RU2812726C2 - Substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I), as well as a pharmaceutical composition based thereon for inhibiting WEE1 and methods of attenuating or treating cancer or attenuating or treating a malignancy or tumour by inhibiting WEE1.

EFFECT: obtaining new compounds that have the ability to inhibit WEE1 and can be used to treat a disease mediated by this activity.

32 cl, 42 ex, 1 tbl

Description

INCLUSION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which foreign or domestic priority has been determined, such as in an application or solicitation data sheet, that are filed with this application are incorporated herein by reference in accordance with 37 CFR § 1.57 and the regulations 4.18 and 20.6, including Provisional Application No. 62/641149, filed March 9, 2018, and No. 62/755163, filed November 2, 2018.

Technical field

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

Description

[0003] WEE1 kinase is important in cell cycle arrest at the G2-M checkpoint for DNA repair prior to mitotic entry. Normal cells repair damaged DNA during G1 arrest. Cancer cells often lack the G1-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various types of cancer.

DISCLOSURE OF THE INVENTION

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

[0005] Certain embodiments described herein relate to a pharmaceutical composition that may include 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 a combination thereof .

[0006] Certain embodiments described herein relate to a method of alleviating and/or treating cancer 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject with a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the relief and/or treatment of cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) for the relief and/or treatment of cancer described herein.

[0007] Certain embodiments described herein relate to a method of inhibiting the replication of a cancer or tumor, which may include contacting the tumor 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the cancer or tumor is caused by a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) to inhibit the replication of a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein.

[0008] Certain embodiments described herein relate to a method of alleviating or treating cancer as described herein, which may include contacting the cancer 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a subject with a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the amelioration or treatment of cancer described herein, which may include contacting it with a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) for the amelioration or treatment of a cancer described herein, which may include bringing it into contact with a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein.

[0009] Certain embodiments described herein relate to a method of inhibiting WEE1 activity in a cell (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting activity in p53-deficient WEE1 cells, and /or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein ( for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for a cancer cell related to 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 that includes an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting WEE1 activity in p53-deficient cells, and /or reducing WEE1 overexpression in cells). However, other embodiments described herein provide 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 that includes 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 (e.g., inhibit WEE1 activity in TP53-mutated cells, inhibit WEE1 activity in wild-type TP53 cells, inhibit WEE1 activity in p53-deficient cells, and/or reducing WEE1 overexpression in cells).

[0010] Certain embodiments described herein relate to a method of alleviating or treating cancer described herein, which may include inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibition of WEE1 activity in p53-deficient cells and/or reduction of overexpression of WEE1 in cells) using an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described in compounds herein (eg, 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the amelioration or treatment of cancer described herein by inhibiting WEE1 activity (e.g., inhibition of WEE1 activity in TP53-mutated cells, inhibition of WEE1 activity in wild-type TP53 cells, inhibition WEE1 activity in p53-deficient cells and/or decreased WEE1 overexpression in cells). 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 that includes an effective amount of a compound described herein (e.g. compounds of formula (I) or a pharmaceutically acceptable salt thereof) for the amelioration or treatment of cancer described herein by inhibiting WEE1 activity (eg, inhibition of WEE1 activity in TP53-mutated cells, inhibition of WEE1 activity in wild-type TP53 cells, inhibition of WEE1 activity in p53-deficient cells and/or decreased overexpression of WEE1 in cells).

DETAILED DESCRIPTION

[0011] WEE1 is a tyrosine kinase that is a critical component of ATR-mediated G2 cell cycle checkpoint control and prevents the onset of mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1 and selectively phosphorylates cyclin-dependent kinase 1 (CDK1) on Tyr15, subsequently stabilizing the CDK1-cyclin B complex and arresting cell cycle progression. The advantage of this process is survival due to the time spent on repairing damaged DNA by tumor cells before the process of mitosis. Due to the inhibition of WEE1, the G2 checkpoint is disrupted, which means that unscheduled mitosis of cancer cells with DNA damage is stimulated and cell death occurs as a result of a mitotic catastrophe. Thus, by inhibiting WEE1, the sensitivity of tumors to DNA-damaging agents such as cisplatin may increase and tumor cell death may occur.

Definitions

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as would be understood by one of ordinary skill in the art. Unless otherwise indicated, all patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety. Unless otherwise noted, where there are multiple definitions for a term presented herein, the definitions given in this section prevail.

[0013] When a group is stated to be "optionally substituted", the group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, if a group is stated to be “unsubstituted or substituted,” if it is substituted, the substituent(s) may be selected from one or more of the indicated compounds. If substituents are not specified, it means that a group indicated as "optionally substituted" or "substituted" may be substituted by one or more groups that are individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amino group, disubstituted amino group and amine (C ₁ -C ₆ alkyl).

[0014] As used herein, the terms "C _a -C _b ", in which "a" and "b" are integers, refer to the number of carbon atoms in the group. Said group may contain from "a" to "b" carbon atoms, inclusive. Thus, for example, the group "C ₁ -C ₄ alkyl" refers to all alkyl groups having from 1 to 4 carbon atoms, i.e. CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )- and (CH ₃ ) ₃ C-. If the designations “a” and “b” are absent, the widest range described in these definitions is assumed.

[0015] When two "R" groups are described as "taken together", the R groups with the atoms to which they are attached may form cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R ^a and R ^b from the group NR ^a R ^b are said to be "taken together", this means that they are covalently linked to each other to form a ring:

[0016] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl functional group may be branched or may have a straight chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-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 may have from 1 to 30 carbon atoms (when referred to herein, a numerical range such as “1 to 30” refers to each integer in the given range ; for example, "from 1 to 30 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers reference to the term "alkyl" ", in which no numeric range is specified). The alkyl group may also be a medium-sized alkyl having from 1 to 12 carbon atoms. The alkyl group may also be lower alkyl having from 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0017] As used herein, the term “alkenyl” refers to a straight- or branched-chain monovalent radical containing from two to twenty carbon atoms, which contains double carbon bond(s), including, without restrictions, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. The alkenyl group may be substituted or unsubstituted.

[0018] As used herein, the term “alkynyl” refers to a linear or branched chain monovalent radical containing from two to twenty carbon atoms, which contains triple carbon bond(s), including, without restrictions, 1-propynyl, 1-butynyl, 2-butynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0019] As used herein, the term “cycloalkyl” refers to a fully saturated (no double or triple bonds) mono- or multicyclic hydrocarbon ring system. If the rings are made up of two or more rings, they can be joined together by condensation, bridging, or spiro bonding. As used herein, the term “fused” refers to two rings that share two atoms and one bond. As used herein, the term “bridged cycloalkyl” refers to compounds in which the cycloalkyl has a bond between one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that have one atom in common and the two rings are not connected by a bridge. Cycloalkyl groups may contain 3 to 30 atoms per ring(s), 3 to 20 atoms per ring(s), 3 to 10 atoms per ring(s), 3 to 8 atoms per ring(s) ) or 3 to 6 atoms in the ring(s). The cycloalkyl group may be substituted or unsubstituted. Examples of monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups include decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridging cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; Examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0020] As used herein, the term “cycloalkenyl” refers to a mono- or multicyclic hydrocarbon ring system that contains one or more double bonds on at least one ring; although if there is more than one bond, the double bonds cannot form a fully delocalized pi-electron system across all rings (otherwise the group would be "aryl" as defined herein). Cycloalkenyl groups may contain 3 to 10 atoms per ring(s), 3 to 8 atoms per ring(s), or 3 to 6 atoms per ring(s). If the rings consist of two or more rings, they can be joined together by condensation, bridging, or spiro bonding. The cycloalkenyl group may be substituted or unsubstituted.

[0021] As used herein, the term “carbocyclyl” refers to a non-aromatic mono- or multicyclic hydrocarbon ring system. If the rings consist of two or more rings, they can be joined together by condensation, bridging or spiro coupling as described herein. Carbocyclyl groups may contain 3 to 30 atoms per ring(s), 3 to 20 atoms per ring(s), 3 to 10 atoms per ring(s), 3 to 8 atoms per ring(s) ) or 3 to 6 atoms in the ring(s). The carbocyclyl group may be substituted or unsubstituted. Examples of carbocyclyl groups include, without limitation, cycloalkyl groups and cycloalkenyl groups as defined herein, and non-aromatic moieties of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8 -tetrahydroquinoline and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0022] As used herein, the term “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a common chemical bond) that has a fully delocalized pi electron system throughout rings The number of carbon atoms in the aryl group can vary. For example, the aryl group may be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. The aryl group may be substituted or unsubstituted.

[0023] As used herein, the term “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with a fully delocalized pi electron system) that contains one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e. to an element other than carbon, including, but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) with a heteroaryl group may vary. For example, a heteroaryl group may have 4 to 14 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms, 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. Moreover, 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, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. The heteroaryl group may be substituted or unsubstituted.

[0024] As used herein, the terms “heterocyclyl” or “heteroalicyclyl” refer to three-, four-, five-, six-, seven-, eight-, nine-, ten-, and up to 18-membered monocyclic, bicyclic and tricyclic ring systems in which carbon atoms together with 1-5 heteroatoms form said ring system. The heterocycle may optionally contain one or more unsaturated bonds, which, however, are arranged in such a way that a completely delocalized pi electron system does not extend to all rings. Heteroatom(s) are element(s) other than carbon, including, without limitation, oxygen, sulfur and nitrogen. The heterocycle may further contain one or more carbonyl or thiocarbonyl functional groups so that the formation includes oxo systems and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. If the rings are made up of two or more rings, they can be joined together by condensation, bridging, or spiro bonding. As used herein, the term “fused” refers to two rings that share two atoms and one bond. As used herein, the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds in which the heterocyclyl or heteroalicyclyl contains a bond between one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that have one atom in common and the two rings are not connected by a bridge. Heterocyclyl and heteroalicyclyl groups may contain from 3 to 30 atoms in the ring(s), from 3 to 20 atoms in the ring(s), from 3 to 10 atoms in the ring(s), from 3 to 8 atoms in the ring ( -ax) or from 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. In addition, any nitrogens in the heterocycle can be quaternized. Heterocyclyl or heteroalicyclic groups may be substituted or unsubstituted. Examples of such heterocyclyl or heteroalicyclyl groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1 ,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazolidine, thiazolidine, morpho lin, oxirane , piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and benzocondenses thereof analogues ( e.g. benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro-heterocyclyl groups include 2-azaspiro[3.3]-heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro-[3.3]heptane, 2-oxaspiro [3.4]octane and 2-azaspiro[3.4]octane.

[0025] As used herein, the terms “aralkyl” and “aryl(alkyl)” refer to an aryl group substituently attached via a lower alkylene group. The lower alkylene and aryl group of aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0026] As used herein, the terms “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group substituently attached via a lower alkylene group. The lower alkylene and heteroaryl group of the heteroalkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and benzo-fused analogs thereof.

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

[0028] As used herein, the term “lower alkylene groups” means straight-chain -CH ₂ -attaching groups that form bonds to attach molecular moieties through terminal carbon atoms. Examples include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -) and butylene (-CH ₂ CH ₂ CH ₂ CH ₂ - ). A lower alkylene group may be substituted by replacing one or more hydrogen atoms of the lower alkylene group and/or replacing both hydrogen atoms on one carbon atom with a cycloalkyl group (e.g. ).

[0029] As used herein, the term “hydroxy” refers to a -OH group.

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

[0031] As used herein, the term "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) substituented through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acrylic. The acyl may be substituted or unsubstituted.

[0032] The "cyano" group refers to the -CN group.

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

[0034] A “thiocarbonyl” group refers to a -C(=S)R group, in which R may be the same as defined with respect to O-carboxy. The thiocarbonyl may be substituted or unsubstituted.

[0035] "O-carbamyl" group refers to the group "-OC(=O)N(R _A R _B )", in which R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0036] "N-Carbamyl" group refers to the group "ROC(=O)N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0037] "O-thiocarbamyl" group refers to the group "-OC(=S)-N(R _A R _B )", where R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0038] "N-thiocarbamyl" group refers to the group "ROC(=S)N( _RA )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0039] The "C-amido" group refers to the group "-C(=O)N(R _A R _B )", in which R _A and R _B may independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). C-amido may be substituted or unsubstituted.

[0040] The "N-amido" group refers to the group "RC(=O)N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-amido may be substituted or unsubstituted.

[0041] The "S-sulfonamido" group refers to the group "-SO ₂ N(R _A R _B )", in which R _A and R _B may independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). S-sulfonamido may be substituted or unsubstituted.

[0042] The "N-sulfonamido" group refers to the "RSO ₂ N(RA ₎ -" group, in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl , cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-sulfonamido may be substituted or unsubstituted.

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

[0044] The terms “ester” and “C-carboxy” refer to the group “-C(=O)OR”, in which R may be the same as defined with respect to O-carboxy. The ester and C-carboxy may be substituted or unsubstituted.

[0045] "Nitro" group is called "-NO" group₂"

[0046] A “sulfenyl” group refers to a “-SR” group, in which R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). Sulfenyl may be substituted or unsubstituted.

[0047] A “sulfinyl” group refers to the “-S(=O)-R” group, in which R may be the same as defined with respect to sulfenyl. Sulfinyl may be substituted or unsubstituted.

[0048] A "sulfonyl" group refers to the group "SO ₂ R", in which R may be the same as defined with respect to sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0049] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen (eg, monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, without limitation, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. Haloalkyl may be substituted or unsubstituted.

[0050] As used herein, the term “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen (eg, monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, without limitation, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Haloalkoxy may be substituted or unsubstituted.

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

[0052] A “mono-amino” group means a “-NHR _A ” group, in which R _A may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl) as defined herein. The R _A group may be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0053] A "disubstituted amino" group means a "-NR _A R _B " group, in which R _A and R _B may independently represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. R _A and R _B may independently be substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -NH(methyl) ₂ , -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0054] As used herein, the term “amino(alkyl)” group refers to an (alkylene)-NR'R” radical in which R' and R” independently represent hydrogen or alkyl as defined herein. The amine(alkyl) may be substituted or unsubstituted. Examples of amino(alkyl) groups include, but are not limited to, -CH ₂ NH(methyl), -CH ₂ NH(phenyl),
-CH ₂ CH ₂ NH(methyl), -CH ₂ CH ₂ NH(phenyl), -CH ₂ N(methyl) ₂ , -CH ₂ N(phenyl)(methyl),
-NCH ₂ (ethyl)(methyl), -CH ₂ CH ₂ N(methyl) ₂ , -CH ₂ CH ₂ N(phenyl)(methyl),
-NCH ₂ CH ₂ (ethyl)(methyl), etc.

[0001] Where the number of substituents is not specified (eg, haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl" may include one or more identical or different alkoxy groups containing one, two or three atoms.

[0056] As used herein, the term “radical” means a compound with one unpaired electron to allow compounds containing the radical to covalently bond with other compounds. Thus, in this context, "radical" is not necessarily a free radical. Instead, "radical" refers to a specific part of a larger molecule. The term "radical" can be used interchangeably with the term "group".

[0057] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the body into which it is administered and does not inhibit the biological effects and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be prepared by reacting the compound with inorganic acids such as hydrohalic acids (eg, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be prepared by reacting the compound with an organic acid, for example an aliphatic or aromatic carboxylic or sulfonic acid, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, trifluoroacetic (TFA), benzoic, salicylic, 2-oxopentanedioic or naphthalene sulfonic acid. Pharmaceutical salts can also be prepared by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a carbonate salt, a bicarbonate salt, salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts of amino acids such as arginine and lysine. With respect to compounds of formula (I), those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-containing group (e.g., NH₂) nitrogen-containing group can be associated with a positive charge (e.g. NH₂ may become NH₃ ⁺), and the positive charge can be balanced by a negatively charged counterion (such as Cl^-).

[0058] It should be understood that in any compound described herein having one or more chiral centers, each center may independently have the R configuration, or the S configuration, or a mixture thereof, unless the absolute stoichiometry is explicitly stated. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, may be a racemic mixture, may be diastereomerically pure, diastereomerically enriched, or may be a stereoisomeric mixture. In addition, it should be understood that in any compound described herein having one or more double bonds creating geometric isomers that may be designated E or Z, each double bond may independently be E or Z or a mixture thereof. Likewise, it should be understood that any compound described is also intended to include all tautomeric forms.

[0059] It should be understood that if there are unfilled valencies in the compounds described herein, these valences should be filled with hydrogen atoms or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0060] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain treatment advantages due to greater metabolic stability, such as, for example, a longer half-life in vivo or a lower dose requirement. Each chemical element present in the structure of a compound can include any isotope of that element. For example, a hydrogen atom may be explicitly described in the structure of a compound, or its presence may be implied in the structure of the compound. At any location in a compound at which a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, without limitation, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, as used herein, reference to a compound includes all potential isotopic forms unless the context clearly indicates otherwise.

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

[0062] Where a range of values is proposed, it should be understood that the embodiments include upper and lower limits, as well as any intermediate value between the upper and lower limits.

[0063] The terms and phrases used herein, and variations thereof, particularly in the appended claims, unless expressly stated otherwise, are to be considered non-limiting and not limiting. As examples of the above, the term "including" should be considered "including without limitation", "including but not limited to" or the like; As used herein, the term “comprising” is synonymous with the terms “including,” “comprising,” or “characterized by,” and is inclusive or non-limiting, and does not exclude additional unspecified elements or process steps; the term "having" should be interpreted as "having at least"; the term “includes” should be interpreted as “includes without limitation”; the term “example” is used to provide examples of implementation of an element of the description, but not an exhaustive or limiting list of them; and the use of terms such as “preferably”, “preferred”, “desirable” or “desirable” and similar words should not be construed as implying that certain features are critical, essential or even important to structure or function, but are intended to highlight alternative or additional features that may or may not be used in a particular embodiment. Additionally, the term “comprising” should be interpreted as synonymous with the phrases “having at least” or “comprising at least.” In the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the specified features or components, but may include additional features or components.

[0064] With respect to the use of substantially any plural and/or singular variations for terms herein, those skilled in the art may change plural to singular and/or singular to plural as the context and/or scope of application requires. Various singular/plural combinations may be indicated explicitly herein for clarity. The use of the singular does not exclude plurality. The mere fact of indicating certain indicators in mutually different dependent claims does not mean that these indicators cannot be combined if necessary. Any reference symbols in the claims should not be considered limiting the scope.

Connections

[0065] Certain embodiments described herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof having the structure:

where: R ¹ can be selected from hydrogen, halogen and substituted or unsubstituted C ₁ -C ₆ alkyl; ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered monocyclic heteroaryl; ring B may be selected from substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and substituted or unsubstituted 5-7 membered monocyclic heterocyclyl; R ₂ can be selected from , And ; m can be 0, 1, 2 or 3; R ³ may be selected from halogen and substituted or unsubstituted C ₁ -C ₆ alkyl; X may be selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine(C ₁ -C ₆ alkyl), substituted or unsubstituted -NH-(CH ₂ ) ₁ - ₆ -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted (C ₁ -C ₆ alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl and substituted or unsubstituted N-carbamyl; Y may represent CH or N (nitrogen); Y ¹ may be CR ^4A or N (nitrogen); Y ² may be CR ^4B or N (nitrogen); ring C may be selected from substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted monocyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and substituted or unsubstituted 7-10 membered bicyclic heterocyclyl; R ^4A and R ^4B may be independently selected from hydrogen, halogen and unsubstituted C ₁ - ₄ alkyl; and R ⁵ may be a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl.

[0066] Certain embodiments described herein provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ can be selected from hydrogen, halogen, and substituted or unsubstituted C ₁ -C ₆ alkyl; ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered monocyclic heteroaryl; ring B may be selected from substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and substituted or unsubstituted 5-7 membered monocyclic heterocyclyl; R ₂ can be selected from And ; m can be 0, 1, 2 or 3; R ³ may be selected from halogen and substituted or unsubstituted C ₁ -C ₆ alkyl; X may be selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine(C ₁ -C ₆ alkyl), substituted or unsubstituted -NH-(CH ₂ ) ₁ - ₆ -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted (C ₁ -C ₆ alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl and substituted or unsubstituted N-carbamyl; Y may represent CH or N (nitrogen); Y ¹ may be CR ^4A or N (nitrogen); Y ² may be CR ^4B or N (nitrogen); ring C may be selected from substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted monocyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and substituted or unsubstituted 7-10 membered bicyclic heterocyclyl; and R ^4A and R ^4B can be independently selected from hydrogen, halogen or unsubstituted C ₁ - ₄ alkyl.

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

[0068] In some embodiments, R ¹ can be selected from hydrogen, halogen, and C ₁ -C ₆ alkyl. In some embodiments, R ¹ may be hydrogen. In other embodiments, R ¹ may be halogen. In some embodiments, R ¹ may be fluorine. In some other embodiments, R ¹ may be an unsubstituted C ₁ -C ₆ alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (straight or branched) or hexyl (straight or branched). In some embodiments, R ¹ may be unsubstituted methyl. In some embodiments, R ¹ may be a substituted C ₁ -C ₆ alkyl, such as the alkyls described herein. In some embodiments, R ¹ may be an unsubstituted C ₁ -C ₆ haloalkyl (such as C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ chloroalkyl or C ₁ -C ₆ chlorofluoroalkyl). In some embodiments, R ¹ may be -CHF ₂ . -CF ₃ , -CF ₂ CH ₃ or
-CH ₂ CF ₃ .

[0069] In some embodiments, Ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered monocyclic heteroaryl.

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

[0071] In some embodiments, ring A may be a substituted 5-6 membered monocyclic heteroaryl. In some embodiments, Ring A may be an unsubstituted 5-6 membered monocyclic heteroaryl. 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 nogo pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine and substituted or unsubstituted pyridazine.

[0072] If substituted, ring A may be substituted with one or more substituents selected from halogen, unsubstituted C ₁ -C ₄ haloalkyl and unsubstituted C ₁ -C ₄ alkyl. In some embodiments, ring A is monosubstituted with a halogen (eg, fluorine).

[0073] In some embodiments can be selected from:

each of the above groups being substituted or unsubstituted. In some embodiments may be substituted or unsubstituted . In some embodiments may be substituted or unsubstituted , in which ring A is unsubstituted. In other embodiments may be selected from substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted . As described herein, the portion of ring A in , And may be unsubstituted.

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

[0075] In some embodiments, ring B may be a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl. In some embodiments, Ring B may be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In other embodiments, Ring B may be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. However, in other embodiments, Ring B may be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0076] In some embodiments can be selected from: , And ; each of the above groups being substituted or unsubstituted.

[0077] In some embodiments, ring B may be a substituted or unsubstituted monocyclic 5-7 membered heterocyclyl. In some embodiments, ring B may be a substituted or unsubstituted monocyclic 5-membered heterocyclyl. In other embodiments, ring B may be a substituted or unsubstituted monocyclic 6-membered heterocyclyl. However, in other embodiments, Ring B may be a substituted or unsubstituted monocyclic 7-membered heterocyclyl.

[0078] In some embodiments can be selected from:

each of the above groups being substituted or unsubstituted, including any -NH group.

[0079] In some embodiments, ring B may be selected from each of the above groups being substituted or unsubstituted, including any -NH group. In some embodiments, ring B may be substituted or unsubstituted .

[0080] In some embodiments, when ring B is substituted, ring B may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-linked amido (e.g., -NHC(O)C ₁ - C ₆ alkyl), unsubstituted C ₁ -C ₆ haloalkyl (such as those described herein) and substituted or unsubstituted C ₁ -C ₆ alkyl (such as those described herein). In some embodiments, when ring B is substituted, ring B may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-linked amido (e.g., -NHC(O)C ₁ -C ₆ alkyl ) and substituted or unsubstituted C ₁ -C ₆ alkyl (such as those described herein). In some embodiments, ring B may be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted -NHC(O)C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ haloalkyl (such as those described herein) and unsubstituted C ₁ -C ₆ alkyl (such as those described herein). In some embodiments, ring B may be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy, -CF ₃ , -CHF ₂ , -CF ₂ CH ₃ , unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH ₃ .

[0081] In some embodiments can be selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; each of the above groups being substituted or unsubstituted, including any -NH group.

[0082] In some embodiments can be selected from: , , , , , , , , , , , , , , , And ; each of the above groups being substituted or unsubstituted. In some embodiments can be selected from: , , , , , , , , And ; each of the above groups being substituted or unsubstituted. In some embodiments may be substituted or unsubstituted . In some embodiments may be substituted or .

[0083] Both ring A and ring B may be substituted or unsubstituted. In some embodiments, ring A and ring B in may be independently substituted or unsubstituted. In some embodiments, both ring A and ring B are may be unsubstituted. In some embodiments, both ring A and ring B are may be independently substituted. In some embodiments, ring A in may be substituted, and ring B in may be unsubstituted. In some embodiments, ring A in may be unsubstituted, and ring B in may be substituted. In some embodiments, ring A in may be unsubstituted, and ring B in may be substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy and substituted or unsubstituted C ₁ -C ₆ alkyl (such as those described herein). In some embodiments, ring A in may be unsubstituted, and ring B in may be substituted with 1, 2 or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted N-linked amido (for example, C ₁ -C ₆ -NHC(O)alkyl), unsubstituted C ₁ -C ₆ haloalkyl (such as as described herein) and unsubstituted C ₁ -C ₆ alkyl (such as described herein). In some embodiments, ring A in may be unsubstituted, and ring B in may be substituted with 1 or 2 substituents independently selected from fluorine, hydroxy, amino, -CF ₃ , -CHF ₂ , -CF ₂ CH ₃ , unsubstituted methyl, unsubstituted ethyl and -NHC(O)CH ₃ .

[0084] In some embodiments, R ² may be selected from And . In some embodiments, R ² may be . In some embodiments, R ² may be .

[0085] 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).

[0086] In some embodiments, R ³ may be selected from halogen and substituted or unsubstituted C ₁ -C ₆ alkyl (such as those described herein). In some embodiments, R ³ may be halogen. In some embodiments, R ³ may be a substituted C ₁ -C ₆ alkyl (such as the alkyls described herein). In some embodiments, R ³ may be an unsubstituted C ₁ -C ₆ alkyl (such as the alkyls described herein).

[0087] In some embodiments, m may be equal to 0, 1, 2, or 3. In some embodiments, m may be equal to 0. In some embodiments, m may be equal to 1. In some embodiments, m may be equal to 2. In In some embodiments, m may be 3. When m is 2 or 3, the R ³ groups may be the same or different from each other.

[0088] In some embodiments, X may be selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine(C ₁ -C ₆ alkyl), substituted or unsubstituted -NH- (CH ₂ ) ₁ - ₆ -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C ₁ -C ₆ alkyl (such as described herein), substituted or unsubstituted C ₁ -C ₆ alkoxy (such as methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy (straight or branched) or hexoxy (straight or branched), substituted or unsubstituted C ₃ -C ₆ cycloalkoxy (such as cyclopropoxy , cyclobutoxy, cyclopentoxy or cyclohexoxy), substituted or unsubstituted (C ₁ -C ₆ alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl and substituted or unsubstituted N-carbamyl.

[0089] 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. However, in other embodiments, X may be hydroxy. In other embodiments, X may be cyano. In some embodiments, X may be amino.

[0090] In some embodiments, X may be an unsubstituted C ₁ -C ₆ alkyl (such as the alkyls described herein). In some embodiments, X may be unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In some embodiments, X may be a substituted C ₁ -C ₆ alkyl (such as the alkyls described herein). In some embodiments, X may be an unsubstituted C ₁ -C ₆ haloalkyl (such as C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ chloroalkyl, or C ₁ -C ₆ chlorofluoroalkyl). In some embodiments, X may be selected from -CHF ₂ , -CF ₃ , -CF ₂ CH ₃ , and -CH ₂ CF ₃ . In some embodiments, X may be an unsubstituted C ₁ -C ₆ hydroxyalkyl (such as C ₁ -C ₆ monohydroxyalkyl or C ₁ -C ₆ dihydroxyalkyl). In some embodiments, X may be selected from -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ and -C(OH)(CH ₃ ) ₂ . In some embodiments, X may be an unsubstituted C ₁ -C ₆ cyanoalkyl (such as C ₁ -C ₆ monocyanoalkyl or C ₁ -C ₆ dicyanoalkyl). In some embodiments, X may be selected from , And . In some embodiments, X may be an unsubstituted C ₁ -C ₆ alkoxyalkyl (such as a C ₁ -C ₆ monoalkoxyalkyl or a C ₁ -C ₆ dialkoxyalkyl). In some embodiments, X may be selected from , , And . In some embodiments, X may be a substituted C ₁ -C ₆ alkyl selected from , , And .

[0091] [0002] In some embodiments, X may be an unsubstituted C ₁ -C ₆ alkoxy (such as those described herein). In some embodiments, X may be unsubstituted methoxy, unsubstituted ethoxy, or unsubstituted isopropoxy. In some embodiments, X may be a substituted C ₁ -C ₆ alkoxy (such as those described herein). In some embodiments, X may be a C ₁ -C ₆ alkoxy substituted with 1, 2, or 3 substituents independently selected from halogen, amino, monosubstituted amine (such as those described herein), and disubstituted amine (such as those described herein ). In some embodiments, X may be a C ₁ -C ₆ alkoxy substituted with 1 substituent selected from halogen, amino, mono-amine (such as those described herein) and disubstituted amine (such as those described herein).

[0092] In some embodiments, X may be selected from , , , And .

[0093] In some embodiments, X may be a substituted C ₃ -C ₆ cycloalkoxy (such as those described herein). In some embodiments, X may be an unsubstituted C ₃ -C ₆ cycloalkoxy (such as those described herein).

[0094] In some embodiments, X may be a substituted (C ₁ -C ₆ alkyl)acyl, such as a substituted -(CO)-CH ₃ . In some embodiments, X may be an unsubstituted (C ₁ -C ₆ alkyl)acyl, such as unsubstituted -(CO)-CH ₃ .

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

[0096] In some embodiments, X may be a 4-6 membered monocyclic heterocyclyl (such as those described herein) substituted with 1 or 2 substituents independently selected from halogen, substituted or unsubstituted C ₁ -C ₆ alkyl (such as described herein), monosubstituted amine (such as described herein), disubstituted amine (such as described herein), amino, substituted or unsubstituted amine(C ₁ -C ₆ alkyl) and substituted or unsubstituted (C ₁ - C ₆ alkyl)acyl. In some embodiments, X may be a 4-6 membered monocyclic heterocyclyl substituted with 1 or 2 substituents independently selected from fluorine, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, -CH ₂ OH and -N(CH ₃ ) ₂ . In some embodiments, X may be selected from , , , , , , , , And .

[0097] In some embodiments, X may be a substituted amine (C ₁ -C ₆ alkyl). In some embodiments, X may be an unsubstituted amine (C ₁ -C ₆ alkyl). In some embodiments, X may be selected from , , , , And ; each of the above groups being substituted or unsubstituted, including any -NH group. .

[0098] In some embodiments, X may be a substituted -NH-(CH ₂ ) ₁ - ₆ -amine. In some embodiments, X may be unsubstituted -NH-(CH ₂ ) ₁ - ₆ -amine. In some embodiments, X may be selected from , , , , And ; each of the above groups being substituted or unsubstituted, including any -NH group.

[0099] In some embodiments, X may be a monosubstituted amine. In some embodiments, the monosubstituted amine substituent is an unsubstituted C ₁ -C ₆ alkyl (such as those described herein) or an unsubstituted C ₃ -C ₆ cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0100] In some embodiments, X may be a disubstituted amine. In some embodiments, the at least two disubstituted amine substituents are independently selected from unsubstituted C ₁ -C ₆ alkyl (such as those described herein) and unsubstituted C ₃ -C ₆ cycloalkyl (such as those described herein).

[0101] In some embodiments, X may be selected from , , , And .

[0102] In some embodiments, X may be a substituted or unsubstituted C-amido. In some embodiments, X may be a substituted or unsubstituted N-amido. In some embodiments, X may be a substituted or unsubstituted C-carboxy. In some embodiments, X may be a substituted or unsubstituted O-carboxy. In some embodiments, X may be substituted or unsubstituted O-carbamyl. In some embodiments, X may be substituted or unsubstituted N-carbamyl. In some embodiments, X may be monosubstituted with an unsubstituted C ₁ -C ₆ hydroxyalkyl (such as those described herein).

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

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

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

[0106] In some embodiments, R ^4A may be hydrogen. In some embodiments, R ^4A may be halogen. In some embodiments, R ^4A may be an unsubstituted C ₁ - ₄ alkyl (such as the alkyls described herein).

[0107] In some embodiments, R ^4B may be hydrogen. In some embodiments, R ^4B may be a halogen. In some embodiments, R ^4B may be an unsubstituted C ₁ - ₄ alkyl (such as the alkyls described herein).

[0108] In some embodiments, each of R ^4A and R ^4B may be hydrogen. In some embodiments, R ^4A and R ^4B may each be a halogen (and the halogens may be the same or different from each other). In some embodiments, R ^4A and R ^4B may each be an unsubstituted C ₁ - ₄ alkyl (such as those described herein, wherein the C ₁ - ₄ alkyls may be the same or different from each other). In some embodiments, one of R ^4A and R ^4B may be hydrogen and the other of R ^4A and R ^4B may be halogen. In some embodiments, one of R ^4A and R ^4B may be hydrogen and the other of R ^4A and R ^4B may be an unsubstituted C ₁ - ₄ alkyl (such as those described herein). In some embodiments, one of R ^4A and R ^4B may be halogen, and the other of R ^4A and R ^4B may be an unsubstituted C ₁ - ₄ alkyl (such as those described herein).

[0109] In some embodiments, R ² may be . For example, R ² may be . If R ² is In some embodiments, R ⁵ may be a substituted 5-7 membered monocyclic heterocyclyl. In other embodiments, R ⁵ may be an unsubstituted 5-7 membered monocyclic heterocyclyl. Examples of R ⁵ groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azepanyl. When replacing the R ⁵ group, possible substituents include unsubstituted C ₁ - ₄ alkyl, halogen, hydroxy and unsubstituted C ₁ - ₄ haloalkyl.

[0110] In some embodiments, ring C may be selected from substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted monocyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, substituted or unsubstituted 5- 7-membered monocyclic heterocyclyl and substituted or unsubstituted 7-10-membered bicyclic heterocyclyl.

[0111] In some embodiments, ring C may be a substituted C ₆ -C ₁₀ aryl. In some embodiments, ring C may be an unsubstituted C ₆ -C ₁₀ aryl. In some embodiments, the C ring may be a substituted C ₆ aryl. In some embodiments, ring C may be unsubstituted C ₆ aryl.

[0112] In some embodiments, ring C may be a substituted 5-10 membered heteroaryl. In some embodiments, ring C may be an unsubstituted 5-10 membered heteroaryl. In some embodiments, ring C may be a substituted 5-6 membered heteroaryl. In some embodiments, ring C may be an unsubstituted 5-6 membered heteroaryl. 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; each of the above groups being substituted or unsubstituted, including any -NH group.

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

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

[0115] In some embodiments, ring C may be a substituted or unsubstituted 7-membered bicyclic heterocyclyl (fused, bridged, or spiroheterocyclyl). In some embodiments, ring C may be a substituted or unsubstituted 8-membered bicyclic heterocyclyl, such as a fused, bridged or spiroheterocyclyl. In some embodiments, ring C may be a substituted or unsubstituted 9-membered bicyclic heterocyclyl (fused, bridged, or spiroheterocyclyl). In some embodiments, ring C may be a substituted or unsubstituted 10-membered bicyclic heterocyclyl, such as a fused, bridged, or spiroheterocyclyl. In some embodiments, ring C may be selected from pyrrolizidine, indoline, 1,2,3,4-tetrahydroquinoline, 2-azaspiro[3,3]heptane, 2-oxaspiro[3,3]heptane, 2-oxa-6- azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, 2-oxaspiro[3,4]octane and 2-azaspiro[3,4]octane; each of the above groups being substituted or unsubstituted, including any -NH group.

[0116] In some embodiments, the C ring may be substituted with one or more substituents independently selected from unsubstituted C ₁ -C ₆ alkyl (as described herein) and unsubstituted (C ₁ -C ₆ alkyl)acyl. In some embodiments, the C ring may be substituted with one substituent selected from unsubstituted C ₁ -C ₆ alkyl (as described herein) and unsubstituted (C ₁ -C ₆ alkyl)acyl.

[0117] In some embodiments, R ² may be selected from: , , , , , , And ; each of the above groups may be substituted or unsubstituted.

[0118] Examples of the compound of formula (I) include:

or a pharmaceutically acceptable salt of any of the above compounds.

Synthesis

[0119] The compounds of formula (I) or pharmaceutically acceptable salts thereof can be prepared by various methods known to those skilled in the art in accordance with the teachings set forth herein. For example, in an embodiment, compounds of formula (I) are prepared in accordance with General Scheme 1 as shown herein.

[0120] In general, coupling reactions between compounds of general formulas A and B to form compounds 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 appropriate adjustment of the reagents and conditions described in the examples. Any preliminary reaction steps necessary to obtain the starting compounds of Formula A and B, or other precursors, can be readily performed by those skilled in the art. In General Scheme 1, ring A, ring B, R ¹ and R ² may be as described herein.

General scheme 1

Pharmaceutical compositions

[0121] Certain embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

[0122] The term "pharmaceutical composition" refers to a mixture of one or more compounds and/or salts described herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound into the body. Pharmaceutical compositions can also be prepared 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 can be substantially optimized for their particular intended route of administration.

[0123] The term "physiologically acceptable" means a carrier, diluent or excipient that does not inhibit the biological effects or properties of the compound and does not cause significant harm or injury to the animal to which the composition is to be administered.

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

[0125] As used herein, the term “diluent” refers to an ingredient in a pharmaceutical composition that does not have significant pharmacological activity, but may be pharmacologically necessary or desirable. For example, a diluent can be used to increase the volume of a potent drug that is too small to be manufactured and/or administered. It may also be a liquid for dissolving the drug for administration by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0126] As used herein, the term “excipient” refers essentially to an inert substance that is added to a pharmaceutical composition to provide, without limitation, volume, consistency, stability, binding ability, lubrication, disintegration ability, etc., to the composition. For example, excipients are stabilizers such as antioxidants and metal chelating agents. In an embodiment, the pharmaceutical composition contains an antioxidant and/or a metal chelating agent. "Diluent" is a type of excipient.

[0127] The pharmaceutical compositions described herein can be administered to a human patient per se or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients, or combinations thereof. The proper formulation depends on the route of administration chosen. Techniques for formulating and administering the compounds described herein are known to one skilled in the art.

[0128] The pharmaceutical compositions described herein can be manufactured in a manner that is per se known, for example through conventional processes of mixing, dissolving, granulating, drageeing, trituration, emulsification, encapsulation, encapsulation or tabletting. In addition, the active ingredients are contained in an amount effective to achieve their intended purpose. Many of the compounds used in the pharmaceutical combinations described herein may be provided as salts with pharmaceutically compatible counterions.

[0129] There are many methods in the art for administering the compound, salt and/or composition, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral administration, including intramuscular, subcutaneous, intravenous, intramedullary injection , intrathecal, direct intranotricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered orally.

[0130] It is also possible to administer the compound, salt, and/or composition locally rather than systemically, such as by injecting or implanting the compound directly into the affected area, often in the form of a depot or sustained-release composition. Moreover, the compound can be administered in a targeted drug delivery system, such as a liposome coated with a tissue-specific antibody. The organ will be the target of the liposomes and will selectively absorb them. For example, intranasal or pulmonary delivery may be desirable for the treatment of a respiratory disease or condition.

[0131] The compositions may optionally be present in a packaging or dispensing device, which may contain one or more dosage forms containing the active ingredient. The packaging may, for example, comprise metal foil or a polymer film such as a blister pack. The packaging or dispensing device may be accompanied by instructions for administration. The packaging device or dispenser may also be accompanied by a notice affixed to the container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, the notice containing the agency's approval of that form of drug for human administration or veterinary use. For example, such a notice could be FDA-approved labeling for prescription drugs or an approved package insert. Compositions, which may include a compound and/or salt described herein, constituting a compatible pharmaceutical carrier, may also be prepared, placed in a suitable container and labeled as useful for treating the specified condition.

Application and treatment methods

[0132] Certain embodiments described herein relate to a method of alleviating and/or treating cancer 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject with a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the relief and/or treatment of cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) for the relief and/or treatment of cancer described herein.

[0133] Certain embodiments described herein relate to a method of inhibiting the replication of a cancer or tumor, which may include contacting the tumor 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the cancer or tumor is caused by a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) to inhibit the replication of a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein.

[0134] Certain embodiments described herein relate to a method of alleviating or treating cancer as described herein, which may include contacting the cancer 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a subject with a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the relief or treatment of cancer, which may include contacting a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein. Other embodiments described herein provide 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 that includes an effective amount of a compound described herein (e.g., a compound of Formula (I) ) or a pharmaceutically acceptable salt thereof) for the amelioration or treatment of cancer, which use may include contacting a cancer or tumor, wherein the cancer or tumor is caused by a cancer described herein.

[0135] Certain embodiments described herein relate to a method of inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting WEE1 activity in p53-deficient cells, and/or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (e.g., a compound of formula (I) (I) or a pharmaceutically acceptable salt thereof), for a cancer cell related to 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 that includes an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting WEE1 activity in p53-deficient cells, and /or reducing WEE1 overexpression in cells). However, other embodiments described herein provide 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 that includes 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 (e.g., inhibit WEE1 activity in TP53-mutated cells, inhibit WEE1 activity in wild-type TP53 cells, inhibit WEE1 activity in p53-deficient cells, and/or reducing WEE1 overexpression in cells). Certain embodiments described herein relate to a method of inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting activity in p53-deficient WEE1 cells, and/or reducing WEE1 overexpression in cells) which may include providing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), for a cancer cell related to the cancer described herein. Other embodiments described herein relate to a method of inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibiting activity in p53-deficient WEE1 cells, and/or reducing WEE1 overexpression in cells), which may include bringing a cancer cell, one of the cancers described herein, into contact 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 that includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), and thereby inhibit the activity of WEE1.

[0136] Certain embodiments described herein relate to a method of alleviating or treating cancer described herein, which may include inhibiting WEE1 activity (e.g., inhibiting WEE1 activity in TP53-mutated cells, inhibiting WEE1 activity in wild-type TP53 cells, inhibition of WEE1 activity in p53-deficient cells and/or reduction of WEE1 overexpression in cells) using an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes one described herein compound (eg, 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the amelioration or treatment of cancer described herein by inhibiting WEE1 activity (e.g., inhibition of WEE1 activity in TP53-mutated cells, inhibition of WEE1 activity in wild-type TP53 cells, inhibition WEE1 activity in p53-deficient cells and/or decreased WEE1 overexpression in cells). 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 that includes an effective amount of a compound described herein (e.g. compounds of formula (I) or a pharmaceutically acceptable salt thereof) for the amelioration or treatment of cancer described herein by inhibiting WEE1 activity (eg, inhibition of WEE1 activity in TP53-mutated cells, inhibition of WEE1 activity in wild-type TP53 cells, inhibition of WEE1 activity in p53-deficient cells and/or decreased overexpression of WEE1 in cells). Certain embodiments described herein relate to a method of alleviating or treating cancer described herein, which may include contacting a cancer cell with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein said compound inhibits WEE1 activity (e.g., inhibits WEE1 activity in TP53-mutated cells, inhibits WEE1 activity in TP53 wild-type cells, inhibits WEE1 activity in p53-deficient cells and/or reduces WEE1 overexpression in cells).

[0137] Certain embodiments described herein relate to a method of inhibiting WEE1 activity, which may include providing an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition, which includes an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a patient having a cancer described herein or a cancer cell related to a 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 that includes an effective amount of a compound described herein (e.g., a compound of formula (I) (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting WEE1 activity. Other embodiments described herein relate to a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (e.g., a compound of formula (I) I) or a pharmaceutically acceptable salt thereof) to inhibit the activity of WEE1.

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

[0139] As described herein, cancer can become resistant to one or more anticancer agents. In some embodiments, a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) , can be used to treat and/or alleviate cancer that has become resistant to one or more anticancer agents (such as one or more WEE1 inhibitors). Examples of anticancer agents to which a patient may develop resistance include, but are not limited to, WEE1 inhibitors (such as AZD1775). In some embodiments, a cancer that has become resistant to one or more anticancer agents may be a cancer described herein.

[0140] Several known WEE1 inhibitors may cause one or more undesirable side effects in a treated patient. Examples of unwanted side effects include, but are not limited to, thrombocytopenia, neutropia, anemia, diarrhea, vomiting, nausea, abdominal pain and constipation. In some embodiments, a compound described herein (eg, a compound of Formula (I) or a pharmaceutically acceptable salt thereof) may reduce the amount and/or severity of one or more side effects associated with a known WEE1 inhibitor. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may cause a severe side effect (such as one described herein) that is 25% less severe than the same side effect in a patient receiving a known inhibitor WEE1 (such as AZD1775, formally known as MK1775 (CAS number: 955365-80-7, 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4 -(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof results in 25% fewer side effects compared to the side effects experienced by a patient receiving a known WEE1 inhibitor (eg, AZD1775). In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof causes the severity of a side effect (such as one described herein) to be less than about 10% to about 30% of the severity level of the same side effect. , which was experienced by a patient receiving a known WEE1 inhibitor (such as AZD1775). In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the number of side effects to a range of about 10% to about 30% less than the number of side effects experienced by a patient receiving a known WEE1 inhibitor (such as AZD1775).

[0141] One or more compounds of formula (I) or a pharmaceutically acceptable salt thereof that can be used to treat, alleviate and/or inhibit the growth of cancer, wherein inhibition of WEE1 activity is advantageous, is provided in any of the embodiments described in paragraphs [0064 ]-[0112] under the “Connections” heading.

[0142 ] As used herein, the term “subject” refers to an animal that is the subject of treatment, observation, or experiment. “Animals” include cold-blooded and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles, and in particular mammals. "Mammals" include, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees and apes, and in particular humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and/or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0143] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean complete cure or elimination of a disease or condition. Any relief of any undesirable signs and symptoms of a disease or condition to any extent may be considered treatment and/or therapy. Moreover, treatment may involve activities that may cause the subject's general health or appearance to become worse.

[0144] The terms “therapeutically effective amount” and “effective amount” are used to refer to the amount of an active compound or pharmaceutical agent that induces a specified biological or medical response. For example, a therapeutically effective amount of a compound, salt or composition may be the amount needed to prevent, reduce or alleviate the symptoms of a disease or condition, or prolong the life of a patient receiving treatment. Such a reaction may occur in a tissue, system, animal or human and involves a reduction in the signs or symptoms of the disease or condition being treated. The determination of an effective amount is well known to those skilled in the art in light of the description presented herein. The therapeutically effective amount of the compounds described herein that is required as a dose will depend on the route of administration, the species of animal being treated, including humans, and the physical characteristics of the particular animal in question. The dose can be optimized to achieve the desired effect, but this procedure will depend on factors such as body weight, diet, concomitant medications and other factors that will be apparent to those skilled in the art.

[0145] For example, an effective amount of a compound or irradiation is an amount that: (a) reduces, alleviates, or eliminates one or more symptoms caused by cancer, (b) reduces the size of a tumor, (c) destroys a tumor, and/or ( d) stabilize the disease in the long term (stop tumor growth). In the treatment of lung cancer (eg, non-small cell lung cancer), a therapeutically effective amount is an amount that relieves or eliminates cough, difficulty breathing and/or pain. As another example, an effective amount or therapeutically effective amount of a WEE1 inhibitor is an amount that reduces the activity and/or phosphorylation of WEE1 (eg, CDC2 phosphorylation). Reduced WEE1 activity is known to those skilled in the art and can be determined by analyzing the intrinsic kinase activity of WEE1 and phosphorylation of downstream substrates.

[0146] The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof required for use in treatment varies not only depending on the particular compound or salt selected, but also depending on the route of administration, the nature and/or symptoms of the disease being treated or condition, age and condition of the patient and is ultimately chosen at the discretion of the attending physician or health care professional. When administering a pharmaceutically acceptable salt, doses can be calculated based on the free base. Those skilled in the art will appreciate that certain situations may require administration of the compounds described herein in amounts that are greater than or even significantly greater than the dosage ranges described herein for the effective and aggressive treatment of certain diseases or conditions.

[0147] However, in general, a suitable dose will often be in the range of about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may range from about 0.10 mg/kg to about 7.5 mg/kg body weight per day, such as from about 0.15 mg/kg to about 5.0 mg/kg body weight of the patient per day. day, from about 0.2 mg/kg to 4.0 mg/kg of the patient's body weight per day, or any amount in between. The compound can be administered as a unit dosage form; for example, containing from 1 to 500 mg, from 10 to 100 mg or from 5 to 50 mg, or any amount therebetween, of active ingredient per unit dosage form.

[0148] The desired dose may conveniently be presented as a single dose or divided doses administered at appropriate intervals, for example, as two, three, four or more portions per day. The portion of the dose itself can be further divided, for example, into several discrete administrations at freely definable intervals.

[0149] It will be apparent to one skilled in the art that the in vivo dose to be administered and the specific route of administration will vary depending on the age, weight, severity of the lesion, the type of mammal being treated, the specific compounds used, and the particular application, in according to which these connections are used. Determination of effective dose levels, i.e., dose levels required to achieve the desired result, can be performed by one skilled in the art using standard methods, for example, human clinical trials, in vivo and in vitro studies. For example, useful dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing their in vitro and in vivo activity in animal models. Such a comparison can be made by comparison with an established drug such as cisplatin and/or gemcitabine).

[0150] The dose amount and interval can be adjusted individually to obtain plasma levels of the active functional moiety that are sufficient to maintain modulatory effects or the minimum effective concentration (MEC). The MEC will vary for each compound, but can be estimated from in vivo and/or in vitro data. Dosages required to achieve MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dose intervals can also be determined using the MEC value. The compositions should be administered using a regimen in which plasma levels are maintained above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. When administered locally or selectively absorbed, the effective local drug concentration may be unrelated to the plasma concentration.

[0151] It should be noted that the attending physician will understand how and when to terminate, interrupt, or adjust administration due to toxicity or organ failure. The treating physician will also understand how to adjust treatment backwards (to higher levels) if clinical response is inadequate (preventing toxicity). The dose amplitude of administration to control the disorder of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of a disease or condition can, for example, be assessed in part by standard prognostic assessment methods. Additionally, the dose and possibly the frequency of dosing will also vary depending on the age, body weight and response of the individual patient. In veterinary medicine, you can use a program comparable to the one described above.

[0152] The effectiveness and toxicity of the compounds, salts and compositions described herein can be assessed using known methods. For example, the toxicology of a particular compound or subset of compounds having certain chemical moieties can be determined by determining in vitro toxicity against a cell line, such as a mammalian cell line, and preferably a human cell line. The results of such studies often make it possible to predict toxicity in animals, such as mammals, or more specifically in humans. In an alternative embodiment, the toxicity of individual compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, can be determined using known methods. The effectiveness of a particular compound can be determined using several generally accepted methods, such as in vitro methods, animal models or human clinical studies. When selecting a model to determine efficacy, one skilled in the art will be guided by recent advances in the art to select the appropriate model, dose, route of administration, and/or regimen.

EXAMPLES

[0153] The following examples describe additional embodiments in more detail, and the examples are not intended to limit the scope of the claims.

Intermediate 1

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

[0154] Intermediate 1 was prepared according to the procedure described in Matheson et al., ACS Chem. Biol. (2016) 11:2066–2067. (MS) (LCMS) 223.0 [M+H] ⁺ .

Intermediate 2

2-Bromo-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-ol

[0155] Step 1. Mixture of propiolamide (62 g, 898.55 mmol), ethyl 2-oxocyclopentanecarboxylate (140.35 g, 898.55 mmol) and Na ₂ CO ₃ (94.3 g, 898.55 mmol) in water (2.25 L) was stirred at rt for 18 hours. The mixture was extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give ethyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentanecarboxylate (40 g, 20%) as a solid. off-white color. (MS) (LCMS) 226.3 [M+H] ⁺ .

[0156] Step 2: A solution of ethyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentanecarboxylate (39 g, 173.33 mmol) in conc. HCl (390 ml) was stirred in a sealed tube at 110 °C for 18 hours. The solvent was removed and aq. NaHCO ₃ solution to adjust pH to 8-9 at 0 °C. The resulting solid was filtered and washed with Et ₂ O (2 x 100 ml) to obtain 6,7-dihydro- 1H- cyclopenta[ b ]pyridin-2( 5H )-one (15 g, 64% yield) as a solid off-white substances. (MS) (LCMS) 135.9 [M+H] ⁺ .

[0157] Step 3: A solution of 6,7-dihydro- 1H -cyclopenta[ b ]pyridin-2( 5H )-one (18 g, 133.33 mmol) in PBr ₃ (180 ml) was heated at 180 °C for 18 hours. The reaction mixture was then allowed to cool to rt and poured into ice water. The pH was adjusted to 8-9 with saturated NaHCO ₃ . The resulting solution was filtered through a celite pad. The filtrate was extracted with EtOAc (2 x 500 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-bromo-6,7-dihydro-5 H -cyclopenta[ b ]pyridine (7 g, 26%) as an off-white solid. (MS) (LCMS) 197.8 [M+H] ⁺ .

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

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

[0160] Step 6: To a stirred solution of 2-bromo-6,7-dihydro- 5H- cyclopenta[ b ]pyridin-7-yl acetate (2 g, 7.84 mmol) in THF/H ₂ O (20 ml , 1:1) LiOH·H ₂ O (0.755 g, 31.49 mmol) was added at rt. The mixture was stirred for 3 hours and then diluted with water and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography (SiO ₂ , 40% EtOAc/petroleum ether) to give intermediate 2 (1.2 g, 71%) as a brown solid. (MS) (LCMS) 214.1 [M+H] ⁺ .

Intermediate 3

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

[0161] To solutionintermediate 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) in 1,4-dioxane (30 ml) was addedN,N'-dimethylethylenediamine (0.43 ml, 4.02 mmol) at 80 °C. The suspension was heated at 95 °C for 18 hours. The mixture was cooled to rt, diluted with aq. N.H.₄OH (30 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with saline (20 ml), dried (Na₂SO₄) filtered and evaporated to dryness. The residue was purified by flash chromatography (SiO₂, 40% EtOAc/petroleum ether) to giveintermediate connections 3 (280 mg, 38%) as a pale yellow oil. MS (IER) 356.4 [M+H]⁺.

Example 1A

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

Example 1B

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

[0162] To solutionintermediate connection 3 (280 mg, 0.79 mmol) in toluene (20 ml) was addedm-CPBA (201 mg, 1.17 mmol) and stirred the mixture at rt for 1 h. DIPEA (0.69 mL, 3.94 mmol) and 4-(4-methylpiperazin-1-yl)aniline (178 mg, 0.93 mmol) and stirred the mixture at rt for 18 hours. Add saturated NaHCO₃ (25 ml) and the mixture was extracted with EtOAc (2 x 30 ml). The combined organic extracts were washed with saline (20 ml), dried (Na₂SO₄) and concentrated. The resulting residue was purified by reverse phase HPLC (acetonitrile/water) to give racemic 2-allyl-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-3(2H)-she (87 mg, 30% yield) as a yellow solid. Enantiomers were separated by SLC chromatography (Chiralpak AD-H, 40% (0.5% DEA in ethanol)) to produce peak 1 (example 1A, 19 mg) and peak 2 (example 1B, 25 mg).Example 1A - yellow solid;¹H NMR (DMSO-d ₆ , 400 MHz) δ 10.08 (br. s, 1H), 8.81 (s, 1H), 7.93 (d,J = 8.0 Hz, 1H), 7.66 (d,J = 8.4 Hz, 1H), 7.60-7.53 (m, 2H), 6.90 (d,J = 8.8 Hz, 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-d ₆ , 400 MHz) δ 10.05 (br. s, 1H), 8.80 (s, 1H), 7.93 (d,J = 8.0 Hz, 1H), 7.66 (d,J = 8.0 Hz, 1H), 7.60-7.53 (m, 2H), 6.90 (d,J = 8.8 Hz, 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]⁺. Forexample 1A Andexample 1B absolute stereochemistry was set arbitrarily.

Intermediate 4

2-Bromo-7-methyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-ol

[0163] Step 1: To a stirred solution of racemic 2-bromo-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-ol (1.4 g, 6.60 mmol) in DCM (15 mL) was added Dessa-Martin periodinan (3.0 g, 7.26 mmol). The mixture was stirred at rt for 16 hours, then quenched with aq. saturated NaHCO ₃ solution and extracted with EtOAc (2 x 30 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 40% EtOAc/petroleum ether) to give 2-bromo- 5H- cyclopenta[ b ]pyridin-7( 6H )-one (780 mg, 60%) as a solid off-white color. (MS) (LCMS) 212.0 [M+H] ⁺ .

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

Intermediate 5

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

[0165] Intermediate 5 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 4 . (MS) (LCMS) 370.1 [M+H] ⁺ .

Example 2A

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

Example 2B

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

[0166] To a stirred solution of intermediate 5 (330 mg, 0.89 mmol) in THF/H ₂ O (20 ml, 1:1) was added oxon (673 mg, 2.68 mmol) and the mixture was stirred at rt for 1 h, diluted with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a mixture of sulfoxide and sulfone (330 mg, 0.822 mmol) as a semi-solid. To a mixture of sulfoxide and sulfone (330 mg, 0.82 mmol) in toluene (10 ml) was added DIPEA (0.43 ml, 2.46 mmol) and then 4-(4-methylpiperazin-1-yl)aniline ( 188 mg, 0.99 mmol) and stirred the reaction mixture at rt for 16 hours. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (neutral alumina, 5% methanol/DCM) to give racemic 2-allyl-1-(7-hydroxy- 7-methyl-6,7-dihydro-5H-cyclopenta[ b ]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3 H -pyrazolo[3,4- d ]pyrimidin-3-one (260 mg) as an off-white solid. The enantiomers were separated by SLC chromatography (Chiralpak AD-H, 15% (15 mmol ammonia in methanol)) to give peak 1 ( Example 2A , 105 mg) and peak 2 ( Example 2B , 96 mg). Example 2A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.16 (s, 1H), 8.81 (s, 1H), 7.92 ₍ d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62-7.55 (m, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.71-5.63 ( m, 1H), 5.17 (s, 1H), 4.99 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.2 Hz, 2H), 1.45 (s, 3H); (MS) (LCMS) 513.4 [M+H] ⁺ . Example 2B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.16 (s, 1H), _8.82 (s, 1H), 7.97-7.89 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.62-7.55 (m, 2H), 6.91 (d, J = 9.6 Hz, 2H), 5.71-5.63 (m, 1H ), 5.17 (br. s, 1H), 4.98 (d, J = 9.6 Hz, 1H), 4.85 (d, J = 16.4 Hz, 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 = 7.2 Hz, 2H), 1.45 (s, 3H); (MS) (LCMS) 513.5 [M+H] ⁺ . For Example 2A and Example 2B, the absolute stereochemistry was arbitrary.

Intermediate 6

2-Bromo-7-(trifluoromethyl)-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-ol

[0167] TMSCF ₃ ( 3 .2 ml, 21.23 mmol), followed by TBAF (1M in THF) (0.7 ml, 0.71 mmol) at 0 °C. The reaction mixture was stirred at 0 °C to rt for 12 h, quenched with 6N HCl and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give intermediate 6 (825 mg, 41%) as a brown solid. (MS) (LCMS) 281.9 [M+H] ⁺ .

Intermediate 7

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

[0168] Intermediate 7 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 6. (MS) (LCMS) 424.3 [M+H] ⁺ .

Example 3A

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

Example 3B

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

[0169] Examples 3A and 3B were prepared using the procedure described for Examples 2A and 2B using intermediate 7 to give racemic 2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro -5 H -cyclopenta[ b ]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3 H -pyrazolo[3,4- d ]pyrimidin-3-one (330 mg). Enantiomers were separated by SLC chromatography (Chiralpak AD-H, 40% (15 mmol ammonia in methanol)) to give peak 1 ( Example 3A , 126 mg) and peak 2 ( Example 3B , 150 mg). Example 3A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.20 (s, 1H), 8.84 (s, 1H), _8.07 (br.s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.65-7.58 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 5.68- 5.60 (m, 1H), 4.96 (d, J = 10.0 Hz, 1H), 4.79 (d, J = 16.4 Hz, 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.20 (s, 1H), 8.84 (s, 1H), _8.07 (br.s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.65-7.58 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 5.70- 5.60 (m, 1H), 4.96 (d, J = 10.0 Hz, 1H), 4.79 (d, J = 16.4 Hz, 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] ⁺ . For Example 3A and Example 3B, the absolute stereochemistry was arbitrary.

Intermediate 8

5-Bromo-3-methyl-2,3-dihydrofuro[3,2- b ]pyridin-3-ol

[0170] Step 1: 2,3-Dihydrofuro[3,2-b]pyridin-5-amine was prepared according to WO Publication No. 2008/069311. (MS) (LCMS) 137.1 [M+H] ⁺ .

[0171] Step 2: To a stirred solution of 2,3-dihydrofuro[3,2- b ]pyridin-5-amine (9.0 g, 66.17 mmol) in CH ₂ Br ₂ (200 mL) was added CuBr ₂ ( 7.303 g, 33.08 mmol), and then isoamyl nitrite (8.515 g, 72.78 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 hours, quenched with saturated aq. NaHCO ₃ (50 ml) and filtered through a celite pad. The filtrate was extracted with DCM (3 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/petroleum ether) to give 5-bromo-2,3-dihydrofuro[3,2- b ]pyridine (6.0 g, 45%) as a brown solid. MS (IER) 200.2 [M+H] ⁺ .

[0172] Step 3: To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2- b ]pyridine (6.0 g, 30.15 mmol) in DCM (100 mL) was added m -CPBA (6, 27 g, 36.18 mmol) at 0 °C and stirred the mixture at rt for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with n -pentane and dried to obtain crude 5-bromo-2,3-dihydrofuro[ 3,2- b ]pyridine-4-oxide (9.5 g) as an off-white solid. MS (IER) 216.2 [M+H] ⁺ . Acetic anhydride (100 ml) was added to 5-bromo-2,3-dihydrofuro[3,2- b ]pyridine-4-oxide (9.5 g, 44.18 mmol) and heated at 90 °C for 1 h The reaction mixture was cooled to rt, concentrated under reduced pressure and the residue was diluted with saturated aq. NaHCO ₃ (100 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , EtOAc/petroleum ether) to give 5-bromo-2,3-dihydrofuro[3,2- b ]pyridin-3-yl acetate (5.0 g, 65%), as a brown solid. MS (IER) 258.2 [M+H] ⁺ .

[0173] Step 4: To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2- b ]pyridin-3-yl acetate (5.0 g, 19.45 mmol) in THF/H ₂ O (1 : 1, 30 ml) LiOH H ₂ O (2.45 g, 58.35 mmol) was added and stirred at rt for 2 hours. The mixture was extracted with EtOAc (3 x 100 ml) and the combined organic layers were washed with water ( 100 ml) and saline solution (100 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 5-bromo-2,3-dihydrofuro[3,2- b ]pyridin-3-ol (2.5 g, 59%) as off-white solid. MS (IER) 216.1 [M+H] ⁺ .

[0174] Step 5: To a stirred solution of 5-bromo-2,3-dihydrofuro[3,2- b ]pyridin-3-ol (2.6 g, 12.09 mmol) in acetone (30 mL) was added the freshly prepared reagent Jones (25 ml, CrO ₃ (3 eq.) and aq. H ₂ SO ₄ (3 eq.) at 0 °C and stir the reaction mixture at 0 °C for 30 min. The reaction mixture was diluted with EtOAc (60 ml ), washed with ice water (50 ml) and brine (50 ml).The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 5-bromofuro[3,2- b ]pyridine-3(2 H )-one (1.2 g, 46% yield) as a brown solid.MS(ESI) 214.4 [M+H] ⁺ .

[0175] [0003] Step 6: To a solution of 5-bromofuro[3,2- b ]pyridin-3( 2H )-one (1.1 g, 5.16 mmol) in Et ₂ O (15 ml) at At 0°C, methylmagnesium iodide (8.6 mL, 3.0 M in Et ₂ O, 25.80 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour, quenched with aq. NH ₄ Cl (30 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give intermediate 8 (510 mg, 43% yield) as a brown solid. MS (IER) 230.3 [M+H] ⁺ .

Intermediate 9

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

[0176] Intermediate 9 was prepared using the procedure described for intermediate 3 , using intermediate 1 and intermediate 8 ; MS (IER) 372.6 [M+H] ⁺ .

Example 4A

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

Example 4B

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

[0177]Examples 4A And4B were obtained using the procedure described forexamples 2A And2B, usingintermediate 9 to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (350 mg). Enantiomers were separated by SLC chromatography (Chiralpak AD-H, 40% (0.5% DEA in ethanol)) to produce peak 1 (example 4A, 120 mg) and pica 2 (example 4B, 120 mg).Example 4A - yellow solid;¹H NMR (400 MHz, DMSO-d ₆) δ 10.10 (br. s, 1H), 8.81 (s, 1H), 7.70-7.53 (m, 4H), 6.85 (d,J = 16.8 Hz, 2H), 5.81 (s, 1H), 5.71-5.64 (m, 1H), 5.01 (d,J = 9.2 Hz, 1H), 4.89 (d,J = 17.2 Hz, 1H), 4.50-4.43 (m, 4H), 3.07 (T,J = 4.4 Hz, 4H), 2.44 (T,J = 4.4 Hz, 4H), 2.21 (s, 3H), 1.55 (s, 3H); MS (IER) 515.6 [M+H]⁺.Example 4B - yellow solid;¹H NMR (400 MHz, DMSO-d ₆) δ 10.10 (br. s, 1H), 8.81 (s, 1H), 7.70-7.53 (m, 4H), 6.85 (d,J = 16.8 Hz, 2H), 5.81 (s, 1H), 5.71-5.64 (m, 1H), 5.01 (d,J = 9.2 Hz, 1H), 4.89 (d,J = 17.2 Hz, 1H), 4.50-4.43 (m, 4H), 3.07 (T,J = 4.4 Hz, 4H), 2.44 (T,J = 4.4 Hz, 4H), 2.21 (s, 3H), 1.55 (s, 3H); MS (IER) 515.5 [M+H]⁺. Forexample 4AAndexample 4B absolute stereochemistry was set arbitrarily.

Intermediate 10

3-Ethyl-5-iodo-2,3-dihydrobenzofuran-3-ol

[0178] Step 1: 5-Iodobenzofuran-3(2H)-one was prepared according to WO Publication No. 2008/068974. MS (ESI) m/z 260.9 [M+H] ⁺ .

[0179] Step 2: To a stirred solution of 5-iodobenzofuran-3(2H)-one (2 g, 7.69 mmol) in toluene (20 mL) at 0 °C, add 3.0 M EtMgBr (12.82 ml, 38.46 mmol). The mixture was allowed to warm to rt and stirred for 16 hours. After completion of the reaction, confirmed by TLC, the reaction was quenched with water (50 ml) and the mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO₂, 20% EtOAc/petroleum ether) to giveintermediate connections 10 (1.5 g, 67%) as a yellow solid. MS (IER) 272.9 [M+H - H₂O]⁺.

Intermediate 11

2-Allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin- 3-he

[0180] Intermediate 11 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 10 . MS (IER) 385.1 [M+H] ⁺ .

Example 5A

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

Example 5B

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

[0181] Examples 5A and 5B were prepared using the procedure described for Examples 2A and 2B using intermediate 11 to give racemic 2-allyl-1-(3-ethyl-3-hydroxy-2,3-dihydrobenzofuran-5 -yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (380 mg). The enantiomers were separated by SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 9.95 (br. s, _1H ), 8.77 (s, 1H), 7.51 (d, J = 2 Hz, 2H), 7.30 -7.28 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 5.70-5.64 ( m, 1H), 5.55 (s, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.93 (d, J = 10.4 Hz, 1H), 4.46 ( d, J = 10.4 Hz, 1H), 4.32 (d, J = 10.4 Hz, 1H), 4.20 (s, 2H), 3.05-3.03 (m, 4H), 2.44-2.42 (m, 4H), 2.20 (s, 3H), 1.91-1.82 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H) ; MS (IER) 528.2 [M+H] ⁺ . Example 5B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 9.95 (br. s, _1H ), 8.77 (s, 1H), 7.51 (d, J = 2 Hz, 2H), 7.30 -7.28 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 5.70-5.64 ( m, 1H), 5.55 (s, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.93 (d, J = 10.4 Hz, 1H), 4.46 ( d, J = 10.4 Hz, 1H), 4.32 (d, J = 10.4 Hz, 1H), 4.20 (s, 2H), 3.05-3.03 (m, 4H), 2.44-2.42 (m, 4H), 2.20 (s, 3H), 1.91-1.82 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H) ; MS (IER) 528.2 [M+H] ⁺ . For Example 5A and Example 5B, the absolute stereochemistry was arbitrary.

Intermediate 12

5-Bromo-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-ol

[0182] A 1/1 by weight mixture of KOH/Celite was ground finely. The KOH/celite mixture (720 mg) was placed in a glass pipette. 5-Bromofuro[3,2-b]pyridin-3(2H)-one (500 mg, 2.35 mmol) and Me ₃ SiCF ₃ (666 mg, 4.69 mmol) were dissolved in DMF (2.0 ml) . The solution was added to a glass pipette using a syringe. The product was eluted with 4.0 ml DMF. The reaction was repeated on a 4 x 500 mg scale. The combined reactions were quenched with saturated NH ₄ Cl (50 ml). The aqueous layer was extracted with Et ₂ O (2 x 75 ml), and the combined organic layers were washed with brine (2 x 100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 20% EtOAc/petroleum ether) to give intermediate 12 (530 mg, 16%) as an off-white solid. MS (IER) 284.2 [M+H] ⁺ .

Intermediate 13

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

[0183] Intermediate 13 was prepared using the procedure described for intermediate 3 using intermediate 1 and intermediate 12. MS (ESI) 426.4 [M+H] ⁺ .

Example 6A

(R)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazine -1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 6B

(S)-2-Allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazine -1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0184] Examples 6A and 6B were prepared using the procedure described for Examples 2A and 2B using intermediate 13 to give racemic 2-allyl-1-(3-hydroxy-3-(trifluoromethyl)-2,3-dihydrofuro [3,2-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d] pyrimidin-3-one (170 mg). The enantiomers were separated by SLC chromatography (Chiral Pak IG, 40.0% (0.5% DEA in MeOH)) to give peak 1 ( Example 6A , 35 mg) and peak 2 ( Example 6B , 40 mg). Example 6A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.2 (br. s, 1H), _8.84 (s, 1H), 7.87-7.85 (m, 2H), 7.60- 7.55 (m, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.67-5.62 (m, 1H), 5.00-4.93 (m, 2H) , 4.83 (d, J = 16 Hz, 1H), 4.63 (d, J = 12 Hz, 1H), 4.59 (d, J = 12 Hz, 2H), 4.48-4.42 (m, 1H), 3.10-3.08 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H); MS (IER) 569.2 [M+H] ⁺ . Example 6B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.2 (br. s, 1H), _8.84 (s, 1H), 7.87-7.85 (m, 2H), 7.60- 7.55 (m, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.67-5.62 (m, 1H), 5.00-4.93 (m, 2H) , 4.83 (d, J = 16 Hz, 1H), 4.63 (d, J = 12 Hz, 1H), 4.59 (d, J = 12 Hz, 2H), 4.48-4.42 (m, 1H), 3.10-3.08 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H); MS (IER) 569.2 [M+H] ⁺ . For Example 6A and Example 6B, the absolute stereochemistry was arbitrary.

Intermediate 14

2-Bromo-7,7-difluoro-6,7-dihydro-5 H -cyclopenta[ b ]pyridine

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

Intermediate 15

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

[0186] Intermediate 15 was prepared using the procedure described for intermediate 3 , using intermediate 1 and intermediate 14 ; MS (IER) 376.4 [M+H] ⁺ .

Example 7

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

[0187] Step 1: Use tert -butyl-4-(4-aminophenyl)piperazine-1-carboxylate and intermediate 15 according to the procedure described for Examples 2A and 2B to produce tert -butyl-4-(4-( (2-allyl-1-(7,7-difluoro-6,7-dihydro-5 H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3 ,4- d ]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate (120 mg, 19% yield). MS (IER) 605.2 [M+H] ⁺ .

[0188] Step 2: To the mixed solutionrubs-butyl-4-(4-((2-allyl-1-(7,7-difluoro-6,7-dihydro-5N-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1N-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate (250 mg, 0.41 mmol) in Et₂O (10 ml) added 2 M HCl in Et₂O (5 ml) at 0 °C. The mixture was stirred at rt for 4 h, concentrated under reduced pressure and triturated with Et₂O with receiptexample 7 in the form of the hydrochloride salt (94 mg, 42%) as a pale yellow solid.¹H NMR (400 MHz, DMSO-d ₆) δ 10.28 (br.s, 1H), 8.95 (br.s, 2H), 8.87 (s, 1H), 8.17 (d,J = 8.4 Hz, 1H), 8.05 (d,J = 8.0 Hz, 1H), 7.62 (br. s, 2H), 7.00 (d,J = 8.8 Hz, 2H), 5.75-5.65 (m, 1H), 5.01 (d,J = 10.4 Hz, 1H), 4.86 (d,J = 17.6 Hz, 1H), 4.61 (d,J = 5.6 Hz, 2H), 3.38-3.20 (m, 8H), 3.14-3.05 (m, 2H), 2.78-2.62 (m, 2H); MS (IER) 505.4 [M+H]⁺.

Example 8

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

[0189] Use 4-(4-methylpiperazin-1-yl)aniline and intermediate 15 according to the procedure described for Examples 2A and 2B to obtain Example 8 (120 mg, 19%) as a yellow solid. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.24 (br.s, 1H), 8.85 (s, 1H), 8.18 (br.s _, 1H), 8.06 (br.s. s, 1H), 7.57 (br. s, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.75-5.65 (m, 1H), 5.00 (d , J = 10.4 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 3.10 (br.s , 6H), 2.78-2.62 (m, 2H), 2.52-2.42 (m, 4H), 2.22 (s, 3H); MS (IER) 519.3 [M+H] ⁺ .

Intermediate 16

2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0190] To a solution of 2-bromo-5,6-dihydro- 7H -cyclopenta[ b ]pyridin-7-one (2 g, 9.43 mmol) in PhMe (20 ml) at 0 °C, add 3M dropwise EtMgBr in DEE (9.4 ml, 28.29 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was cooled to 0 °C and quenched with sat. NH ₄ Cl solution (30 ml) and extracted with EtOAc (2 x 50 ml). The organic layer was separated, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give intermediate 16 (860 mg, 38%) as an oil. MS (IER) 244.2 [M+H] ⁺ .

Intermediate 17

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

[0191] Intermediate 17 was prepared using the procedure described for intermediate 3 using intermediate 1 and intermediate 16. (MS) (LCMS) 384.5 [M+H] ⁺ .

Example 9A

(S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine-1 -yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 9B

(R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine-1 -yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0192] To solutionintermediate connection 17 (4.5 g, 11.7 mmol) in toluene (90 ml) at 0 °C addedm-CPBA (3.7 g, 12.9 mmol). The ice bath was removed and the reaction mixture was stirred for 30 minutes. After completion of the reaction, confirmed by TLC, 4-(4-methylpiperazin-1-yl)aniline (2.9 g, 15.2 mmol) and DIPEA (10.9 mL, 61.05 mmol) were added at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. The reaction was determined to be complete by TC, and water (100 mL) was added to the reaction mixture and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. NaHCO solution₃ (250 ml), saline (300 ml), dried (Na₂SO₄) and evaporated under reduced pressure. The crude material was triturated with 30% Et₂O/pentane to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine -1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.2 g, 84%). The racemic material (3.5 g) was separated by SLC chromatography (Chiralpak AD-H, 35% (0.5% DEA in methanol)) to obtain peak 1 (example 9A, 1.38 g) and peak 2 (example 9B, 1.26 g).Example 9A- yellow solid;¹H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (br.s, 1H), 8.82 (s, 1H), 7.92 (br.s, 1H), 7.70 (d,J = 8.4 Hz, 1H), 7.58 (br. s, 2H), 6.92 (d,J = 8.8 Hz, 2H), 5.70-5.63 (m, 1H), 5.05 (s, 1H), 4.99 (d,J = 10.4 Hz, 1H), 4.85 (d,J = 17.6 Hz, 1H), 4.74 (br. s, 1H), 4.56 (d,J = 10.8 Hz, 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 = 7.2 Hz, 3H); MS (IER) 527.5 [M+H]⁺.Example 9B - yellow solid;¹H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (br.s, 1H), 8.82 (s, 1H), 7.92 (br.s, 1H), 7.70 (d,J = 8.4 Hz, 1H), 7.58 (br. s, 2H), 6.92 (d,J = 8.8 Hz, 2H), 5.70-5.63 (m, 1H), 5.05 (s, 1H), 4.99 (d,J = 10.4 Hz, 1H), 4.85 (d,J = 17.6 Hz, 1H), 4.74 (br. s, 1H), 4.56 (d,J = 10.8 Hz, 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 = 7.2 Hz, 3H); MS (IER) 527.5 [M+H]⁺. Forexample 9AAndexample 9B absolute stereochemistry was set arbitrarily.

Example 10A

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

Example 10B

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

[0193] Examples 10A and 10B were prepared using the procedure described for Examples 2A and 2B using intermediate 5 to give racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H -cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4- d]pyrimidin-3-one (400 mg). Enantiomers were separated by chiral SLC chromatography (Chiralpak AD-H, 20% (15 mmol ammonia in methanol)) to obtain peak 1 ( Example 10A , 120 mg) and peak 2 ( Example 10B , 125 mg). Example 10A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.13 (br. s, _1H ), 8.84 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7 .71 (d, J = 8.4 Hz, 1H), 7.66 (br.s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.72-5.63 (m, 1H), 5.19 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.85 ( d, J = 17.2 Hz, 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 = 6.8 Hz, 2H ), 1.45 (s, 3H); MS (IER) 527.5 [M+H] ⁺ . Example 10B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.13 (br. s, 1H), 8.84 (s, 1H), 7.90 ₍ d, J = 8.4 Hz, 1H), 7 .71 (d, J = 8.4 Hz, 1H), 7.66 (br. s, 1H), 7.41 (k, J = 8.4, 2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.72-5.63 (m, 1H), 5.19 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4, 85 (d, J = 17.2 Hz, 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), 2.24 (s, 3H), 2.23 (s, 3H), 2.13 (t, J = 6.8 Hz, 2H), 1.44 (s, 3H); MS (IER) 527.4 [M+H] ⁺ . For Example 10A and Example 10B, the absolute stereochemistry was arbitrary.

Example 11A

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

Example 11B

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

[0194] Examples 11A and 11B were prepared using the procedure described for Examples 2A and 2B using intermediate 5 to give racemic 2-allyl-6-((3-fluoro-4-(4-methylpiperazin-1-yl )phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3, 4-d]pyrimidin-3-one (370 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, 25% (0.5% DEA in EtOH)) to give peak 1 ( Example 11A , 90 mg) and peak 2 ( Example 11B , 90 mg). Example 11A - yellow solid; ^1H NMR (300 MHz, DMSO- d6 ) δ 10.25 (br. s, _1H ), 8.88 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7 .75 (br. s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 7.02 (t, J = 9, 6 Hz, 1H), 5.73-5.64 (m, 1H), 5.19 (s, 1H), 5.01 (d, J = 10 Hz, 1H), 4.89 (d, J = 17.2 Hz, 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 = 6.6 Hz, 2H), 1.45 (s, 3H); MS (IER) 531.4 [M+H] ⁺ . Example 11B. ^1H NMR (300 MHz, DMSO- d6 ) δ 10.25 (br. s, _1H ), 8.88 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7 .75 (br. s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 7.02 (t, J = 9, 6 Hz, 1H), 5.73-5.64 (m, 1H), 5.19 (s, 1H), 5.01 (d, J = 10 Hz, 1H), 4.89 (d, J = 17.2 Hz, 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 = 6.6 Hz, 2H), 1.45 (s, 3H); MS (ESI) 531.4. For Example 11A and Example 11B, the absolute stereochemistry was arbitrary.

Example 12A

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

Example 12B

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

[0195] Examples 12A and 12B were prepared using the procedure described for Examples 9A and 9B using intermediate 17 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline to give racemic 2-allyl-1 -(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl) amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg). The enantiomers were separated by SLC chromatography (Chiral Pak AD-H, 35% (0.5% DEA in MeOH)) to give peak 1 ( Example 12A , 169 mg) and peak 2 ( Example 12B , 166 mg). Example 12A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.05 (br. s, _1H ), 8.83 (s, 1H), 7.89 (d, J = 8 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.65 (br.s, 1H), 7.42 (dd, J = 8.4 Hz, J = 8.4 Hz 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.70-5.63 (m, 1H), 5.04 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4, 85 (d, J = 16.8 Hz, 1H), 4.77-4.74 (m, 1H), 4.56 (dd, J = 16.4 Hz, J = 6.4 Hz, 1H) 3 .09-2.93 (m, 1H), 2.81-2.74 (m, 4H), 2.5-2.49 (m, 4H), 2.32-2.17 (m, 7H) , 2.05-1.98 (m, 1H), 1.92-1.80 (m, 1H), 1.73-1.69 (m, 1H), 1.91-1.86 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H); MS (IER) 541.3 [M+H] ⁺ . Example 12b is a yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.05 (br. s, _1H ), 8.83 (s, 1H), 7.89 (d, J = 8 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.65 (br.s, 1H), 7.42 (dd, J = 8.4 Hz, J = 8.4 Hz 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.70-5.63 (m, 1H), 5.04 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4, 85 (d, J = 16.8 Hz, 1H), 4.77-4.74 (m, 1H), 4.56 (dd, J = 16.4 Hz, J = 6.4 Hz, 1H) 3 .09-2.93 (m, 1H), 2.81-2.74 (m, 4H), 2.5-2.49 (m, 4H), 2.32-2.17 (m, 7H) , 2.05-1.98 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.67 (m, 1H), 1.91-1.86 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H); MS (IER) 541.3 [M+H] ⁺ . For Example 12A and Example 12B, the absolute stereochemistry was arbitrary.

Example 13A

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

Example 13B

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

[0196] Step 1. 2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4- (4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure described in Examples 9A and 9B using intermediate 17 and 1-(4-(4-amino-2-methylphenyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one. MS (IER) 623.2 [M+H] ⁺ .

[0197] Step 2: To a stirred solution of 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl -4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (900 mg , 1.45 mmol) in methanol (15 ml) was added K₂CO₃ (399 mg, 2.89 mmol). The reaction mixture was stirred at rt for 4 hours. After completion of the reaction, confirmed by TLC, the solvent was evaporated. The reaction mixture was diluted with water (30 ml) and the solid was filtered to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6 -((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg, 86%) in as a pale yellow solid. Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, 40% (0.5% DEA in MeOH)) to obtain peak 1 (example 13A, 162 mg) and peak 2 (example 13B, 108 mg).Example 13A - yellow solid;¹H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (br. s, 1H), 8.84 (s, 1H), 7.89 (d,J = 8.4 Hz, 1H), 7.71 (d,J = 8.1 Hz, 1H), 7.67 (br. s, 1H), 7.41 (d,J = 8.4 Hz, 1H), 6.96 (d,J = 8.4 Hz, 1H), 5.67-5.66 (m, 1H), 5.05 (s, 1H), 4.99 (d,J = 10.5 Hz, 1H), 4.85 (d,J = 18 Hz, 1H), 4.77-4.74 (m, 1H), 4.56 (dd,J = 6.3, 6.6 Hz, 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 = 7.2 Hz, 3H); MS (IER) 527.2 [M+H]⁺.Example 13B - yellow solid;¹H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (br. s, 1H), 8.84 (s, 1H), 7.89 (d,J = 8.4 Hz, 1H), 7.71 (d,J = 8.1 Hz, 1H), 7.67 (br. s, 1H), 7.41 (d,J = 8.4 Hz, 1H), 6.96 (d,J = 8.4 Hz, 1H), 5.67-5.66 (m, 1H), 5.05 (s, 1H), 4.99 (d,J = 10.5 Hz, 1H), 4.85 (d,J = 18 Hz, 1H), 4.77-4.74 (m, 1H), 4.56 (dd,J = 6.3, 6.6 Hz, 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 = 7.2 Hz, 3H); MS (IER) 527.4 [M+H]⁺. Forexample 13AAndexample 13B absolute stereochemistry was assigned arbitrarily.

Intermediate 18

(S)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

Intermediate 19

(R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0198] Racemic intermediate 16 (6 g, 24.79 mmol) was purified by SLC purification ( Lux Cellulose-2, 10% ethanol) of intermediate 18 (1.9 g, 7.88 mmol) and intermediate 19 (1.8 g, 7.47 mmol). Intermediate 18 is a colorless oil; [α] _D ²⁵ (c = 0.5, CHCl ₃ ) - 27.31 ^o ; MS (IER) 242.3 [M+H] ⁺ . Intermediate 19 is a colorless oil; [α] _D ²⁵ (c = 0.5, CHCl ₃ ) + 35.53 ^o ; MS (IER) 242.3 [M+H] ⁺ .

Intermediate 20

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

[0199] Intermediate 20 was prepared using the procedure described for intermediate 3 using intermediate 1 and intermediate 19. [α] _D ²⁵ (c = 0.1, CHCl ₃ ) + 17.84 ^o ; (MS) (LCMS) 384.5 [M+H] ⁺ .

Example 14

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

[0200] Step 1. (R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4- (4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure described in examples 9A and 9B , using intermediate 20 . MS (IER) 609.6 [M+H] ⁺ .

[0201] Step 2: To a stirred solution of ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-( (4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3( 2H )-one (350 mg, 0.575 mmol) in MeOH (6 ml) was added K ₂ CO ₃ (238 mg, 1.72 mmol) at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was concentrated under reduced pressure. Water (15 ml) was added and the mixture was stirred for 10 minutes. The mixture was diluted with sat. NaHCO ₃ and extracted with EtOAc (3 x 40 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (water/CH ₃ CN) to give Example 14 (220 mg, 74%) as an off-white solid. ^1H NMR (400 MHz, DMSO- d6 ) 10.25 (br. s, _1H ), 8.81 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7. 69 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.70-5.63 (m , 1H), 5.04 (s, 1H), 4.99 (d, J = 9.2 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.74 (ush .s, 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 = 7.2 Hz, 3H); MS (IER) 513.3 [M+H] ⁺ .

Intermediate 21

2-Bromo-7-(difluoromethyl)-6,7-dihydro-5H-cyclopenta[ b ]pyridin-7-ol

[0202] To a stirred solution of Me ₃ SiCF ₂ H (1.175 g, 9.48 mmol) in 1,2-DME (10 ml) was added 18-crown-6 (625 mg, 2.37 mmol) and CsF (715 mg , 4.739 mmol) at 0 °C and stirred the reaction mixture for 15 min. 2-bromo-5,6-dihydro- 7H -cyclopenta[ 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 mixture was stirred at rt for 16 hours. The reaction was determined to be complete by TLC and the reaction mixture was diluted with water (30 ml) and extracted with EtOAc (2 x 50 ml). The separated organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain the crude compound. The above reaction was repeated on a 4 x 1 g scale. The residue was purified by flash chromatography (SiO ₂ , EtOAc/petroleum ether) to give intermediate 21 (470 mg) as an off-white solid; MS (IER) 266.3 [M+H] ⁺ .

Intermediate 22

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

[0203] Intermediate 22 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 21 ; MS (IER) 406.3 [M+H] ⁺ .

Example 15A

(S)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine -1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 15B

(R)-2-Allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine -1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0204] Examples 15A and 15B were prepared using the procedure described for Examples 9A and 9B using intermediate 22 to give racemic 2-allyl-1-(7-(difluoromethyl)-7-hydroxy-6,7-dihydro -5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d] pyrimidin-3-one (120 mg). The enantiomers were separated by SLC 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 (400 MHz, DMSO- d6 ) δ 10.2 (br.s, 1H), 8.83 (s, 1H) _, 8.02 (br.s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.26 (t, J = 59.1 Hz, 1H), 6.22 (s, 1H), 5.68-5.61 (m, 1H), 4.97 (d, J = 9.9 Hz, 1H), 4.82 (d, J = 17 ,4 Hz, 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 (IER) 549.2 [M+H] ⁺ . Example 15B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.2 (br.s, 1H), 8.83 (s, 1H) _, 8.02 (br.s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.26 (t, J = 59.1 Hz, 1H), 6.22 (s, 1H), 5.68-5.61 (m, 1H), 4.97 (d, J = 9.9 Hz, 1H), 4.82 (d, J = 17 ,4 Hz, 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 (IER) 549.2 [M+H] ⁺ . For Example 15A and Example 15B, the absolute stereochemistry was arbitrary.

Intermediate 23

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

Intermediate connection 24

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

[0206] Intermediate 24 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 23 . MS (IER) 396.5 [M+H] ⁺ .

Example 16A

(R)-2-Allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine-1 -yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 16B

(S)-2-Allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazine-1 -yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0207] Examples 16A and 16B were prepared using the procedure described for Examples 2A and 2B using intermediate 24 to give racemic 2-allyl-1-(7-cyclopropyl-7-hydroxy-6,7-dihydro-5H -cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin- 3-ona (400 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, 45% (0.5% DEA in methanol)) to give peak 1 ( Example 16A , 159 mg) and peak 2 ( Example 16B , 111 mg). Example 16A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.13 (br.s, 1H), 8.82 (s, 1H), 7.92 ₍ m, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58 (m, 2H), 6.92 ( J = 7.6 Hz, 2H), 5.70-5.64 (m, 1H), 5.04 (s, 1H), 4.98 (d, J = 10 Hz, 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 (IER) 539.5 [M+H] ⁺ . Example 16B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.13 (br.s, 1H), 8.82 (s, 1H), 7.92 ₍ m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.58 (m, 2H), 6.92 ( J = 8.7 Hz, 2H), 5.70-5.64 (m, 1H), 5.04 (s, 1H), 4.98 (d, J = 9.6 Hz, 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 (IER) 539.5 [M+H] ⁺ . For Example 16A and Example 16B, the absolute stereochemistry was arbitrary.

Example 17A

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

Example 17B

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

[0208] Examples 17A and 17B were prepared using the procedure described for Examples 9A and 9B using intermediate 5 and (S)-4-(3,4-dimethylpiperazin-1-yl)aniline to give a mixture of diastereomers 2- allyl-6-((4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b ]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg). Diastereomers were separated by chiral SLC chromatography (Chiral Pak IG, (0.5% DEA in methanol:hexane (80:20)) to obtain peak 1 ( Example 17A , 130 mg) and peak 2 ( Example 17B , 75 mg). Example 17A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.1 (br.s, _1H ), 8.82 (s, 1H), 7.92 (d, J =6, 8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.57 (br.s, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5 .71-5.63 (m, 1H), 5.17 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 17.6 Hz, 1H), 4.78-4.71 (m, 1H), 4.65-4.57 (m, 1H), 3.47 (t, J = 10.8 Hz, 2H), 3.00-2 .93 (m, 1H), 2.83-2.67 (m, 3H), 2.34-2.22 (m, 5H), 2.13 (t, J = 6.8 Hz, 3H), 1.45 (s, 3H), 1.05 (d, J = 6.0 Hz, 3H); MS (ESI) 527.3 [M+H] ⁺ Example 17B - yellow solid; ¹ H NMR ( 400 MHz, DMSO- d6 ) δ 10.1 (br. s, 1H), 8.82 (s, 1H), _7.93 (d, J = 7.2 Hz, 1H), 7.68 (d , J = 8.8 Hz, 1H), 7.57 (br. s, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.71-5.63 (m, 1H) , 5.17 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 6.0 Hz, 3H); MS (IER) 527.3 [M+H] ⁺ . For Example 17A and Example 17B, the absolute stereochemistry was arbitrary.

Example 18A

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

Example 18B

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

[0209] Examples 18A and 18B were prepared using the procedure described for Examples 9A and 9B using intermediate 5 and (R)-4-(3,4-dimethylpiperazin-1-yl)aniline to produce a mixture of diastereomers 2- allyl-6-((4-((R)-3,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b ]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. Diastereomers were separated by chiral SLC chromatography (Chiralpak AD-H, 20.0% (0.5% DEA in methanol)) to obtain peak 1 ( Example 18A , 94 mg) and peak 2 ( Example 18B , 85 mg). Example 18A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.09 (br. s, _1H ), 8.81 (s, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7 .68 (d, J = 8.0 Hz, 1H), 7.57 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.71-5.62 (m, 1H), 5.16 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 16.8 Hz, 1H), 4.78-4, 55 (m, 2H), 3.47 (t, J = 10.4 Hz, 2H), 3.31-2.93 (m, 1H), 2.83-2.67 (m, 3H), 2 .36-2.11 (m, 8H), 1.45 (s, 3H), 1.05 (d, J = 5.6 Hz, 3H); MS (IER) 527.3 [M+H] ⁺ . Example 18B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.10 (br. s, _1H ), 8.82 (s, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7 .68 (d, J = 8.0 Hz, 1H), 7.57 (m, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.72-5.62 (m, 1H), 5.16 (s, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 16.8 Hz, 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 (IER) 527.3 [M+H] ⁺ . For Example 18A and Example 18B , the absolute stereochemistry of the tertiary alcohol was arbitrarily assigned.

Example 19A

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

Example 19B

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

[0210] Examples 19A and 19B were prepared using the procedure described for Examples 9A and 9B using intermediate 5 and (S)-4-(2,4-dimethylpiperazin-1-yl)aniline to give a mixture of diastereomers 2- allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b ]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). Diastereomers were separated by chiral SLC chromatography (Chiralpak AD-H, 25.0% (0.5% DEA in MeOH)) to give peak 1 ( Example 19A , 158 mg) and peak 2 ( Example 19B , 103 mg). Example 19A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.1 (br. s, _1H ), 8.82 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7 .69 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.88 (d, J = 9.2 Hz, 2H), 5.71-5.63 ( m, 1H), 5.18 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 6.8 Hz, 3H), 1.45 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H); MS (IER) 527.3 [M+H] ⁺ . Example 19B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.1 (br. s, 1H), 8.82 (s, 1H), 7.92 ₍ d, J = 7.2 Hz, 1H), 7 .69 (d, J = 8.0 Hz, 1H), 7.57 (br. s, 2H), 6.88 (d, J = 8.0 Hz, 2H), 5.71-5.64 ( m, 1H), 5.18 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.2 Hz, 3H), 1.45 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H); MS (IER) 527.2 [M+H] ⁺ . For Example 19A and Example 19B , the absolute stereochemistry of the tertiary alcohol was arbitrarily assigned.

Example 20A

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

Example 20B

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

[0211] Examples 20A and 20B were prepared using the procedure described for Examples 9A and 9B using intermediate 5 and (R)-4-(2,4-dimethylpiperazin-1-yl)aniline to produce a mixture of diastereomers 2- allyl-6-((4-((R)-2,4-dimethylpiperazin-1-yl)phenyl)amino)-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b ]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (400 mg). Diastereomers were separated by chiral SLC chromatography (Chiralpak AD-H, 20.0% (0.5% DEA in MeOH)) to obtain peak 1 ( Example 20A , 170 mg) and peak 2 ( Example 20B , 170 mg). Example 20A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.1 (br. s, _1H ), 8.82 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7 .69 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.71-5.63 ( m, 1H), 5.18 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.2 Hz, 3H), 1.45 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H); MS (IER) 527.2 [M+H] ⁺ . Example 20B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.1 (br. s, _1H ), 8.82 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7 .69 (d, J = 8.4 Hz, 1H), 7.57 (br. s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.71-5.63 ( m, 1H), 5.18 (s, 1H), 4.99 (d, J = 10 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.2 Hz, 3H), 1.45 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H); MS (IER) 527.3 [M+H] ⁺ . For Example 20A and Example 20B , the absolute stereochemistry of the tertiary alcohol was arbitrarily assigned.

Intermediate 25

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

[0212] A suspension of anhydrous CeCl ₃ (17.5 g, 71.08 mmol) in THF (100 ml) was stirred at rt for 1 hour and cooled to -78 °C. Add 1.6 M MeLi in DEE (44 mL, 71.08 mmol) at -78 °C and stir the reaction mixture for 30 min. To this was added a solution of 6-bromo-2,3-dihydro- 1H -inden-1-one (10 g, 47.39 mmol) in THF (100 ml) at -78 °C. The ice bath was removed and the reaction mixture was stirred at rt for 2 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with aq. NH ₄ Cl (200 ml). The mixture was extracted with EtOAc (2 x 200 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give intermediate 25 (6 g, 55%) as a colorless oil. ^1H NMR (400 MHz, DMSO- d6 ) δ 7.43 (d, J = 2.0 Hz _, 1H), 7.35 (dd, J = 8.0, 2.0 Hz, 1H), 7 .16 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H) 2.89-2.81 (m, 1H), 2.75-2.66 (m, 1H), 2 .07 (t, J = 4.4 Hz, 2H), 1.40 (s, 3H).

Intermediate 26

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

[0213] Intermediate 26 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 25 . MS (IER) 369.4 [M+H] ⁺ .

Example 21A

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

Example 21B

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

[0214] Examples 21A and 21B were prepared using the procedure described for Examples 2A and Examples 2B using intermediate 26 to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydro- 1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3- she (350 mg). Enantiomers were separated by chiral SLC 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 (400 MHz, DMSO- d6 ) δ 10.03 (br.s, 1H), 8.79 (s, 1H), 7.54 (br.s _, 2H), 7.38-7, 34 (m, 2H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (d, J = 9.2 Hz, 2H), 5.68-5.62 (m, 1H), 5.15 (s, 1H), 5.09 (d, J = 9.6 Hz, 1H), 4.93 (d, J = 17.6 Hz, 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 = 6.8 Hz, 2H), 1.43 (s, 3H); MS (IER) 512.3 [M+H] ⁺ . Example 21B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.03 (br.s, 1H), 8.79 (s, 1H), 7.54 (br.s _, 2H), 7.38-7, 34 (m, 2H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (d, J = 9.2 Hz, 2H), 5.68-5.62 (m, 1H), 5.15 (s, 1H), 5.09 (d, J = 9.6 Hz, 1H), 4.93 (d, J = 17.6 Hz, 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 = 6.8 Hz, 2H), 1.43 (s, 3H); MS (IER) 512.3 [M+H] ⁺ . For Example 21A and Example 21B, the absolute stereochemistry was arbitrary.

Intermediate 27

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

[0215] To a stirred solution of 6-bromo-2,3-dihydro- 1H -inden-1-one (5.0 g, 23.68 mmol) in toluene (50 mL), EtMgBr (23.70 mL) was added dropwise , 71.07 mmol) at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. The reaction was quenched with sat. aq. NH ₄ Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (SiO ₂ , 20% EtOAc/petroleum ether) to give intermediate 27 (4 g, 70%) as a colorless liquid. MS (ESI) 223.1 [M+HH ₂ O] ⁺ .

Intermediate 28

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

[0216] Intermediate 28 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 27 . MS (IER) 383.4 [M+H] ⁺ .

Example 22A

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

Example 22B

(R)-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

[0217] Examples 22A and 22B were prepared following the procedure described for Examples 9A and 9B using intermediate 28 to give racemic 2-allyl-1-(3-ethyl-3-hydroxy-2,3-dihydro- 1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (340 mg). Enantiomers were separated by chiral SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.01 (br.s, 1H), 8.79 (s, 1H), 7.55 (br.s _, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 6.8 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 5.71-5.62 ( m, 1H), 5.08 (d, J = 10.4 Hz, 1H), 5.02 (s, 1H), 4.92 (d, J = 17.2 Hz, 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 = 7.6 Hz, 3H); MS (IER) 526.2 [M+H] ⁺ . Example 22B . ^1H NMR (400 MHz, DMSO- d6 ) δ 10.01 (br.s, 1H), 8.79 (s, 1H), 7.55 (br.s _, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 6.8 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 5.67-5.63 ( m, 1H), 5.09 (d, J = 10.4 Hz, 1H), 5.02 (s, 1H), 4.92 (d, J = 17.2 Hz, 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 = 7.6 Hz, 3H); MS (IER) 526.3 [M+H] ⁺ . For Example 22A and Example 22B, the absolute stereochemistry was arbitrary.

Example 23A

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

Example 23B

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

[0218] Examples 23A and 24B were prepared using the procedure described for Examples 9A and 9B using intermediate 26 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline to give racemic 2-allyl-1 -(3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1 ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (635 mg). The enantiomers were separated by SLC chromatography (Chiral Pak AD-H, 40% (0.5% isopropylamine in isopropyl alcohol)) to give peak 1 ( Example 23A , 223 mg) and peak 2 ( Example 23B , 223 mg). Example 23A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.00 (br. s, _1H ), 8.81 (s, 1H), 7.47-7.29 (m, 5H), 6.93 ( d, J = 8.4 Hz, 1H), 5.71-5.64 (m, 1H), 5.14 (s, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.93 (d, J = 17.2 Hz, 1H), 4.25 (br. s, 2H), 2.99-2.91 (m, 1H), 2.85-2.76 (m, 5H), 2.45 (br. s, 4H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12-2.09 (m, 2H), 1.42 (s , 3H); MS (IER) 526.3 [M+H] ⁺ . Example 23B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.00 (br. s, _1H ), 8.81 (s, 1H), 7.47-7.29 (m, 5H), 6.93 ( d, J = 8.4 Hz, 1H), 5.71-5.64 (m, 1H), 5.14 (s, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.93 (d, J = 17.2 Hz, 1H), 4.25 (br. s, 2H), 2.99-2.91 (m, 1H), 2.85-2.76 (m, 5H), 2.45 (br. s, 4H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12-2.09 (m, 2H), 1.42 (s , 3H); MS (IER) 526.7 [M+H] ⁺ . For Example 23A and Example 23B, the absolute stereochemistry was arbitrary.

Intermediate 29

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

[0219] Step 1: 6-Bromo-4-fluoro-2,3-dihydro-1H-inden-1-one was prepared according to WO Publication No. 2005/095387. ^1H NMR (400 MHz, CDCl3- d6 ) δ 7.70 (s, 1H) _, 7.42 (d, J = 9.6 Hz, 1H), 3.10 (t, J = 6.0 Hz , 2H), 2.75 (t, J = 6.4 Hz, 2H).

[0220] Step 2: To a solution of 6-bromo-4-fluoro-2,3-dihydro- 1H -inden-1-one (6 g, 26 mmol) in diethyl ether (60 ml) at 0 °C dropwise add a 3.0 M solution of MeMgBr in DEE (87 ml, 262 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with water (50 ml) and extracted using EtOAc (2 x 100 ml). The combined organic layers were washed with water (150 ml), brine (150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ , 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. ^1H NMR (400 MHz, CDCl3) δ 7.28 (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).

Intermediate 30

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

[0221] Intermediate 30 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 29 . MS (IER) 387.3 [M+H] ⁺ .

Example 24A

(S)-2-Allyl-1-(7-fluoro-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

Example 24B

(R)-2-Allyl-1-(7-fluoro-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

[0222] Examples 24A and 24B were prepared following the procedure described for Examples 9A and 9B using intermediate 30 to give racemic 2-allyl-1-(7-fluoro-3-hydroxy-3-methyl-2. 3-dihydro-1H-inden-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine -3-one (165 mg). The enantiomers were separated by SLC chromatography (Chiral Pak AD-H, 30% (0.5% isopropylamine in isopropyl alcohol)) to give peak 1 ( Example 24A , 43 mg) and peak 2 ( Example 24B , 47 mg). Example 24A - yellow solid; 1H NMR (400 MHz, DMSO- d6 ) δ 10.10 (br.s, 1H), 8.81 (s, 1H) _, 7.55 (br.s, 2H), 7.21 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 5.71-5.64 (m, 1H), 5.31 (s, 1H), 5.09 (d, J = 10.8 Hz, 1H), 4.96 (d, J = 17.2 Hz, 1H), 4.28 (br.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 (IER) 530.3 [M+H] ⁺ . Example 24B is a yellow solid; 1H NMR (400 MHz, DMSO- d6 ) δ 10.10 (br.s, 1H), 8.81 (s, 1H) _, 7.55 (br.s, 2H), 7.21 (d, J = 9.6 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 5.71-5.64 (m, 1H), 5.31 (s, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.96 (d, J = 16.8 Hz, 1H), 4.28 (br. 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 (IER) 530.3 [M+H] ⁺ . ] ⁺ . For Example 24A and Example 24B, the absolute stereochemistry was arbitrary.

Intermediate 31

2-Bromo-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol

[0223 ] Step ₁ : TMS-Br ( 2.86 g, 18.78 mmol) and heated the reaction mixture at 150 °C in a CEM microwave oven for 20 min. After completion of the reaction, confirmed by TLC, the reaction mixture was diluted with DCM (100 ml) and washed with aq. NaHCO ₃ (50 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO ₂ , 20% EtOAc/petroleum ether) to give 2-bromo-6,7-dihydroquinolin-8(5H)-one (1.2 g, 57%) as a brown oil . MS (IER) 226.3 [M+H].

[0224] Step 2: To a solution of 2-bromo-6,7-dihydroquinolin-8( 5H )-one (1.20 g, 5.33 mmol) in DEE (30 ml) at 0 °C, add 3 .0 M solution of CH ₃ MgI in DEE (8.88 ml, 26.65 mmol). The mixture was allowed to warm to rt and stirred for 16 hours. After completion of the reaction, confirmed by TLC, the reaction was quenched with water (25 ml) and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO ₂ , 20% EtOAc/petroleum ether) to give intermediate 31 (900 mg, 70%) as an off-white solid. MS (IER) 241.9 [M+H] ⁺ .

Intermediate 32

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

[0225] Intermediate 32 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 31 . MS (IER) 384.1 [M+H] ⁺ .

Example 25A

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

Example 25B

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

[0226] Examples 25A and 25B were prepared using the procedure described for Examples 2A and 2B using intermediate 32 to give racemic 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8 -tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (450 mg). Enantiomers were separated by chiral SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.04 (br. s, _1H ), 8.81 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7 .69 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.72 -5.61 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.89 (s, 1H), 4.84 (s, 1H), 4.81 (br. s, 1H), 4.65 (dd, J = 16.0, 5.2 Hz, 1H), 3.14-3.07 (m, 4H), 2.83-2.75 (m, 2H) , 2.49-2.43 (m, 4H), 2.23 (s, 3H), 1.98-1.87 (m, 2H), 1.82 (d, J = 10.8 Hz, 1H ), 1.77-1.68 (m, 1H), 1.49 (s, 3H); MS (IER) 527.3 [M+H] ⁺ . Example 25B is a yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.04 (br. s, _1H ), 8.81 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7 .69 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.71 -5.61 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.89 (s, 1H), 4.84 (s, 1H), 4.81 (s, 1H), 4.66 (dd, J = 15.6, 5.2 Hz, 1H), 3.09 (s, 4H), 2.86-2.72 (m, 2H), 2.47-2 .44 (m, 4H), 2.22 (s, 3H), 1.96-1.93 (m, 2H), 1.83-177 (m, 1H), 1.73-1.70 (m , 1H), 1.49 (s, 3H); MS (IER) 527.3 [M+H] ⁺ . For Example 25A and Example 25B, the absolute stereochemistry was arbitrary.

Intermediate 33

2-Bromo-8-ethyl-5,6,7,8-tetrahydroquinolin-8-ol

[0227] To a solution of 2-bromo-6,7-dihydroquinolin-8( 5H )-one (2.00 g, 8.88 mmol) in diethyl ether (40 ml) at 0 °C, add 3.0 M solution of EtMgBr in DEE (14.82 ml, 44.44 mmol). The ice bath was removed and the mixture was allowed to warm to rt and stirred for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with water (50 ml) and extracted using EtOAc (2 x 30 ml). The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO ₂ , 10% EtOAc/petroleum ether) to give intermediate 33 (900 mg, 40%) as a pale yellow oil. MS (IER) 256.2 [M+H] ⁺ .

Intermediate 34

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

[0228] Intermediate 34 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 33 . MS (IER) 398.0 [M+H] ⁺ .

Example 26A

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

Example 26B

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

[0229] Examples 26A and 26B were prepared using the procedure described for Examples 2A and 2B using intermediate 34 to give racemic 2-allyl-1-(8-ethyl-8-hydroxy-5,6,7,8 -tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (600 mg). Enantiomers were separated by chiral SLC 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 is a yellow solid. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.11 (br. s, _1H ), 8.81 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7 .69 (d, J = 7.8 Hz, 1H), 7.60-7.54 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.70-5, 61 (m, 1H), 4.99 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 (IER) 541.3. Example 26B is a yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.11 (br. s, _1H ), 8.81 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7 .69 (d, J = 7.8 Hz, 1H), 7.60-7.54 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.70-5, 61 (m, 1H), 4.99 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 (IER) 541.3 [M+H] ⁺ . For Example 26A and Example 26B, the absolute stereochemistry was arbitrary.

Example 27A

(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

Example 27B

(R)-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

[0230] Examples 27A and 27B were prepared using the procedure described for Examples 2A and 2B using intermediate 32 and 3-methyl-4-(4-methylpiperazin-1-yl)aniline to give racemic 2-allyl-1 -(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1 ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (800 mg). Enantiomers were separated by chiral SLC 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 (400 MHz, DMSO- d6 ) δ 10.12 (br. s, _1H ), 8.84 (s, 1H), 7.75-7.67 (m, 3H), 7.39 ( d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.71-5.61 (m, 1H), 4.98 (d, J = 10 Hz, 1H), 4.89 (d, J = 8.4 Hz, 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 (IER) 541.2 [M+H] ⁺ . Example 27B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.12 (br. s, _1H ), 8.84 (s, 1H), 7.75-7.67 (m, 3H), 7.39 ( d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.71-5.61 (m, 1H), 4.98 (d, J = 10 Hz, 1H), 4.89 (d, J = 8.4 Hz, 2H), 4.84-4.80 (m, 1H), 4.67-4.61 (m, 1H), 2.85 -2.67 (m, 6H), 2.52-2.48 (m, 4H), 2.25-2.24 (m, 6H), 1.96-1.92 (m, 2H), 1 .83-1.70 (m, 2H), 1.49 (s, 3H); MS (IER) 541.2 [M+H] ⁺ . For Example 27A and Example 27B, the absolute stereochemistry was arbitrary.

Example 28A

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

Example 28B

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

[0231] 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 according to the procedure described in Examples 9A and 9B , using the intermediate connections 32 . MS (IER) 609.5 [M+H] ⁺ .

[0232] Step 2: To a solution of 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-(2, 2,2-Trifluoroacetyl)piperazin-1-yl)phenyl)amino) -1H -pyrazolo[3,4- d ]pyrimidin-3( 2H )-one (400 mg, 0.66 mmol) in MeOH (6 ml) at 0 °C, K ₂ CO ₃ (272 mg, 1.97 mmol) was added. The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was concentrated under reduced pressure. Water (10 ml) was added and the mixture was stirred for 10 minutes. 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). Enantiomers were separated by chiral SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.10 (br. s, 1H), 8.81 (s, 1H), 7.76 ₍ d, J = 8.4 Hz, 1H), 7 .69 (d, J = 8.4 Hz, 1H), 7.56 (br. s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.69-5.62 ( m, 1H), 4.98 (d, J = 10.0 Hz, 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 (IER) 513.3 [M+H] ⁺ . Example 28B is a yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.09 (br. s, _1H ), 8.81 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7 .69 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.71 -5.621 (m, 1H), 4.98 (d, J = 9.2 Hz, 1H), 4.88 (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 (IER) 513.3 [M+H] ⁺ . For Example 28A and Example 28B, the absolute stereochemistry was arbitrary.

Intermediate 35

1-(7'-amino-1'H-spiro[cyclopropan-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethan-1-one

[0233] Step 1: 7'-Nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] was prepared in accordance with US Publication No. 7,507,748.

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

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

Example 29A

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

Example 29B

(R)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)amino)-1-(7-hydroxy -7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4'-d]pyrimidin-3-one

[0236] Step 1. 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((2'-(2, 2,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin-3-one was prepared according to the procedure described in Examples 9A and 9B using intermediate 5 and intermediate 35 . MS (IER) 592.4 [M+H] ⁺ .

[0237] Step 2: To a solution of 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-6-((2'- (2,2,2-trifluoroacetyl)-2',3'-dihydro- 1'H -spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one (135 mg, 0.23 mmol) in MeOH (6 ml) at 0 °C was added K ₂ CO ₃ (94 mg, 0.68 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was concentrated under reduced pressure. Water (10 ml) was added to the crude compound and stirred for 10 minutes. The precipitate was filtered and dried under vacuum to give racemic 2-allyl-6-((2',3'-dihydro- 1'H -spiro[cyclopropan-1,4'-isoquinolin]-7'-yl)amino)-1 -(7-hydroxy-7-methyl-6,7-dihydro-5 H -cyclopenta[ b ]pyridin-2-yl)-1,2-dihydro-3 H -pyrazolo[3,4- d ]pyrimidin-3 -one (85 mg) in the form of an off-white solid. Enantiomers were separated by chiral SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) 10.16 (br. s, _1H ), 8.85 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7. 70 (d, J = 8.4 Hz, 1H), 7.55 (br.s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8 .4 Hz, 1H), 5.71-5.63 (m, 1H), 5.18 (s, 1H), 4.99 (d, J = 9.6 Hz, 1H), 4.85 (d , J = 17.6 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.60 (dd, J = 16.4 Hz, 6.0 Hz, 1H), 3, 91 (s, 2H), 3.03-2.94 (m, 1H), 2.87-2.72 (m, 3H), 2.13 (t, J = 6.8 Hz, 2H), 1 .45 (s, 3H), 0.88 (s, 2H), 0.77 (s, 2H). MS (IER) 496.2 [M+H] ⁺ . Example 29B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) 10.16 (br. s, _1H ), 8.85 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7. 70 (d, J = 8.4 Hz, 1H), 7.55 (br.s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8 .4 Hz, 1H), 5.71-5.63 (m, 1H), 5.18 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.85 (d , J = 18 Hz, 1H), 4.74 (d, J = 14 Hz, 1H), 4.60 (dd, J = 16 Hz, 5.2 Hz, 1H), 3.91 (s, 2H) , 3.01-2.96 (m, 1H), 2.84-2.67 (m, 3H), 2.13 (t, J = 6.8 Hz, 2H), 1.45 (s, 3H ), 0.88 (s, 2H), 0.77 (s, 2H). MS (IER) 496.2 [M+H] ⁺ . For Example 29A and Example 29B, the absolute stereochemistry was arbitrary.

Intermediate 36

tert-Butyl-7'amino-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate

[0238] Step 1: To a stirred solution of 7'-nitro-2',3'-dihydro-1' H -spiro[cyclopropane-1,4'-isoquinoline] (3 g, 14.63 mmol) in 1.4 -dioxane: H ₂ O (45 ml, 2: 1) was added 1 N NaOH (15 ml) at 0 °C. After 5 min. di- tert -butyl dicarbonate (3.7 mL, 16.91 mmol) was added at 0 °C and the reaction mixture was stirred at rt for 2 h. The reaction mixture was acidified with KHSO ₄ (pH: 2-3), then the mixture was extracted ethyl acetate (2 x 100 ml). The combined organic layers were washed with water (25 ml), dried (Na ₂ SO ₄ ) and concentrated. The resulting crude mixture was purified by column chromatography (SiO2 _, 20% EA/pet. ether) to give tert -butyl 7'-nitro-1'H - spiro[cyclopropane-1,4'-isoquinoline]-2'(3' H )-carboxylate (2.5 g, 56%) as a yellow solid. MS (LCMS) 249.0 [MC ₄ H ₁₀ ] ⁺ .

[0239] Step 2: To a stirred solution of tert -butyl 7'-nitro- 1'H -spiro[cyclopropane-1,4'-isoquinoline]-2'( 3'H )-carboxylate (1.0 g, 3. 28 mmol) in EtOH (50 ml) was added SnCl ₂ (3.74 g, 19.67 mmol), followed by NH ₄ Cl (1.04 g, 19.67 mmol) at rt. The reaction mixture was stirred at 70 °C for 1 h. After completion of the reaction, confirmed by LCMS, the crude reaction mixture was concentrated under reduced pressure, diluted with water (50 ml) and made basic with saturated NaHCO ₃ solution (pH: 8-9). The mixture was filtered through a celite pad and extracted using 30% MeOH:DCM (3 x 100 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give intermediate 36 (615 mg, 93%) as an off-white solid. (MS) (LCMS) 275.4 [M+H] ⁺ .

Intermediate connection 37A

tert-Butyl (S)-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3- oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H) -carboxylate

Intermediate connection 37B

tert-Butyl (R)-7'-((2-allyl-1-(7-hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3- oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H) -carboxylate

[0240] Examples 37A and 37B were prepared using the procedure described for Examples 2A and 2B using intermediate 7 and intermediate 36 to give racemic tert-butyl-7'-((2-allyl-1-(7- Hydroxy-7-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6 -yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'( 3'H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'( 3'H- spiro[cyclopropane-1,4 '-isoquinoline]-2'( 3'H )-carboxylate (364 mg) Enantiomers were separated by chiral SLC 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 ] ⁺ For intermediate 37A and intermediate 37B, the absolute stereochemistry was arbitrary.

Example 30A

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

[0241] To a stirred solution of intermediate 37A (140 mg, 0.22 mmol) in DCM (4 ml) was added 2 M HCl in Et ₂ O (1 ml) at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to give Example 30A (60 mg, 50%) as the HCl salt after drying under high vacuum. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.38 (br.s, 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 = 15.4 Hz, 1H), 4.81-4, 77 (m, 2H), 4.60-4.55 (m, 1H), 4.43-4.33 (m, 2H), 3.26 (br. s, 1H), 3.13-2, 94 (m, 2H), 2.67-2.56 (m, 2H), 2.33-2.23 (s, 1H), 1.09 (s, 4H); MS (IER) 550.5 [M+H] ⁺ .

Example 30B

[0242] Example 30B was prepared according to the procedure described for Example 30A as the hydrochloride salt. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.38 (br.s, 1H), _9.4 (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 = 15.4 Hz, 1H), 4.81-4, 77 (m, 2H), 4.60-4.55 (m, 1H), 4.43-4.33 (m, 2H), 3.26 (br. s, 1H), 3.13-2, 94 (m, 2H), 2.67-2.56 (m, 2H), 2.33-2.23 (s, 1H), 1.09 (s, 4H); MS (IER) 550.5 [M+H] ⁺ . For Example 30A and Example 30B, the absolute stereochemistry was arbitrary.

Example 31A

(S)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)amino)-1-(8-hydroxy -8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4'-d]pyrimidin-3-one

Example 31B

(R)-2-Allyl-6-((2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)amino)-1-(8-hydroxy -8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4'-d]pyrimidin-3-one

[0243] Step 1. 2-Allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((2'-(2,2,2- trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d ]pyrimidin-3-one (364 mg, 26%) was prepared according to the procedure described in Examples 2A and 2B using intermediate 32 and intermediate 35 . MS (IER) 606.4 [M+H] ⁺ .

[0244] Step 2: To a stirred solution of 2-allyl-1-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((2'-(2,2 ,2-trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3, 4-d]pyrimidin-3-one (400 mg, 0.66 mmol) in MeOH (12 ml), K ₂ CO ₃ (183 mg, 1.32 mmol) was added and the reaction mixture was stirred at rt for 16 hours. completion of the reaction, confirmed by TLC, the solvent was evaporated. The reaction mixture was diluted with water (20 ml) and extracted with 10% MeOH in DCM (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 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-tetrahydroquinolin-2-yl)-1,2-dihydro- 3H -pyrazolo[3,4 - d ]pyrimidin-3-one (310 mg) as a pale yellow solid. Enantiomers were separated by chiral SLC chromatography (Chiralpak AD-H, (0.5% isopropylamine in IPA)) to give peak 1 ( Example 31A , 120 mg) and peak 2 ( Example 31B , 123 mg). Example 31A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.15 (br. s, _1H ), 8.85 (s, 1H), 7.75-7.69 (m, 2H), 7.56 ( br.s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.71-5.61 (m, 1H ), 4.99 (d, J = 9.2 Hz, 1H), 4.90-4.81 (m, 3H), 4.67-4.62 (dd, J = 16 Hz, J = 6, 0 Hz, 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 (IER) 510.2 [M+H] ⁺ . Example 31B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.15 (br. s, _1H ), 8.85 (s, 1H), 7.75-7.69 (m, 2H), 7.56 ( br.s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.70-5.63 (m, 1H ), 4.99 (d, J = 9.2 Hz, 1H), 4.89-4.80 (m, 3H), 4.67-4.62 (dd, J = 16 Hz, J = 5, 6 Hz, 1H), 3.92 (s, 2H), 2.86-2.74 (m, 4H), 1.96-1.92 (m, 2H), 1.84-1.78 (m , 1H), 1.73-1.71 (m, 1H), 1.49 (s, 3H), 0.88 (s, 2H), 0.78 (s, 2H); MS (IER) 510.2 [M+H] ⁺ . For Example 31A and Example 31B, the absolute stereochemistry was arbitrary.

Intermediate 38

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

[0245] Step 1: 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine was synthesized according to the procedure described in WO 2016138821.

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

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

Intermediate 39

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

[0248] Intermediate 39 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 38 . The mixture was degassed for 20 min and then heated in a microwave oven at 100 °C for 2 h. MS (ESI) 345.5 [M+H] ⁺ .

Example 32

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

[0249] Example 32 (5 mg) was prepared using the procedure described for Examples 2A and 2B using intermediate 39 . ^1H NMR (400 MHz, DMSO- d6 ) δ 9.94 (s, 1H), _8.77 (s, 1H), 7.53-7.48 (m, 3H), 6.86 (d, J = 8.8 Hz, 1H), 5.76 (s, 1H), 5.73-5.71 (m, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5, 03 (d, J = 17.6 Hz, 1H), 4.71 (s, 2H), 4.24 (s, 2H), 4.10-4.05 (m, 4H), 3.06 (t , J = 4.4 Hz, 4H), 2.50-2.42 (m, 4H), 2.21 (s, 3H); MS (ESI) m/z 488.2 [M+H] ⁺ .

Intermediate 40

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

[0250] Step 1: To a stirred solution of methyl 6-chloro-3-methylpicolinate (10 g, 54 mmol) in CH ₃ CN (50 ml) was added NaI (40 g, 270 mmol) followed by TMS-Cl (36 ml, 270 mmol) at ct. The reaction mixture was refluxed for 8 hours. After completion of the reaction, confirmed by TLC, the solvent was evaporated, the residue was diluted with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 50% EtOAc/petroleum ether) to give 6-iodo-3-methylpicolinic acid (8 g, 57%) as an off-white solid. ^1H NMR (300 MHz, DMSO- d6 ) δ 13.50 (br. s, 1H), _7.72 (d, J = 3 Hz, 2H), 2.41 (s, 3H).

[0250] Step 2: To a stirred solution of 6-iodo-3-methylpicolinic acid (8 g, 30 mmol) in MeOH (80 mL), add H ₂ SO ₄ (4.8 mL, 91 mmol) dropwise at 0 °C . The ice bath was removed and the mixture was stirred under reflux for 12 hours. After completion of the reaction, confirmed by TLC, the solvent was evaporated and the residue was diluted with water (100 ml). The pH was adjusted to 9 with saturated NaHCO ₃ solution and the reaction mixture was extracted using EtOAc (3 x 50 ml). The combined extracts were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 20% EtOAc/petroleum ether) to give methyl 6-iodo-3-methylpicolinate (7 g, 83%) as a pale yellow solid. MS (IER) 278.3 [M+H] ⁺ .

[0252] Step 3: To a stirred solution of methyl 6-iodo-3-methylpicolinate (8.5 g, 30 mmol) in CCl ₄ (100 ml) was added NBS (7.1 g, 39 mmol), AIBN (492 mg , 3 mmol). The reaction mixture was heated at 65 °C for 16 h. After completion of the reaction, confirmed by TLC, the solvent was evaporated and the residue was suspended in water (100 ml). The mixture was extracted with DCM (3 x 50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 15% EtOAc/petroleum ether) to give methyl 3-(bromomethyl)-6-iodopicolinate (4.31 g, 40%) as a brown liquid. MS (IER) 356.1 [M+H] ⁺ .

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

Intermediate 41

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

[0254] Intermediate 41 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 40 . 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] ⁺ .

Example 33

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

[0255] Example 33 (150 mg) was prepared using the procedure described for Examples 2A and 2B using intermediate 41 . ^1H NMR (400 MHz, DMSO- d6 ) δ 10.11 (s, 1H), 8.85 (s, 1H), 8.33 ₍ d, J = 7.2 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.58 (br. s, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.73-5.66 (m, 1H) , 5.00 (d, J = 10 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 (IER) 512.3 [M+H] ⁺ .

Intermediate 42

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

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

Intermediate 43

2-Allyl-1-(6-(tert-butyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-6-(methylthio)-1, 2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0257] Intermediate 43 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 42 . The mixture was degassed for 20 min and then heated in a microwave oven at 100 °C for 2 h. MS (ESI) 411.14 [M+H] ⁺ .

Example 34

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

[0258] 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 according to the procedure described inexamples 2A And2B, usingintermediate connection 43. MS (IER) 554.0 [M+H]⁺.

[0259] Step 2: To a stirred solution of 2-allyl-1-(6-(tert-butyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl) -6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (150 mg, 7.05 mmol ) trifluoromethanesulfonic acid (0.7 ml) was added at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 2 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was neutralized with NaHCO ₃ and extracted using EtOAc (3 x 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H ₂ O/CH ₃ CN gradient) to give Example 34 (10 mg) as an off-white solid. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.20 (br.s, 1H) _, 9.09 (br.s, 1H), 8.85 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.58 (br. s, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.74-5.67 (m, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.80 (d, J = 18.0 Hz, 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 (IER) 498.2 [M+H] ⁺ .

Intermediate 44

5-Bromo-3-methyl-2,3-dihydrofuro[2,3-b]pyridin-3-ol

[0260] Step 1: To a stirred solution of ethyl 2-hydroxyacetate (27.67 g, 266.14 mmol) in DME (200 mL) was added portionwise 60% NaH (8.744 g, 380.2 mmol) at 0°. The ice bath was removed and the reaction mixture was stirred for 30 minutes. Ethyl 5-bromo-2-chloronicotinate (20 g, 76.04 mmol) was added and the reaction mixture was refluxed for 16 hours. After completion of the reaction as confirmed by TLC, 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 x 80 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give ethyl 5-bromo-3-oxo-2,3-dihydrofuro[2,3- b ]pyridine-2-carboxylate (8.5 g, 30%) in the form of an off-white solid. MS (IER) 285.9 [M+H] ⁺ .

[0261] Step 2: Mixture of ethyl 5-bromo-3-oxo-2,3-dihydrofuro[2,3- b ]pyridine-2-carboxylate (9 g, 31.57 mmol) and 50% aqueous H ₂ solution SO ₄ (90 ml) was heated to 60 °C and stirred for 16 hours. After completion of the reaction, confirmed 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), brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 5-bromofuro[2,3- b ]pyridine-3( 2H ) -ona (4.5 g, 66%) as a pale brown solid. MS (IER) 213.8 [M+H] ⁺ .

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

Intermediate 45

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

[0263] Intermediate 45 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 44 . The mixture was degassed for 20 min and then heated in a microwave oven at 100 °C for 6 h. MS (ESI) 372.4 [M+H] ⁺ .

Example 35A

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

Example 35B

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

[0264] Examples 35A and 35B were prepared using the procedure described for Examples 2A and Examples 2B using intermediate 45 to give racemic 2-allyl-1-(3-hydroxy-3-methyl-2,3-dihydrofuro[0264] 2,3-b]pyridin-5-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine -3-one (150 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, (35.0% (0.5% isopropylamine in IPA)) to give peak 1 ( Example 35A , 48 mg) and peak 2 ( Example 35B , 46 mg) Example 35A - yellow solid, ^1H NMR (400 MHz, DMSO- d6 ) δ 10.30 (br.s, 1H) _, 8.81 (s, 1H), 8.18 (d, J =2 .4 Hz, 1H), 7.83 (br. s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.83 (s, 1H), 5.73-5.64 (m, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.97 (d, J = 17.2 Hz , 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 H NMR (400 MHz, DMSO- d ₆ ) δ 10.04 (br.s, 1H), 8.81 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.83 (br.s, 1H), 7 .49 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.83 (s, 1H), 5.74-5.65 (m, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.97 (d, J = 17.2 Hz, 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 (IER) 515.2 [M+H] ⁺ . For Example 35A and Example 35B, the absolute stereochemistry was arbitrary.

Intermediate 46

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

[0265] Step 1: 5,6-Dihydro-7H-pyrrolo[1,2-a]imidazol-7-one was prepared in accordance with US Publication No. 2012/0214762.

[0266] Step 2: To a solution of 5,6-dihydro- 7H -pyrrolo[1,2- a ]imidazol-7-one (15 g, 123.0 mmol) in THF (150 ml) at 0 °C 3M MeMgBr (49 mL, 147.0 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at rt for 5 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with sat. NH ₄ Cl solution at 0 °C. The mixture was extracted with 10% MeOH/DCM (2 x 200 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 3% MeOH/DCM) to give 7-methyl-6,7-dihydro- 5H -pyrrolo[1,2- a ]imidazol-7-ol (5.1 g, 30%) as a yellow solid. MS (IER) 139.1 [M+H] ⁺ .

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

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

Intermediate 47

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

[0269] Intermediate 47 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 46 . MS (IER) 359.1 [M+H] ⁺ .

Example 36A

(S)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4 -methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 36B

(R)-2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4 -methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0270] Examples 36A and 36B were prepared using the procedure described for Examples 2A and Examples 2B using intermediate 47 to give racemic 2-allyl-1-(7-hydroxy-7-methyl-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3, 4-d]pyrimidin-3-one (250 mg). Enantiomers were separated by chiral SLC 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; ^1H NMR (400 MHz, DMSO- d6 ) δ 9.92 (br. s, 1H), 8.77 (s, 2H), 7.50 ₍ d, J = 8.4 Hz, 2H), 7 .45 (s, 1H), 6.85 (d, J = 7.2 Hz, 2H), 5.75-5.68 (m, 1H), 5.55 (s, 1H), 5.10 ( d, J = 10.0 Hz, 1H), 5.02 (d, J = 17.2 Hz, 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 (IER) 502.2 [M+H] ⁺ . Example 36B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 9.92 (br. s, 1H), 8.77 (s, 2H), 7.50 ₍ d, J = 8.4 Hz, 2H), 7 .45 (s, 1H), 6.85 (d, J = 7.2 Hz, 2H), 5.75-5.68 (m, 1H), 5.55 (s, 1H), 5.10 ( d, J = 10.0 Hz, 1H), 5.02 (d, J = 17.2 Hz, 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 (IER) 502.3 [M+H] ⁺ . For Example 36A and Example 36B, the absolute stereochemistry was arbitrary.

Intermediate 48

3-Bromo-5-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol

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

[0272] Step 2: To a solution of 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (200 mg, 1.34 mmol, at 0 °C) in dibromethane (2 ml) CuBr ₂ (0.149 g, 0.668 mmol) was added in portions. Isoamyl nitrite (0.179 g, 1.49 mmol) was then added dropwise. The reaction mixture was heated to rt and stirred for 16 hours. The reaction mixture was quenched with water (50 ml), made alkaline with sat. NaHCO ₃ and extracted using DCM (2 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give 3-bromo-6,7-dihydro- 5H- cyclopenta[ c ]pyridin-5-one (60 mg, 21%) as brown solid. MS (IER) 212.3 [M+H] ⁺ .

[0273] Step 3: To a solution of 3-bromo-6,7-dihydro- 5H -cyclopenta[ c ]pyridin-5-one (50 mg, 0.23 mmol) in Et2O (2 ml) at 0 °C at 3.0 M MeMgBr in Et2O (0.4 ml, 1.15 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was poured into ice water (15 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 30% EtOAc/petroleum ether) to give intermediate 48 (15 mg, 28%) as a brown solid. MS (IER) 228.4 [M+H] ⁺ .

Intermediate 49

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

[0274] Intermediate 49 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 48 . MS (IER) 370.4 [M+H] ⁺ .

Example 37A

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

Example 37B

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

[0275] Examples 37A and 37B were prepared using the procedure described for Examples 9A and Examples 9B using intermediate 49 to give racemic 2-allyl-1-(5-hydroxy-5-methyl-6,7-dihydro- 5H-cyclopenta[c]pyridin-3-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)-amino)-1,2-dihydro-3H-pyrazolo[3,4-d] pyrimidin-3-one (25 mg). Enantiomers were separated by chiral SLC chromatography (Chiralpak AD-H 20.0% (0.5% DEA in methanol)) to give peak 1 ( Example 37A , 10 mg) and peak 2 ( Example 37B , 10 mg). Example 37A - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.14 (br.s, 1H), 8.81 (s, 1H), 8.37 ₍ s, 1H), 7.75 (br.s, 1H), 7.58 (br. s, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.70-5.61 (m, 1H), 5.49 (s, 1H ), 5.02 (d, J = 10 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.6 Hz, 2H), 1.45 (s, 3H); MS (IER) 513.4 [M+H] ⁺ . Example 37B - yellow solid; ^1H NMR (400 MHz, DMSO- d6 ) δ 10.14 (br.s, 1H), 8.81 (s, 1H), 8.37 ₍ s, 1H), 7.75 (br.s, 1H), 7.58 (br. s, 2H), 6.93 (d, J = 12.4 Hz, 2H), 5.70-5.61 (m, 1H), 5.49 (s, 1H ), 5.02 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 17.2 Hz, 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 = 7.6 Hz, 2H), 1.45 (s, 3H); MS (IER) 513.7 [M+H] ⁺ . For Example 37A and Example 37B, the absolute stereochemistry was arbitrary.

Intermediate 50

2-Bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0276] Step 1: To a stirred solution of 2-bromo-5,6-dihydro- 7H -cyclopenta[ b ]pyridin-7-one (5 g, 23.58 mmol) in THF (50 mL) at 0 °C 0.5 M i PrMgCl in THF (70.7 ml, 35.37 mmol) was added dropwise. The reaction mixture was stirred at rt for 16 hours. After completion, the reaction mixture was cooled to 0 °C and quenched with sat. NH ₄ Cl solution (100 ml) and extracted with EtOAc (2 x 200 ml). The combined extracts were washed with saline (200 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by flash chromatography (SiO ₂ , 15% EtOAc/hexanes) to give 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro- 5H- cyclopenta[ b ]pyridine -7-ol (1.7 g, 28%) as a yellow liquid. MS (IER) 254.1 [M+H] ⁺ .

[0277] Step 2: To a stirred solution of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro- 5H- cyclopenta[ b ]pyridin-7-ol (2.5 g , 9.82 mmol) to THF (25 ml) was added 60% NaH (590 g, 14.76 mmol) at 0 °C. The mixture was stirred for 30 minutes. and dropwise acetic anhydride (1.39 ml, 14.76 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with ice water and extracted with EtOAc (2 x 100 ml). The combined extracts were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by flash chromatography (neutral alumina, 10% EtOAc/petroleum ether) to give 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-yl acetate (1.7 g, 58%) as a yellow liquid. MS (IER) 296.0 [M+H] ⁺ .

[0278] Step 3: Through a stirred solution of 2-bromo-7-(prop-1-en-2-yl)-6,7-dihydro- 5H -cyclopenta[b]pyridin-7-yl acetate (3,4 g, 11.5 mmol) in MeOH (40 ml) at -78 °C for 30 min. purged ozone gas. After completion of the reaction, confirmed by TLC, the reaction mixture was quenched with 1 ml of dimethyl sulfide at -78 °C and stirred at rt for 1 hour. The reaction mixture was concentrated and diluted with water (100 ml) and EtOAc (200 ml). The organic layer was separated, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give 7-acetyl-2-bromo-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-7-yl acetate (2.1 g , 61%) as a white solid. MS (ESI) m/z 298.1 [M+H].

[0279] Step 4: In a sealed tube , add DAST (8 .9 ml, 67.34 mmol) and stirred the reaction mixture at rt for 2 days. Once complete, the reaction mixture was added dropwise to crushed ice and extracted with EtOAc (2 x 100 ml). The organic layer was separated, washed with water (2 x 50 ml), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 10% EtOAc/hexanes) to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro- 5H- cyclopenta-[ b ]pyridine-7- yl acetate (85 mg, 10%) as a brown oil. MS (IER) 320.1 [M+H] ⁺ .

[0280] Step 5: To a stirred solution of the resulting 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro- 5H -cyclopenta-[ b ]pyridin-7-yl acetate (300 mg, 0.937 mmol ) in MeOH (5 ml) was added K ₂ CO ₃ (259 mg, 1.88 mmol) at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 3 hours. After completion of the reaction, confirmed by TLC, the reaction mixture was concentrated under reduced pressure. Water (20 ml) was added and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with water (2 x 50 ml), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give 2-bromo-7-(1,1-difluoroethyl)-6,7-dihydro-5H-cyclopenta[ b]pyridin-7-ol (230 mg, 0.83 mmol, 88%) as a brown liquid. MS (IER) 278.0 [M+H] ⁺ .

Intermediate 51

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

[0281] Intermediate 51 was prepared using the procedure described for Intermediate 3 using Intermediate 1 and Intermediate 50 . MS (IER) 420.2 [M+H] ⁺ .

Example 38A

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

Example 38B

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

[0282] Examples 38A and 38B were prepared using the procedure described for Examples 9A and 9B using intermediate 51 to give racemic 2-allyl-1-(7-(1,1-difluoroethyl)-7-hydroxy-6 ,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3, 4-d]pyrimidin-3-one (105 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give peak 1 ( Example 38A , 10 mg) and peak 2 ( Example 38B , 20 mg) Example 38A ^1H NMR (400 MHz, DMSO- d6 ) δ 10.03 (br.s, 1H ₎ , 8.82 (s, 1H), 8.01 (br.s, 1H), 7, 81 (d, J = 8.0 Hz, 1H), 7.57 (br. s, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.12 (s, 1H), 5.6-5.62 (m, 1H), 4.99 (d, J = 9.6 Hz, 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 = 19.6 Hz, 3H); MS (IER) 563.5 [M+H] ⁺ Example 38B ^1H NMR (400 MHz, DMSO- d6 ) δ 10.03 (br.s, 1H ₎ , 8.82 (s, 1H), 8.01 (br.s, 1H), 7, 81 (d, J = 8.0 Hz, 1H), 7.57 (br. s, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.12 (s, 1H), 5.66-5.64 (m, 1H), 5.00-4.97 (d, J = 9.6 Hz, 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 = 19.6 Hz, 3H); MS (IER) 563.5 [M+H] ⁺ . For example 38A and example 38B absolute stereochemistry was set arbitrarily.

Intermediate 52

1-(1-Methylpiperidin-4-yl)-1H-indol-5-amine

[0283] Intermediate 52 was prepared according to the procedure described in EP 2141163. MS (ESI) 230.6 [M+H] ⁺ .

Example 39A

(S)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4 -yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 39B

(R)-2-Allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4 -yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0284] Examples 39A and 39B were prepared using the procedure described for Examples 9A and 9B using intermediate 17 and intermediate 52 to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7 -dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((1-(1-methylpiperidin-4-yl)-1H-indol-5-yl)amino)-1,2-dihydro-3H -pyrazolo[3,4-d]pyrimidin-3-one (240 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give peak 1 ( Example 39A , 69 mg) and peak 2 ( Example 39B , 67 mg) Example 39A - yellow solid, ^1H NMR (400 MHz, DMSO- d6 ) δ 10.21 (br.s, 1H ₎ , 8.84 (s, 1H), 8.09 (br.s, 1H ), 7.90 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 2H), 7.40 -7.30 (m, 1H), 6.43 (d, J = 3.2 Hz, 1H), 5.73-5.63 (m, 1H), 5.06 (s, 1H), 4. 99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 16.4 Hz, 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 = 7.4 Hz, 3H); MS (ESI) 565.5 [M+H] ⁺ . Example 39B - yellow solid; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.21 (br.s , 1H), 8.84 (s, 1H), 8.09 (br. s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8, 4 Hz, 1H), 7.49-7.46 (m, 2H), 7.40-7.30 (m, 1H), 6.43 (d, J = 3.2 Hz, 1H), 5, 71-5.63 (m, 1H), 5.06 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.6 Hz, 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 = 7.4 Hz, 3H); MS (IER) 565.4 [M+H] ⁺ . For Example 39A and Example 39B, the absolute stereochemistry was arbitrary.

Intermediate 53

3-Methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[0285] Intermediate 53 was prepared according to a procedure similar to that described in WO Publication No. 2014/134308. MS (IER) 203.4 [M+H] ⁺ .

Example 40A

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

Example 40B

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

[0286] Examples 40A and 40B were prepared using the procedure described for Examples 9A and 9B using intermediate 17 and intermediate 53 to give racemic 2-allyl-1-(7-ethyl-7-hydroxy-6,7 -dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)amino)- 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (217 mg). Enantiomers were separated by chiral SLC chromatography (Chiral Pak AD-H, (30.0% (0.5% DEA in MeOH)) to give peak 1 ( Example 40A , 35 mg) and peak 2 ( Example 40B , 33 mg) Example 40A - yellow solid, ^1H NMR (400 MHz, DMSO- d6 ) δ 10.20 (br.s, 1H) _, 8.88 (s, 1H), 7.90 (d, J =8 .4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65 (br. s, 1H), 7.45 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.51-5.50 (m, 1H), 5.50 (s, 1H), 5.05 (s, 1H ), 4.99 (d, J = 10 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.74-4.59 (m, 2H), 2.97-2 .95 (m, 3H), 2.82-2.80 (m, 1H), 2.56-2.50 (m, 2H), 2.28-2.19 (m, 9H), 2.01 -1.69 (m, 3H), 0.86 (t, J = 7.6 Hz, 3H); MS (ESI) 538.2 [M+H] ⁺ Example 40B - yellow solid; ¹ H NMR (400 MHz, DMSO- d6 ) δ 10.20 (br. s, 1H), 8.88 (s, 1H), _7.90 (d, J = 8.4 Hz, 1H), 7.72 ( d, J = 8.0 Hz, 1H), 7.65 (br. s, 1H), 7.45 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.51-5.50 (m, 1H), 5.50 (s, 1H), 5.05 (s, 1H), 4.99 (d, J = 10 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.74-4.59 (m, 2H), 2.97-2.95 (m, 3H), 2.82 -2.80 (m, 1H), 2.56-2.50 (m, 2H), 2.28-2.19 (m, 9H), 2.01-1.69 (m, 3H), 0 .86 (t, J = 7.6 Hz, 3H); MS (IER) 538.2 [M+H] ⁺ . For Example 40A and Example 40B, the absolute stereochemistry was arbitrary.

Intermediate 54

N-(2-Bromo-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide

[0287] To a stirred solution of intermediate 31 ( 250 mg, 1.037 mmol) in acetonitrile (6 ml) was added chlorosulfonic acid (0.2 ml) at rt and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water ( 10 ml), extracted with EtOAc (2 x 10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The above reaction was repeated on a 3 x 250 mg scale. The combined residues were purified by flash chromatography (SiO ₂ , 40% EtOAc/petroleum ether) to give intermediate 54 (480 mg, 41%) as an off-white solid. MS (IER) 283.1 [M+1] ⁺ .

Intermediate 55

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

Example 41A

(S)-N-(2-(2-Allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3, 4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide

Example 41B

(R)-N-(2-(2-Allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3, 4-d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide

[0289]Examples 41A And41B were obtained using the procedure described forexamples 9A And9B, usingintermediate connection 17 Andintermediate connection 55 to give racemic N-(2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4 -d]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (220 mg). Enantiomers were separated using chiral SLC chromatography (Chiralpak IC, (40.0% (0.5% DEA in MeOH)) to obtain peak 1 (example 41A, 70 mg) and peak 2 (example 41B, 50 mg).Example 41A - yellow solid;¹H NMR (400 MHz, DMSO-d ₆) δ 10.12 (br. s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.71 (d,J = 7.6 Hz, 1H), 7.60 (d,J = 8.0 Hz, 3H), 6.96 (d,J = 8.8 Hz, 2H), 5.60-5.55 (m, 1H), 4.97 (d,J = 10.0 Hz, 1H), 4.87 (d,J = 17.2 Hz, 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 (IER) 568.2 [M+H]⁺.Example 41B - yellow solid;¹H NMR (400 MHz, DMSO-d ₆) δ 10.12 (br. s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.71 (d,J = 7.6 Hz, 1H), 7.60 (d,J = 8.0 Hz, 3H), 6.92 (d,J = 8.8 Hz, 2H), 5.60-5.55 (m, 1H), 4.97 (d,J = 10.4 Hz, 1H), 4.87 (d,J = 17.2 Hz, 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 (IER) 568.2 [M+H]⁺. Forexample 41AAndexample 41B absolute stereochemistry was set arbitrarily.

Example 42

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

[0290] To a stirred solution of N- (2-(2-allyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro- 1H -pyrazolo [3,4- d ]pyrimidin-1-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (500 mg, 0.881 mmol) was added to a thick-walled test tube with 1,4-dioxane ( 10 ml) and 6M HCl (10 ml). The reaction mixture was kept at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and adjusted to pH 8 with 1 M NaOH solution. The mixture was extracted with 10% MeOH/DCM (3 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by HPLC chromatography (C18, water/CH ₃ CN) to give Example 42 (90 mg, 19%) as a pale yellow solid. ^1H NMR (300 MHz, DMSO- d6 ) δ 10.15 (br. s, 1H), 8.81 (s, 1H), 7.74 ₍ d, J = 8.1 Hz, 1H), 7 .65-7.52 (m, 3H), 6.92 (d, J = 9.3 Hz, 2H), 5.76-5.60 (m, 1H), 5.00 (d, J = 10 .2 Hz, 1H), 4.86 (d, J = 17.1 Hz, 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 (IER) 526.2 [M+H] ⁺ .

Procedure A

Wee1 binding assay

[0291] Wee 1 kinase was determined using the fluorescence resonance energy transfer (FRET) assay. In 384-well plates, Weel kinase (final concentration 2 nM) was mixed with AlexaFluor-labeled indicator 178 (final concentration 50 nM, K _d = 24 nM), Eu-anti-GST antibody (final concentration 2 nM) and then inhibitor ( from 0.003 to 10 μmol) in a final volume of 16 μl of kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM ethylene glycol tetraacetic acid (EGTA)). The plate was shaken for 30 seconds, incubated for 60 minutes at rt, and recorded on a fluorescence plate reader. The results are shown in Table 1.

Procedure B

H23 Cell Proliferation Assay

[0292] H23[ATCC (CRL-5800™)] cells were grown and maintained in RPMI-1640 medium with 10% fetal bovine serum and 1% penicillin-streptomycin. Cells were treated with compounds diluted in DMSO and 5-fold 9-point serial dilutions were performed. The plates were placed in 37°C, 5% CO ₂ and incubated for 4 days. The plates were briefly shaken for 2 min and allowed to incubate at rt for 10 min before being developed by adding 100 μl of CellTiter-Glo reagent (Promega) to the plates. The plates were read using an M5e plate reader according to the CellTiter-Glo protocol. GraphPad Prism was used to obtain IC ₅₀ values. The results are shown in Table 1.

Table 1. Enzymatic and cellular data of Wee1

Example No. Enzymatic Wee1 (nM) H23 (nM) AZD1775 A B 1A A C 1B A 2A A C 2B A B 3A A C 3B A B 4A A C 4B A C 5A -- C 5B -- B 6A -- C 6B -- B 7 A C 8 A B 9A A B 9B A B 10A A B 10B A B 11A A C 11B A B 12A A B 12B A A 13A -- B 13B -- A 14 -- B 15A A C 15B A B 16A -- B 16B A B 17A -- B 17B -- B 18A -- B 18B -- B 19A -- C 19B -- B 20A -- C 20B -- B 21A A C 21B A B 22A B C 22B A B 23A -- B 23B -- A 24A -- B 24B -- B 25A A B 25B A B 26A A C 26B A A 27A A B 27B A B 28A -- B 28B -- B 30A A B 30B A B 31A -- A 31B -- A 32 B C 33 B C 34 A -- 35A B C 35B B C 36A B C 36B C C 37A -- C 37B -- C 38A -- C 38B -- B 39A -- B 39B -- B 40A -- B 40B -- A 41A -- C 41B -- C

For Wee1 enzymatic _IC50 : A = single _IC50 ≤ 10 nM; B = single IC ₅₀ > 10 nM and < 100 nM; C = single IC ₅₀ ≥ 100 nM. For H23 CTG _IC50 : A = single _IC50 ≤ 100 nM; B = one IC ₅₀ > 100 nM and < 1000 nM; C = one IC ₅₀ ≥ 1000 nM.

[0293] Moreover, although the foregoing has been described in more detail by way of illustration and example for purposes of clarity, it will be apparent to those skilled in the art that numerous and various variations may be made without departing from the spirit or scope of the present invention. Therefore, it should be clearly understood that the forms described herein are illustrative only and are not intended to limit the scope of the present specification, but rather to cover all modifications and alternatives within the true scope and spirit of the invention.

Claims (66)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof having the structure where R ¹ is selected from the group consisting of hydrogen and halogen; ring A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted imidazole and substituted or unsubstituted pyridine, wherein when ring A is substituted, ring A is substituted with halogen; ring B is selected from the group consisting of a substituted monocyclic 5-6 membered carbocyclyl and a substituted 5-6 membered monocyclic heterocyclyl containing 1 heteroatom selected from the group consisting of nitrogen and oxygen, wherein when ring B is substituted, ring B is substituted with 1 , 2 or 3 substituents independently selected from the group consisting of fluorine, hydroxy, amino, -NHC(O)C ₁ -C ₆ alkyl, unsubstituted cyclopropyl, unsubstituted C ₁ -C ₆ haloalkyl and unsubstituted C ₁ -C ₆ alkyl; R ² is selected from the group consisting of , And ; m is 0 or 1; R ³ is selected from the group consisting of halogen and unsubstituted C ₁ -C ₆ alkyl; X represents a substituted or unsubstituted 6-membered monocyclic heterocyclyl containing 1 or 2 nitrogens, and when X is substituted, X is substituted with an unsubstituted C ₁ -C ₆ alkyl; Y represents CH; Y ¹ represents CR ^4A ; Y ² represents CR ^4B ; ring C represents an unsubstituted 8-membered bicyclic heterocyclyl containing 1 nitrogen; R ^4A and R ^4B each represent hydrogen; And R ⁵ is a substituted or unsubstituted 6-membered monocyclic heterocyclyl containing 1 nitrogen, and when R ⁵ is substituted, R ⁵ is substituted with an unsubstituted C ₁ -C ₆ alkyl. 2. The compound according to claim 1, wherein R ¹ represents hydrogen. 3. Connection according to any one of paragraphs. 1, 2, in which ring A is a substituted or unsubstituted pyridine. 4. Connection according to any one of paragraphs. 1, 2, in which selected from the group consisting of: each of the above groups being substituted or unsubstituted. 5. The compound according to claim 4, in which ring A is . 6. Connection according to any one of paragraphs. 1–5, in which ring A is unsubstituted. 7. Connection according to any one of paragraphs. 1–6, in which ring B is a substituted monocyclic 5–6 membered carbocyclyl. 8. Connection according to any one of paragraphs. 1–6, in which ring B is a substituted monocyclic 5-membered carbocyclyl. 9. Connection according to any one of paragraphs. 1–6, in which selected from the group consisting of: , , , , , , , , , , , , , , , And , each of the above groups being substituted. 10. The connection according to claim 9, in which represents . 11. Connection according to any one of paragraphs. 1-10, in which ring B is substituted with 1, 2 or 3 substituents independently selected from the group consisting of hydroxy and unsubstituted C ₁ -C ₆ alkyl. 12. Connection according to any one of paragraphs. 1–11, in which R ² represents . 13. The compound according to claim 12, in which X represents a substituted or unsubstituted 6-membered monocyclic heterocyclyl. 14. The compound according to claim 12, wherein X is selected from the group consisting of substituted or unsubstituted piperidine and substituted or unsubstituted piperazine. 15. A compound according to claim 14, wherein X is a substituted or unsubstituted piperazine. 16. Connection according to any one of paragraphs. 1–15 in which X is substituted. 17. The compound according to claim 16, in which X is substituted with unsubstituted methyl, unsubstituted ethyl or unsubstituted isopropyl. 18. The compound according to claim 12, in which X represents . 19. Connection according to any one of paragraphs. 12–17, in which m is equal to 0. 20. Connection according to any one of paragraphs. 1–11, in which R ² represents or . 21. The compound according to claim 1, which is selected from the group consisting of: or a pharmaceutically acceptable salt of any of the above compounds. 22. The compound according to claim 1, which is selected from the group consisting of: or a pharmaceutically acceptable salt of any of the above compounds. 23. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 24. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 25. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 26. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 27. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 28. The connection according to claim 22, which is or a pharmaceutically acceptable salt thereof. 29. Pharmaceutical composition for inhibiting WEE1, containing an effective amount of a compound according to any one of paragraphs. 1-28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. 30. A method of attenuating or treating cancer by inhibiting WEE1, comprising administering an effective amount of a compound according to any one of claims. 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 to a subject with cancer, wherein the cancer is selected from brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer , lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, uterine and cervical cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing tumor, soft parts sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma. 31. A method of inhibiting the replication of a malignancy or tumor by inhibiting WEE1, comprising bringing the malignancy or tumor into contact with an effective amount of a compound according to any one of claims. 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, wherein the malignancy or tumor is caused by a cancer selected from brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, uterine and cervical cancer, renal pelvis cancer /ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing tumor, soft parts sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma. 32. A method of attenuating or treating a cancer or tumor by inhibiting WEE1, comprising bringing the cancer or tumor into contact with an effective amount of a compound according to any one of claims. 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, wherein the malignancy or tumor is caused by a cancer selected from brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, uterine and cervical cancer, renal pelvis cancer /ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing tumor, soft parts sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma.