiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0606]

[0607] Example 35B

[0608] (S)-2-Allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[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

[0609]

[0610] Examples 35A and 35B were prepared using intermediate 45 following the steps described for Examples 2A and 2B, yielding racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofurano[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 solution)) to give peak 1 (Example 35A, 48 mg) and peak 2 (Example 35B, 46 mg). 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 s,2H),3.09-3.01(m,4H),2.46-2.41(m,4H),2.21(s,3H),1.57(s,3H); MS(ESI)515.2[M+H] + Example 35B: Yellow solid; 1 HNMR(400MHz,DMSO-d6)δ10.04(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 s,2H),3.09-3.01(m,4H),2.47-2.39(m,4H),2.21(s,3H),1.57(s,3H); MS(ESI)515.2[M+H] + Any absolute configuration may be specified for Examples 35A and 35B.

[0611] Intermediate 46

[0612] 2-Bromo-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0613]

[0614] Step 1: Prepare 5,6-dihydro-7H-pyrrolo[1,2-a]imidazol-7-one according to US Patent Publication No. 2012 / 0214762.

[0615] Step 2: 3M MeMgBr solution (49 mL, 147.0 mmol) was added dropwise to a 0°C THF solution (150 mL) of 15,6-dihydro-7H-pyrrolo[1,2-a]imidazol-7-one (15 g, 123.0 mmol). The ice bath was removed, and the reaction was stirred at room temperature for 5 h. TLC showed that the reaction was complete, and the reaction was quenched with saturated NH4Cl solution at 0°C. The mixture was extracted with 10% methanol:DCM (2 × 200 mL). The organic layers were combined, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 3% methanol / 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] + .

[0616] Step 3: Over 10 min, NaHCO3 (0.111 mmol) and NBS (37.7 g, 0.212 mol) were added fractionally to 140 mL of 0 °C DCM solution of 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (14 g, 0.101 mol). The ice bath was removed, and the reaction was stirred at room temperature for 3 h. After the reaction was complete as indicated by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 3% methanol / 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] + .

[0617] Step 4: A 1.3 M THF solution of i-PrMgCl (29 mL, 37.9 mmol) was added dropwise to a 0°C THF solution (70 mL) of 2,3-dibromo-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (7 g, 23.7 mmol). The ice bath was removed, and the reaction was stirred at room temperature for 2 h. TLC showed that the reaction was complete. The reaction was quenched with saturated NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (2 × 300 mL). The organic layers were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 3% methanol / DCM) to give intermediate 46 (3.5 g, 68%) as a grayish-white solid. MS (ESI) 217.3 [M+H] + .

[0618] Intermediate 47

[0619] 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

[0620]

[0621] Intermediate 47 was prepared using intermediates 1 and 46 following the steps described for intermediate 3. MS(ESI) 359.1 [M+H] + .

[0622] Example 36A

[0623] (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

[0624]

[0625] Example 36B

[0626] (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

[0627]

[0628] Examples 36A and 36B were prepared using intermediate 47 following the steps described for Examples 2A and 2B, yielding 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)δ9.92(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)δ9.92(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] + Any absolute configuration may be specified for Examples 36A and 36B.

[0629] Intermediate 48

[0630] 3-Bromo-5-methyl-6,7-dihydro-5H-cyclopenten[c]pyridine-5-ol

[0631]

[0632] Step 1: Prepare 3-amino-6,7-dihydro-5H-cyclopenteno[c]pyridin-5-one according to Sakairi, M., Arzneimittel Forschung (Vol. 62 (No. 11), pp. 537-544, 2012).

[0633] Step 2: CuBr2 (0.149 g, 0.668 mmol) was added dropwise to a 0°C solution of 3-amino-6,7-dihydro-5H-cyclopenten[c]pyridin-5-one (200 mg, 1.34 mmol) in dibromomethane (2 mL). Amyl nitrite (0.179 g, 1.49 mmol) was then added dropwise. The reaction mixture was brought to room temperature and stirred for 16 h. The reaction was quenched with water (50 mL), alkalized with saturated NaHCO3, and extracted with DCM (2 × 50 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to give 3-bromo-6,7-dihydro-5H-cyclopenten[c]pyridin-5-one (60 mg, 21%) as a brown solid. MS(ESI)212.3[M+H] + .

[0634] Step 3: Add 0.4 mL of 3.0 M MeMgBr in Et2O solution to 2 mL of 3-bromo-6,7-dihydro-5H-cyclopenteno[c]pyridin-5-one (50 mg, 0.23 mmol) in Et2O solution at 0 °C. Remove the ice bath and stir the reaction at room temperature for 16 h. After TLC showed the reaction was complete, pour the reaction mixture into ice water (15 mL) and extract with EtOAc (2 × 20 mL). Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by rapid chromatography (SiO2, 30% EtOAc / petroleum ether) to intermediate 48 (15 mg, 28%) as a brown solid. MS (ESI) 228.4 [M+H + .

[0635] Intermediate 49

[0636] 2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenten[c]pyridin-3-yl)-6-(methylthio) 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0637]

[0638] Intermediate 49 was prepared using intermediates 1 and 48 following the steps described for intermediate 3. MS(ESI) 370.4 [M+H] + .

[0639] Example 37A

[0640] (S)-2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenten[c]pyridin-3-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0641]

[0642] Example 37B

[0643] (R)-2-Allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenten[c]pyridin-3-yl)-6- ((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0644]

[0645] Examples 37A and 37B were prepared using intermediate 49 following the steps described for Examples 9A and 9B to obtain racemic 2-allyl-1-(5-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenten[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; 1 H NMR(400MHz,DMSO-d6)δ10.14(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; 1 H NMR(400MHz,DMSO-d6)δ10.14(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 configurations of Examples 37A and 37B can be arbitrarily specified.

[0646] Intermediate 50

[0647] 2-Bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenten[b]pyridine-7-ol

[0648]

[0649] Step 1: 0.5 M iPrMgCl THF solution (70.7 mL, 35.37 mmol) was added dropwise to a THF stirred solution (50 mL) of 2-bromo-5,6-dihydro-7H-cyclopenten[b]pyridin-7-one (5 g, 23.58 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. After the reaction was complete, the mixture was cooled to 0 °C, quenched with saturated NH4Cl solution (100 mL), and extracted with EtOAc (2 × 200 mL). The extracts were combined, washed with brine (200 mL), dried (Na2SO4), and evaporated to dryness. The residue was purified by rapid chromatography (SiO2, 15% EtOAc / hexane) to give 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenten[b]pyridin-7-ol (1.7 g, 28%) as a yellow liquid. MS(ESI)254.1[M+H] + .

[0650] Step 2: 60% NaH solution (590 mg, 14.76 mmol) was added to a THF stirred solution (25 mL) of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenteno[b]pyridin-7-ol (2.5 g, 9.82 mmol) at 0 °C. The mixture was stirred for 30 min, and then acetic anhydride (1.39 mL, 14.76 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 16 h. After TLC showed the reaction was complete, the reaction was quenched with ice water, and the reaction mixture was extracted with EtOAc (2 × 100 mL). The extracts were combined, washed with water (100 mL) and brine (100 mL), dried (Na₂SO₄), and evaporated to dryness. The residue was purified by rapid chromatography (neutral alumina, 10% EtOAc / petroleum ether) to give 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenten[b]pyridin-7-yl acetate (1.7 g, 58%) as a yellow liquid. MS (ESI) 296.0 [M+H] + .

[0651] Step 3: Ozone gas was bubbled into a stirred methanol solution (40 mL) of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenten[b]pyridin-7-yl acetate (3.4 g, 11.5 mmol) for 30 min at -78 °C. After TLC showed the reaction was complete, the reaction was quenched with 1 mL of dimethyl sulfide at -78 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated and diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (Na₂SO₄), and evaporated under reduced pressure to give 7-acetyl-2-bromo-6,7-dihydro-5H-cyclopenten[b]pyridin-7-yl acetate (2.1 g, 61%) as a white solid. MS (ESI) m / z 298.1 [M+H].

[0652] Step 4: In a sealed tube, DAST (8.9 mL, 67.34 mmol) was added to 7-acetyl-2-bromo-6,7-dihydro-5H-cyclopentenno[b]pyridin-7-yl acetate (800 mg, 2.69 mmol), and the reaction was stirred at room temperature for 2 days. After the reaction was complete, 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 (Na2SO4), and evaporated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 10% EtOAc / hexane) to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopentenno[b]pyridin-7-yl acetate (85 mg, 10%) as a brown oil. MS (ESI) 320.1 [M+H] + .

[0653] Step 5: K₂CO₃ (259 mg, 1.88 mmol) was added to a stirred methanol solution (5 mL) of 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopentenno[b]pyridin-7-yl acetate (300 mg, 0.937 mmol) at 0 °C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. After TLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added, and the mixture was extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with water (2 × 50 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopentenno[b]pyridin-7-ol (230 mg, 0.83 mmol, 88%) as a brown liquid. MS (ESI) 278.0 [M+H] + .

[0654] Intermediate 51

[0655] 2-Allyl-1-(7-(1,1-difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridine-2- 6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0656]

[0657] Intermediate 51 was prepared using intermediate 1 and intermediate 50 following the steps described for intermediate 3. MS(ESI) 420.2 [M+H] + .

[0658] Example 38A

[0659] (S)-2-Allyl-1-(7-(1,1-difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridine- 2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0660]

[0661] Example 38B

[0662] (R)-2-Allyl-1-(7-(1,1-difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[b]pyridine- 2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0663]

[0664] Examples 38A and 38B were prepared using intermediate 51 following the steps described for Examples 9A and 9B, yielding racemic 2-allyl-1-(7-(1,1-difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 methanol)) to give peak 1 (Example 38A, 10 mg) and peak 2 (Example 38B, 20 mg). Example 38A: 1H NMR (400MHz, DMSO-d6) δ10.03(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: 1 H NMR (400MHz, DMSO-d6) δ10.03(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] + The absolute configurations of Examples 38A and 38B can be arbitrarily specified.

[0665] Intermediate 52

[0666] 1-(1-Methylpiperidin-4-yl)-1H-indole-5-amine

[0667]

[0668] Intermediate 52 was prepared according to the steps described in EP2141163. MS(ESI)230.6[M+H + .

[0669] Example 39A

[0670] (S)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0671]

[0672] Example 39B

[0673] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0674]

[0675] Examples 39A and 39B were prepared using intermediates 17 and 52 according to the steps described for Examples 9A and 9B, yielding racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 methanol)) 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)δ10.21(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(400MHz,DMSO-d6)δ10.21(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] + Any absolute configuration may be specified for Examples 39A and 39B.

[0676] Intermediate 53

[0677] 3-Methyl-4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[0678]

[0679] Intermediate 53 was prepared following similar procedures as described in WO Publication No. 2014 / 134308. MS(ESI) 203.4 [M+H] + .

[0680] Example 40A

[0681] (S)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0682]

[0683] Example 40B

[0684] (R)-2-Allyl-1-(7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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

[0685]

[0686] Examples 40A and 40B were prepared using intermediates 17 and 53 according to the steps described for Examples 9A and 9B, yielding racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenten[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 methanol)) to give peak 1 (Example 40A, 35 mg) and peak 2 (Example 40B, 33 mg). Example 40A: Yellow solid; 1 H NMR(400MHz,DMSO-d6)δ10.20(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)δ10.20(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] + The absolute configurations of Examples 40A and 40B can be arbitrarily specified.

[0687] Intermediate 54

[0688] N-(2-bromo-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide

[0689]

[0690] At room temperature, 0.2 mL of chlorosulfonic acid solution was added to a stirred acetonitrile solution (250 mg, 1.037 mmol) of intermediate 31 (6 mL) and stirred for 2 h. The reaction solution was concentrated under reduced pressure, diluted in water (10 mL), extracted with EtOAc (2 × 10 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The above reaction was repeated at a scale of 3 × 250 mg. The residues were combined and purified by rapid chromatography (SiO₂, 40% EtOAc / petroleum ether) to give intermediate 54 (480 mg, 41%) as a grayish-white solid. MS (ESI) 283.1 [M+1] + .

[0691] Intermediate 55

[0692]

[0693] Intermediate 55 was prepared using intermediates 1 and 54 following the steps described for intermediate 3. MS(ESI) 425.1 [M+H] + .

[0694] Example 41A

[0695] (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-tetrahydroquinoline-8-yl)acetamide

[0696]

[0697] Example 41B

[0698] (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-tetrahydroquinoline-8-yl)acetamide

[0699]

[0700] Examples 41A and 41B were prepared using intermediates 17 and 55 according to the steps described for Examples 9A and 9B, yielding 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-tetrahydroquinoline-8-yl)acetamide (220 mg). The enantiomers were separated by chiral SFC chromatography (Chiralpak IC, 40.0% (0.5% DEA in methanol)) to give peak 1 (Example 41A, 70 mg) and peak 2 (Example 41B, 50 mg). Example 41A: Yellow solid; 1 H NMR (400MHz, DMSO-d6) δ10.12(brs,1H),8.80(s,1H),8.18(s,1H),7.71(d,J=7.6Hz,1H ),7.60(d,J=8.0Hz,3H),6.96(d,J=8.8Hz,2H),5.60-5.55(m,1H),4.97(d,J=10.0Hz,1 H),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; 1H NMR (400MHz, DMSO-d6) δ10.12(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] + The absolute configurations of Examples 41A and 41B can be arbitrarily specified.

[0701] Example 42

[0702] 2-Allyl-1-(8-amino-8-methyl-5,6,7,8-tetrahydroquinoline-2-yl)-6-((4-(4-methylpiperazine-1-) (B-)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0703]

[0704] 1,4-Dioxane (10 mL) and 6 M HCl (10 mL) were added to a stirred solution (500 mg, 0.881 mmol) 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-tetrahydroquinoline-8-yl)acetamide in a pressure tube. The reaction was heated at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 8 with 1 M NaOH. The mixture was extracted with 10% methanol:DCM (3 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by HPLC (C18, water / CH3CN) to give Example 42 (90 mg, 19%) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ10.15(brs,1H),8.81(s,1H),7.74(d,J=8.1Hz,1H),7.65 -7.52(m,3H),6.92(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] + .

[0705] Program A

[0706] Wee1 binding assay

[0707] Weel kinase was measured using fluorescence resonance energy transfer (FRET) assay. In 384-well plates, Weel kinase (2 nM final concentration) was mixed with Alexa Fluor-labeled tracer 178 (50 nM final concentration, K2). d =24 nM), Eu-anti-GST antibody (2 nM final concentration), and then inhibitor (0.003 μmol to 10 μmol) were mixed in 16 μl final volume of kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). The plate was shaken for 30 seconds, incubated at room temperature for 60 min, and recorded on a fluorescence plate reader. The results are shown in Table 1.

[0708] Program B

[0709] H23 cell proliferation assay

[0710] Make H23[ATCC(CRL-5800)] TM Cells were grown and maintained in RPMI-1640 medium containing 10% FBS and 1% penicillin-streptomycin. Cells were treated with compounds diluted in DMSO and serially diluted 9 times (5-fold). Plates were incubated at 37°C and 5% CO2 for 4 days. The detection plates were briefly shaken for 2 min and incubated at room temperature for 10 min, followed by the addition of 100 μL of CellTiter-Glo reagent (Promega) for color development. The plates were read using an M5e plate reader according to the CellTiter-Glo protocol. IC50 values ​​were obtained using GraphPad Prism software.50 Values. The results are shown in Table 1.

[0711] Table 1: Wee1 enzyme and cell data

[0712]

[0713]

[0714] For Wee1 enzyme IC 50 A = a single IC 50 ≤10nM; B = single IC 50 >10nM and <100nM; C = single IC 50 ≥100nM. For H23 CTG IC 50 A = a single IC 50 ≤100nM; B = single IC 50 >100nM and <1000nM; C = single IC 50 ≥1000nM.

[0715] Furthermore, although some detailed description has been provided for clarity and understanding purposes by way of illustration and example, those skilled in the art will understand that many and various modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of this disclosure, but rather to cover all modifications and alternatives consistent with the true scope and spirit of the invention.

Claims

1. A method for preparing compounds of formula (I) having the following structure or pharmaceutically acceptable salts thereof: in: R 1 It is hydrogen; Ring A is selected from the group consisting of unsubstituted phenyl groups and unsubstituted pyridyl groups; Choose free replacement Replacement Replacement and replacement The group consisting of ring B, wherein ring B is substituted by one, two or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl and unsubstituted ethyl groups; R 2 for m is 0 or 1; R 3 Choose from the group consisting of free halogens and unsubstituted C1-C6 alkyl groups; X is an unsubstituted piperazine group or a C1-C6 alkyl-substituted piperazine group; and Y represents CH; The method includes using a compound of formula (A) having the following structure: Where R 2 As defined above; Coupled with compounds of formula (B) having the following structure: Where R 1 Ring A and ring B are as defined above; To provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein Choose from the following groups: The ring B is substituted by one, two, or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl, and unsubstituted ethyl.

3. The method according to claim 1, wherein For replacement 4. The method according to claim 1, wherein Choose from the following groups: The ring B is substituted by one, two, or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl, and unsubstituted ethyl.

5. The method according to claim 4, wherein for The ring B is substituted by one, two, or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl, and unsubstituted ethyl.

6. The method according to claim 1, wherein X is a C1-C6 alkyl-substituted piperazine group.

7. The method of claim 6, wherein X is substituted with an unsubstituted methyl group.

8. The method according to claim 6, wherein X is 9. The method of claim 8, wherein m is 0.

10. The method of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

11. The method of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

12. The method according to claim 1, wherein the compound of formula (I) is Or its pharmaceutically acceptable salt.

13. The method according to claim 1, wherein the compound of formula (I) is Or its pharmaceutically acceptable salt.

14. Compounds of formula (B) having the following structure, or pharmaceutically acceptable salts thereof: Where R 1 It is hydrogen; Ring A is selected from the group consisting of unsubstituted phenyl groups and unsubstituted pyridyl groups; and Choose free replacement Replacement Replacement and replacement The group consisting of ring B, wherein ring B is substituted by one, two or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl and unsubstituted ethyl.

15. The compound according to claim 14, wherein... For replacement 16. The compound according to claim 14, wherein... Choose from the following groups: The ring B is substituted by one, two, or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl, and unsubstituted ethyl.

17. The compound according to claim 16, wherein... for 18. The compound according to claim 14, wherein... for The ring B is substituted by one, two, or three substituents independently selected from the group consisting of fluorine, hydroxyl, amino, unsubstituted –NHC(O)CH3, –CF3, –CHF2, –CF2CH3, unsubstituted methyl, and unsubstituted ethyl.

19. The compound according to claim 14, wherein X is a C1-C6 alkyl-substituted piperazine group.

20. The compound of claim 19, wherein X is substituted with an unsubstituted methyl group.

21. The compound according to claim 19, wherein X is 22. The compound according to claim 18, wherein... for 23. The compound according to claim 18, wherein... for 24. The compound according to claim 18, wherein... for 25. The compound according to claim 18, wherein... for 26. A method for preparing compounds having the following structures or pharmaceutically acceptable salts thereof: It includes compounds having the following structures or pharmaceutically acceptable salts thereof: Reacts with m-chloroperoxybenzoic acid (m-CPBA) and compounds having the following structures or pharmaceutically acceptable salts thereof:

27. The method of claim 26, further comprising making a compound having the following structure or a pharmaceutically acceptable salt thereof: Reacts with compounds having the following structures or their pharmaceutically acceptable salts: To provide compounds having the following structures or pharmaceutically acceptable salts thereof:

28. Compounds having the following structures or pharmaceutically acceptable salts thereof:

29. Compounds having the following structures or pharmaceutically acceptable salts thereof:

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