combination

Abstract

This document discloses combinations of compounds for treating diseases or conditions, such as cancer. Combinations of compounds for treating diseases or conditions may include Bcl-2 inhibitors and WEE1 inhibitors, as well as pharmaceutically acceptable salts of either of the foregoing.

Description

[0001] Incorporate any priority claim by reference

[0002] For example, any and all applications that identify a foreign or domestic priority claim against it in an application data sheet or request filed together with this application are hereby incorporated by reference under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 62 / 952,032, filed December 20, 2019. Technical Field

[0003] This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, this document discloses combination therapies and methods for treating diseases and / or conditions using the combination therapies described herein. Background Technology

[0004] Cancer is a family of diseases involving abnormal cell growth that can potentially invade or spread to other parts of the body. Current cancer treatments include surgery, hormone therapy, radiation therapy, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary depending on the type of cancer and the stage at which it is diagnosed. In 2019, approximately 1.8 million people were diagnosed with cancer, and an estimated 606,880 people in the United States died from cancer. Therefore, there remains a need for effective cancer treatments. Summary of the Invention

[0005] Some embodiments described herein involve combinations of compounds that may include an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of one or more compounds (B) or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of one or more compounds (B) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of one or more compounds (B) or a pharmaceutically acceptable salt thereof.

[0007] In some implementations, the disease or condition may be cancer, as described herein. Attached Figure Description

[0008] Figure 1 Examples of Bcl-2 inhibitors are provided.

[0009] Figure 2 An example of compound (A) is provided.

[0010] Figure 3 The percentage of inhibition of DMS-53 (lung cancer cell line) by compounds 1a and 3 as single agents and in combination is shown.

[0011] Figure 4 Results of tumor growth studies in response to monotherapy and combination therapy with compounds 1a and 3 are presented in the MV4-11 mouse model. Detailed Implementation

[0012] definition

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, publications, and other disclosures cited herein are incorporated herein by reference in their entirety unless otherwise stated. Where multiple definitions exist for terms herein, the definition in that section shall prevail unless otherwise stated.

[0014] Whenever a group is described as “optionally substituted,” the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as “unsubstituted or substituted,” if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated “optionally substituted” or “substituted” group may be substituted by one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclic(alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, nitro, thionyl, thionyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amine group, disubstituted amine group and amine (C1-C6 alkyl).

[0015] As used in this article, "C" a To C bThe term “C1 to C4 alkyl” indicates the number of carbon atoms in the group. The indicated group may contain “a” to “b” carbon atoms (inclusive). Therefore, for example, “C1 to C4 alkyl” refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If “a” and “b” are not specified, the widest range described in these definitions is assumed.

[0016] If two "R" groups are described as "joined together," then the R groups and the atoms they are attached to can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic compounds. For example, but not limited to, if NR a R b R of the group a and R b When indicated as "together," it means that they are covalently bonded to each other to form a ring:

[0017]

[0018] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. An alkyl group can have 1 to 30 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 30" refer to every integer within a given range; for example, "1 to 30 carbon atoms" means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, but the definition of this invention also covers the term "alkyl" when no numerical range is specified). An alkyl group can also be a medium-sized alkyl group having 1 to 12 carbon atoms. An alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. An alkyl group can be substituted or unsubstituted.

[0019] As used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group having two to twenty carbon atoms, containing one or more carbon double bonds, including but not limited to 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. Alkenyl groups can be unsubstituted or substituted.

[0020] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group having two to twenty carbon atoms and containing one or more carbon triple bonds, including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, etc. The alkynyl group may be unsubstituted or substituted.

[0021] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers to two rings sharing two atoms and one bond. As used herein, the term “bridged cycloalkyl” refers to a compound in which the cycloalkyl group contains a bond connecting one or more atoms that are not adjacent atoms. As used herein, the term “spiro” refers to two rings sharing one atom and said two rings not connected by a bridge. Cycloalkyl groups may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. Cycloalkyl groups may be unsubstituted or substituted. Examples of monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-benzothiophene, and tetradecahydroanthrayl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantyl, and norbornyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0022] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bond cannot form a fully delocalized π-electron system throughout all rings (otherwise the group would be “aryl” as defined herein). A cycloalkenyl group may contain 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. When the ring consists of two or more rings, these rings may be fused, bridged, or spiro-linked together. The cycloalkenyl group may be unsubstituted or substituted.

[0023] As used herein, “carbocyclic” refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. As described herein, when the ring consists of two or more rings, these rings can be fused, bridged, or spirolinked together. A carbocyclic group may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. The carbocyclic group may be unsubstituted or substituted. Examples of carbocyclic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups as defined herein, and the non-aromatic portions of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-cyclopenten[b]pyridine.

[0024] As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a chemical bond) with a fully delocalized π-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C. 14 aryl group, C6-C 10 An aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group can be substituted or unsubstituted.

[0025] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), the heteroatoms being elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in one or more rings, 5 to 10 atoms in one or more rings, or 5 to 6 atoms in one or more rings, such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused-ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazolidone, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, borazine, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0026] As used herein, "heterocyclic group" or "heterocyclic group" refers to a ternary, quaternary, pentaneary, hexanal, heptanal, octaneary, nonanal, decanal, or up to 18-membered monocyclic, bicyclic, and tricyclic ring system in which a carbon atom, together with one to five heteroatoms, constitutes the ring system. The heterocycle may optionally contain one or more unsaturated bonds positioned in such a manner that a fully delocalized π-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. The heterocycle may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, these rings may be fused, bridged, or spiro-linked together. As used herein, the term "fused" refers to two rings sharing two atoms and one bond. As used herein, the term "bridged heterocyclic group" or "bridged alicyclic group" refers to a compound in which the heterocyclic group or alicyclic group comprises a bond connecting one or more atoms that are not adjacent atoms. As used herein, the term "spiral" refers to two rings that share a common atom and are not connected by a bridge. The heterocyclic group or alicyclic group may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogen in the alicyclic ring may be quaternized. The heterocyclic group or alicyclic group may be unsubstituted or substituted.Examples of such "heterocyclic" or "heterocyclic" groups include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxopentane, 1,3-dioxopentane, 1,4-dioxopentane, 1,3-oxothiocyclohexane, 1,4-oxothiocyclohexadiene, 1,3-oxothiocyclopentane, 1,3-dithiocyclopentadiene, 1,3-dithiopentane, 1,4-oxothiocyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, and dioxane. Hydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazolidinone, thiazoline, thiazoline, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, aziridine, pyrrolidone, pyrrolidone, 4-piperidinone, pyrazoline, pyrazole, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and their benzo[a]-fused analogues (e.g., benzimidazolinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spirochetal groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

[0027] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and aryl group of an aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0028] As used herein, “heteroarylalkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and heteroaryl group of a heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furanylalkyl, thienylalkyl, pyrroliylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzofused analogs.

[0029] "Heterocyclic (alkyl)" and "heterocyclic (alkyl)" refer to heterocyclic or heterocyclic groups that are substituents connected via a lower alkylene group. The lower alkylene group and heterocyclic group of the (heterocyclic)alkyl group can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiaran-4-yl (methyl), and 1,3-thiazin-4-yl (methyl).

[0030] As used herein, a “lower alkylene group” is a straight-chain -CH2-chain group that forms a bond to connect a molecular segment via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group may be replaced by one or more hydrogen atoms and / or by a cycloalkyl group (e.g., It replaces two hydrogen atoms on the same carbon atom.

[0031] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0032] As used herein, “alkoxy” refers to the formula –OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0033] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), and heterocyclic(alkyl) group connected as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl groups can be substituted or unsubstituted.

[0034] The "cyano" group refers to the "-CN" group.

[0035] As used herein, the term "halogen atom" or "halogen" refers to any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0036] A "thiocarbonyl" group is one in which R can be the same "-C(=S)R" group as defined relative to the O-carboxyl group. Thiocarbonyl groups can be substituted or unsubstituted.

[0037] The "O-carbamoyl" group refers to the R group in the carbamoyl group. A and R B "-OC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The O-carbamoyl group can be substituted or unsubstituted.

[0038] The "N-carbamoyl" group refers to the combination of R and R... A "ROC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-carbamoyl group can be substituted or unsubstituted.

[0039] The "O-thiocarbamoyl" group refers to the R group in the R group. A and R B "-OC(=S)-N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The O-thiocarbamoyl group can be substituted or unsubstituted.

[0040] The "N-thiocarbamoyl" group refers to the group containing R and R. A "ROC(=S)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-thiocarbamoyl group can be substituted or unsubstituted.

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

[0042] The "N-acylamino" group refers to the combination of R and R... A "RC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-amino group can be substituted or unsubstituted.

[0043] The "S-sulfonamide" group refers to the R group within it. A and R B"-SO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A R B The S-sulfonamide group can be substituted or unsubstituted.

[0044] The "N-sulfonamide" group refers to the combination of R and R... A "RSO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A The N-sulfonamide group can be substituted or unsubstituted.

[0045] The “O-carboxyl” group refers to an “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0046] The terms "ester" and "C-carboxyl" refer to esters where the R group can be the same "-C(=O)OR" group as defined relative to the O-carboxyl group. Esters and C-carboxyl groups can be substituted or unsubstituted.

[0047] The "nitro" group refers to the "-NO2" group.

[0048] The "sulfonyl" group refers to a "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The sulfonyl group can be substituted or unsubstituted.

[0049] The "sulfinyl" group refers to a group in which R can be the same "-S(=O)-R" group as defined relative to the sulfoxide group. The sulfinyl group can be substituted or unsubstituted.

[0050] A "sulfonyl" group is one in which R can be the same "SO2R" group as defined relative to the sulfoxide group. The sulfonyl group can be substituted or unsubstituted.

[0051] As used herein, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups may be substituted or unsubstituted.

[0052] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy groups may be substituted or unsubstituted.

[0053] As used in this article, the term "amino" refers to the -NH2 group.

[0054] The "monosubstituted amine" group refers to the group in which R... A "-NHR" can be any of the following as defined herein: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A "group. R" A It can be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH (methyl), -NH (phenyl), etc.

[0055] The "disubstituted amine" group refers to the R group in the amine group. A and R B "-NR" can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) as defined herein. A R B "group. R" A and R B It can be substituted or unsubstituted independently. Examples of disubstituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), etc.

[0056] As used herein, the "amine (alkyl)" group refers to the -(alkylene)-NR'R" group, wherein R' and R" are independently hydrogen or alkyl as defined herein. The amine (alkyl) group may be substituted or unsubstituted. Examples of amine (alkyl) groups include, but are not limited to, -CH2NH (methyl), -CH2NH (phenyl), -CH2CH2NH (methyl), -CH2CH2NH (phenyl), -CH2N (methyl)2, -CH2N (phenyl)(methyl), -NCH2 (ethyl)(methyl), -CH2CH2N (methyl)2, -CH2CH2N (phenyl)(methyl), -NCH2CH2 (ethyl)(methyl), etc.

[0057] Where the number of substituents (e.g., haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens. As another example, "C1 to C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two, or three atoms.

[0058] As used herein, a free radical refers to a substance having a single unpaired electron, allowing the free radical-containing substance to covalently bond to another substance. Therefore, in this context, a free radical is not necessarily a free radical in the sense of a free radical. Rather, a free radical refers to a specific part of a larger molecule. The term "free radical" is used interchangeably with the term "group".

[0059] The term "pharmaceutically acceptable salt" refers to a salt of a compound that will not cause significant irritation to the organism to which it is applied and will not eliminate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrophosphate). Pharmaceutical salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids (e.g., formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid, or naphthalenesulfonic acid). Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salts, alkali metal salts (e.g., sodium, potassium, or lithium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), carbonates, bicarbonates, organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tri(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reacting with amino acids (e.g., arginine and lysine). Those skilled in the art will understand that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group can associate with a positive charge (e.g., NH2 can become NH3). +And this positive charge can be generated by negatively charged counterions (such as Cl-). - )balance.

[0060] It should be understood that in any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly specified, each center may independently be an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds presented herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, or diastereomeric pure, diastereomeric enriched stereoisomers. Furthermore, it should be understood that in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond may independently be E or Z, or a mixture thereof. Likewise, it should be understood that all tautomeric forms are intended to be included in any of the compounds described herein.

[0061] It should be understood that in cases where the compounds disclosed herein have unfilled valences, they are filled with hydrogen or its isotopes (e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0062] It should be understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to increased metabolic stability, such as, for example, an increased in vivo half-life or a reduced dose requirement. Each chemical element represented in the compound structure may contain any isotope of that element. For example, in the compound structure, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless the context clearly specifies otherwise, the compounds mentioned herein encompass all possible isotopic forms.

[0063] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which comprise different crystalline arrangements of the same elemental composition of the compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein are present in a solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). In other embodiments, the compounds described herein are present in a non-solvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during crystallization with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcohols are formed when the solvent is an alcohol. Furthermore, the compounds provided herein can exist in both non-solvated and solvated forms. Generally, a solvated form is considered equivalent to a non-solvated form used for the purposes of the compounds and methods provided herein.

[0064] Regarding the range values ​​provided, it should be understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are covered within the implementation scheme.

[0065] The terms and phrases and their variations used in this application, particularly in the appended claims, should be understood as open-ended rather than restrictive, unless otherwise expressly stated. For the foregoing examples, the term “comprising” should be understood as “including but not limited to,” “including but not limited to,” etc.; as used herein, the term “comprising” is synonymous with “including,” “containing,” or “characterized as” and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term “having” should be interpreted as “having at least”; the term “comprising” should be interpreted as “including but not limited to”; the term “example” is used to provide exemplary instances of the items under discussion, not an exhaustive or restrictive list thereof; and the use of terms such as “preferred,” “ideal,” “desired,” and “expected,” and words with similar semantic meanings, should not be construed as implying that certain features are critical, necessary, or even important to the structure or function, but are merely intended to highlight alternative or additional features that may or may not be used in a particular embodiment. Furthermore, the term “comprising” should be interpreted as synonymous with the phrase “having at least” or “containing at least.” When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device contains at least the stated features or components, but may also contain additional features or components.

[0066] For virtually any plural and / or singular term used herein, those skilled in the art can convert from plural to singular and / or from singular to plural, as appropriate to the context and / or application. For clarity, various singular / plural substitutions may be explicitly stated herein. The indefinite article “a” or “an” does not exclude multiple. The fact that certain measures are referred to in mutually different dependent claims does not indicate that a combination of these measures cannot be used to make the advantages more pronounced. Any reference numerals in the claims should not be construed as limiting their scope.

[0067] compound

[0068] Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination may include an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of one or more compounds (B) or a pharmaceutically acceptable salt thereof, wherein: compound (A) has the following structure:

[0069]

[0070] Where: R 1The ring can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl groups; ring A can be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups; ring B can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups; R 2 Optional m can be 0, 1, 2, or 3; R 3 X can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups; X can be selected from hydrogen, halogens, hydroxyl groups, cyano groups, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and substituted or unsubstituted -NH-(CH2). 1-6 -Amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl) acyl, substituted or unsubstituted C-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl, and substituted or unsubstituted N-carbamoyl; Y can be CH or N; Y 1 CR 4A Or N; Y 2 CR 4B Or N; the ring C can be self-substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic and substituted or unsubstituted 7-10 membered bicyclic heterocyclic; R 4A and R 4B It can be independently selected from hydrogen, halogens, and unsubstituted C. 1-4 Alkyl; and R 5 It may be a substituted or unsubstituted 5-7 membered monocyclic heterocyclic group; and one or more compounds (B) may be a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0071] In some implementation schemes, R 1 The ring can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, ring A can be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups. In some embodiments, ring B can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups. In some embodiments, R... 2 Optional In some implementations, m can be 0, 1, 2, or 3. In some implementations, R 3X can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, X can be selected from hydrogen, halogens, hydroxyl groups, cyano groups, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and substituted or unsubstituted -NH-(CH2). 1-6 -Amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl, and substituted or unsubstituted N-carbamoyl. In some embodiments, Y may be CH or N. In some embodiments, Y 1 CR 4A Or N. In some implementations, Y 2 CR 4B Or N. In some embodiments, the ring C may be self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic, and substituted or unsubstituted 7-10 membered bicyclic heterocyclic. In some embodiments, R 4A and R 4B Independently selected from hydrogen, halogens and unsubstituted C 1-4 alkyl.

[0072] In some implementation schemes, R 1 It can be selected from hydrogen, halogen, and C1-C6 alkyl. In some embodiments, R 1 It can be hydrogen. In other embodiments, R 1 It can be halogen. In some implementations, R 1 It can be fluorine. In other embodiments, R 1 It can be an unsubstituted C1-C6 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight-chain or branched) or hexyl (straight-chain or branched)). In some embodiments, R 1 It can be an unsubstituted methyl group. In some embodiments, R 1 It can be a substituted C1-C6 alkyl group, such as those described herein. In some embodiments, R 1 It can be an unsubstituted C1-C6 haloalkyl (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, R 1 It can be -CHF2, -CF3, -CF2CH3 or -CH2CF3.

[0073] In some embodiments, ring A may be selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted 5-6 membered monocyclic heteroaryl groups.

[0074] In some embodiments, ring A may be a substituted phenyl group. In other embodiments, ring A may be an unsubstituted phenyl group.

[0075] In some embodiments, ring A may be a substituted 5-6 membered monocyclic heteroaryl group. In some embodiments, ring A may be an unsubstituted 5-6 membered monocyclic heteroaryl group. In some embodiments, ring A may be selected from substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyridazine.

[0076] When substituted, ring A may be substituted with one or more substituents selected from halogens, unsubstituted C1-C4 haloalkyls, and unsubstituted C1-C4 alkyls. In some embodiments, ring A is monosubstituted with a halogen (e.g., fluorine).

[0077] In some implementation schemes, Optional Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Can be replaced or not replaced In some implementation schemes, Can be replaced or not replaced Ring A is unsubstituted. In other embodiments, Optional self-replacement or non-replacement Replaced or not replaced and replaced or unreplaced As described in this article, The ring A portion can be unsubstituted.

[0078] In some embodiments, ring B may be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclic groups and substituted or unsubstituted 5-7 membered monocyclic heterocyclic groups.

[0079] In some embodiments, ring B may be a substituted or unsubstituted 5- to 7-membered monocyclic carbocyclic group. In some embodiments, ring B may be a substituted or unsubstituted 5-membered monocyclic carbocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 6-membered monocyclic carbocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 7-membered monocyclic carbocyclic group.

[0080] In some implementation schemes, Optional from: Each of the above groups is either substituted or unsubstituted.

[0081] In some embodiments, ring B may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclic group. In some embodiments, ring B may be a substituted or unsubstituted 5-membered monocyclic heterocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 6-membered monocyclic heterocyclic group. In other embodiments, ring B may be a substituted or unsubstituted 7-membered monocyclic heterocyclic group.

[0082] In some implementation schemes, Optional from: Each of the above groups is either substituted or unsubstituted, including any -NH group.

[0083] In some implementation schemes, ring B can be selected from... Each of the aforementioned groups may be substituted or unsubstituted, including any -NH group. In some embodiments, ring B may be substituted or unsubstituted.

[0084] In some embodiments, when ring B is substituted, ring B may be substituted by one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, amino groups, and unsubstituted N-linked amide groups (e.g., -NHC(O)C). 1- C6 alkyl, unsubstituted C1-C6 haloalkyl (such as those described herein), and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, when ring B is substituted, ring B may be substituted by one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, amino groups, unsubstituted N-linked amide groups (e.g., -NHC(O)C). 1- C6 alkyl groups and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, ring B may be substituted with one, two, or three substituents, which are independently selected from fluorine, hydroxyl, amino, unsubstituted -NHC(O)C 1- C6 alkyl, unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring B may be substituted with one or two substituents, which are independently selected from fluorine, hydroxyl, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0085] In some implementation schemes, Optional from: Each of the above groups is either substituted or unsubstituted, including any -NH group.

[0086] In some implementation schemes, Optional from: Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Optional from: Each of the aforementioned groups may be substituted or unsubstituted. In some embodiments, Can be replaced or not replaced In some implementation schemes Can be replaced or

[0087] Both ring A and ring B may be substituted or unsubstituted. In some embodiments, Rings A and B can be independently substituted or unsubstituted. In some embodiments, Both ring A and ring B can be unsubstituted. In some implementations, Rings A and B can both be replaced independently. In some implementations, Ring A can be replaced, and Ring B may be unsubstituted. In some implementations, Ring A can be unsubstituted, and Ring B can be replaced. In some implementations, Ring A can be unsubstituted, and The ring B can be substituted with one, two, or three substituents, which are independently selected from halogens, hydroxyl groups, and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, Ring A can be unsubstituted, and The ring B can be substituted with one, two, or three substituents, which are independently selected from fluorine, hydroxyl, amino, unsubstituted N-linked amide (e.g., -NHC(O)C). 1- C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Ring A can be unsubstituted, and The ring B can be substituted by one or two substituents, which are independently selected from fluorine, hydroxyl, amino, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl and -NHC(O)CH3.

[0088] In some implementation schemes, R 2 Optional In some implementation schemes, R 2 Can be In some implementation schemes, R 2 Can be

[0089] 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).

[0090] In some implementation schemes, R 3 It can be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups (such as those described herein). In some embodiments, R 3 It can be halogen. In some implementations, R 3 It can be a substituted C1-C6 alkyl group (such as those described herein). In some embodiments, R 3 It can be an unsubstituted C1-C6 alkyl group (such as those described herein).

[0091] In some implementations, m can be 0, 1, 2, or 3. In some implementations, m can be 0. In some implementations, m can be 1. In some implementations, m can be 2. In some implementations, m can be 3. When m is 2 or 3, R 3 The groups can be the same as or different from each other.

[0092] In some embodiments, X may be selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclic groups, substituted or unsubstituted amines (C1-C6 alkyl), or substituted or unsubstituted -NH-(CH2). 1-6-Amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (straight or branched) or hexoxy (straight or branched)), substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy), substituted or unsubstituted (C1-C6 alkyl) acyl, substituted or unsubstituted C-amide, substituted or unsubstituted N-amide, substituted or unsubstituted C-carboxyl, substituted or unsubstituted O-carboxyl, substituted or unsubstituted O-carbamoyl and substituted or unsubstituted N-carbamoyl.

[0093] In some embodiments, X may be hydrogen. In other embodiments, X may be a halogen. In some embodiments, X may be fluorine. In some embodiments, X may be chlorine. In other embodiments, X may be a hydroxyl group. In other embodiments, X may be a cyano group. In some embodiments, X may be an amino group.

[0094] In some embodiments, X may be an unsubstituted C1-C6 alkyl group (such as those described herein). In some embodiments, X may be an unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl group. In some embodiments, X may be a substituted C1-C6 alkyl group (such as those described herein). In some embodiments, X may be an unsubstituted C1-C6 haloalkyl group (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, X may be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, X may be an unsubstituted C1-C6 hydroxyalkyl group (such as C1-C6 monohydroxyalkyl or C1-C6 dihydroxyalkyl). In some embodiments, X may be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3)2. In some embodiments, X may be an unsubstituted C1-C6 cyanoalkyl (such as a C1-C6 monocyanoalkyl or a C1-C6 dicyanoalkyl). In some embodiments, X may be selected from... In some embodiments, X may be an unsubstituted C1-C6 alkoxyalkyl group (such as a C1-C6 monoalkoxyalkyl group or a C1-C6 dialkoxyalkyl group). In some embodiments, X may be selected from... In some implementations, X may be selected from... Substituted C1-C6 alkyl groups.

[0095] In some embodiments, X may be an unsubstituted C1-C6 alkoxy group (such as those described herein). In some embodiments, X may be an unsubstituted methoxy group, an unsubstituted ethoxy group, or an unsubstituted isopropoxy group. In some embodiments, X may be a substituted C1-C6 alkoxy group (such as those described herein). In some embodiments, X may be a C1-C6 alkoxy group substituted with one, two, or three substituents, which are independently selected from halogens, amino groups, monosubstituted amines (such as those described herein), and disubstituted amines (such as those described herein). In some embodiments, X may be a C1-C6 alkoxy group substituted with one substituent, which is selected from halogens, amino groups, monosubstituted amines (such as those described herein), and disubstituted amines (such as those described herein).

[0096] In some implementations, X can be selected from...

[0097] In some embodiments, X may be a substituted C3-C6 cycloalkoxy group (such as those described herein). In some embodiments, X may be an unsubstituted C3-C6 cycloalkoxy group (such as those described herein).

[0098] In some embodiments, X may be a substituted (C1-C6 alkyl)acyl group, such as a substituted -(CO)-CH3. In some embodiments, X may be an unsubstituted (C1-C6 alkyl)acyl group, such as an unsubstituted -(CO)-CH3.

[0099] In some embodiments, X may be a substituted 4-6 membered monocyclic heterocyclic group. In some embodiments, X may be an unsubstituted 4-6 membered monocyclic heterocyclic group. In some embodiments, X may be selected from aziridine, oxacyclobutane, diaziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, and dioxacyclohexane; wherein each of the above groups is substituted or unsubstituted, including any -NH group. In some embodiments, X may be selected from... Each of the above groups is either substituted or unsubstituted, including any -NH group.

[0100] In some embodiments, X may be a 4-6 membered monocyclic heterocyclic group (such as those described herein) substituted with one or two substituents, wherein these substituents are independently selected from halogens, substituted or unsubstituted C1-C6 alkyl groups (such as those described herein), monosubstituted amines (such as those described herein), disubstituted amines (such as those described herein), amino groups, substituted or unsubstituted amines (C1-C6 alkyl groups), and substituted or unsubstituted (C1-C6 alkyl) acyl groups. In some embodiments, X may be a 4-6 membered monocyclic heterocyclic group substituted with one or two substituents, wherein these substituents are independently selected from fluorine, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, -CH2OH, and -N(CH3)2. In some embodiments, X may be selected from...

[0101] In some embodiments, X may be a substituted amine (C1-C6 alkyl). In some embodiments, X may be an unsubstituted amine (C1-C6 alkyl). In some embodiments, X may be selected from... Each of the above groups is either substituted or unsubstituted, including any -NH group.

[0102] In some implementations, X may be replaced by -NH-(CH2). 1-6 -amine. In some embodiments, X may be unsubstituted -NH-(CH2). 1-6 -amine. In some embodiments, X may be selected from... Each of the above groups is either substituted or unsubstituted, including any -NH group.

[0103] In some embodiments, X may be a monosubstituted amine. In some embodiments, the substituent of the monosubstituted amine is an unsubstituted C1-C6 alkyl (such as those described herein) or an unsubstituted C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0104] In some embodiments, X may be a disubstituted amine. In some embodiments, the two substituents of the disubstituted amine are independently selected from unsubstituted C1-C6 alkyl groups (such as those described herein) and unsubstituted C3-C6 cycloalkyl groups (such as those described herein).

[0105] In some implementations, X can be selected from...

[0106] In some embodiments, X may be a substituted or unsubstituted C-amide. In some embodiments, X may be a substituted or unsubstituted N-amide. In some embodiments, X may be a substituted or unsubstituted C-carboxyl group. In some embodiments, X may be a substituted or unsubstituted O-carboxyl group. In some embodiments, X may be a substituted or unsubstituted O-carbamoyl group. In some embodiments, X may be a substituted or unsubstituted N-carbamoyl group. In some embodiments, X may be monosubstituted with an unsubstituted C1-C6 hydroxyalkyl group (such as those described herein).

[0107] In some implementation schemes, Y 1 CR 4A Or N (nitrogen). In some implementations, Y 1 CR 4A In some implementation schemes, Y 1 It can be N (nitrogen).

[0108] In some implementation schemes, Y 2 CR 4B Or N (nitrogen). In some implementations, Y 2 CR 4B In some implementation schemes, Y 2 It can be N (nitrogen).

[0109] In some implementation schemes, Y 1 and Y 2 Each can be N (nitrogen). In some implementations, Y 1 CR 4A And Y 2 CR 4B In some implementation schemes, Y 1 CR 4A And Y 2 It can be N (nitrogen). In some implementations, Y 1 It can be N (nitrogen), and Y 2 CR 4B .

[0110] In some implementation schemes, R 4A It can be hydrogen. In some implementations, R 4A It can be halogen. In some implementations, R 4A Can be unreplaced C 1-4 Alkyl groups (such as those described herein).

[0111] In some implementation schemes, R 4B It can be hydrogen. In some implementations, R 4B It can be halogen. In some implementations, R 4BCan be unreplaced C 1-4 Alkyl groups (such as those described herein).

[0112] In some implementation schemes, R 4A and R 4B Each can be hydrogen. In some implementations, R 4A and R 4B Each can be a halogen (wherein the halogens may be the same or different from each other). In some embodiments, R 4A and R 4B Each can be an unreplaced C 1-4 Alkyl groups (such as those described herein, and wherein C...) 1-4 Alkyl groups may be the same as or different from each other. In some embodiments, R 4A and R 4B One of them can be hydrogen, and R 4A and R 4B The other component can be a halogen. In some implementations, R 4A and R 4B One of them can be hydrogen, and R 4A and R 4B The other one could be the unsubstituted C. 1-4 Alkyl groups (such as those described herein). In some embodiments, R 4A and R 4B One of them can be a halogen, and R 4A and R 4B The other one could be the unsubstituted C. 1-4 Alkyl groups (such as those described herein).

[0113] In some implementations, R2 can be For example, R2 can be In some implementations, when R2 is In this case, R5 may be a substituted 5-7 membered monocyclic heterocyclic group. In other embodiments, R5 may be an unsubstituted 5-7 membered monocyclic heterocyclic group. Examples of R5 groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azaheptanyl. When the R5 group is substituted, possible substituents include unsubstituted C1-4 alkyl, halogen, hydroxyl, and unsubstituted C1-4 haloalkyl.

[0114] In some implementations, the ring C may be either self-substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted 5-10 membered monocyclic heteroaryl, substituted or unsubstituted 5-7 membered monocyclic carbocyclic, substituted or unsubstituted 5-7 membered monocyclic heterocyclic and substituted or unsubstituted 7-10 membered bicyclic heterocyclic.

[0115] In some implementations, ring C may be replaced by C6-C. 10 Aryl. In some embodiments, the ring C may be an unsubstituted C6-C. 10 Aryl group. In some embodiments, the ring C may be a substituted C6 aryl group. In some embodiments, the ring C may be an unsubstituted C6 aryl group.

[0116] In some embodiments, ring C may be a substituted 5-10-membered heteroaryl group. In some embodiments, ring C may be an unsubstituted 5-10-membered heteroaryl group. In some embodiments, ring C may be a substituted 5-6-membered heteroaryl group. In some embodiments, ring C may be an unsubstituted 5-6-membered heteroaryl group. In some embodiments, ring C may be selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, benzimidazole, indole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, quinoline, isoquinoline, quinazoline, and quinoxaline; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0117] In some embodiments, ring C may be a substituted or unsubstituted 5-membered monocyclic carbocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 6-membered monocyclic carbocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 7-membered monocyclic carbocyclic group.

[0118] In some embodiments, ring C may be a substituted or unsubstituted 5-membered monocyclic heterocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 6-membered monocyclic heterocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 7-membered monocyclic heterocyclic group. In some embodiments, ring C may be selected from imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline, oxazoline, thiazoline, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidinone, pyrazolinone, pyrazolinone, pyrazole, tetrahydropyran, azepine, oxazepine, and diazepine; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0119] In some embodiments, ring C may be a substituted or unsubstituted 7-membered bicyclic heterocyclic group (e.g., fused, bridged, or spirocyclic). In some embodiments, ring C may be a substituted or unsubstituted 8-membered bicyclic heterocyclic group, such as a fused, bridged, or spirocyclic group. In some embodiments, ring C may be a substituted or unsubstituted 9-membered bicyclic heterocyclic group (e.g., fused, bridged, or spirocyclic). In some embodiments, ring C may be a substituted or unsubstituted 10-membered bicyclic heterocyclic group, such as a fused, bridged, or spirocyclic group. In some embodiments, the ring C may be selected from pyrrolizidine, dihydroindole, 1,2,3,4-tetrahydroquinoline, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane; wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0120] In some embodiments, the ring C may be substituted with one or more substituents, which are independently selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl. In some embodiments, the ring C may be substituted with one substituent, which is selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl.

[0121] In some implementation schemes, R 2 Optional from: Each of the above groups may be substituted or unsubstituted.

[0122] This article describes a non-restrictive list of Bcl-2 inhibitors, and it includes... Figure 1 Those provided in [the document]. Regarding... Figure 1 More information about the Bcl-2 inhibitors shown is provided in the following publications: WO 2020 / 089286, WO 2015 / 011400, US2014 / 0199234, WO 2018 / 027097, WO 2019 / 210828, WO 2018 / 192462, WO 2018 / 127130 and WO 2018 / 154004, for the purpose of description Figure 1 The limited purpose of each of the compounds shown is hereby cited in each of these documents.

[0123] Examples of compound (A) include the following:

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] Or a pharmaceutically acceptable salt of any of the aforementioned.

[0131] Compound (A) and its pharmaceutically acceptable salts can be prepared as described herein and in WO 2019 / 173082 (which is incorporated herein by reference in its entirety). As described in WO 2019 / 173082, compound (A) is a WEE1 inhibitor.

[0132] Table 1 provides embodiments of combinations of compounds (A) and (B) (including pharmaceutically acceptable salts of any of the foregoing). The numbers in Table 1 represent... Figure 1 and Figure 2 The compounds provided. For example, in Table 1, the combination represented by 3:5A corresponds to (including a pharmaceutically acceptable salt of any of the aforementioned).

[0133] Table 1

[0134]

[0135]

[0136] The order in which the compounds are administered in the combinations described herein may vary. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered before all compounds (B) or their pharmaceutically acceptable salts. In other embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered before at least one compound (B) or its pharmaceutically acceptable salts. In other embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered concurrently with compound (B) or its pharmaceutically acceptable salts. In other embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered after the administration of at least one compound (B) or its pharmaceutically acceptable salts. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered after the administration of all compounds (B) or their pharmaceutically acceptable salts.

[0137] Several advantages exist in using the combinations of compounds described herein. For example, combining compounds that simultaneously attack multiple pathways may be more effective in treating cancers (such as those described herein) than when the combined compounds are used as a monotherapy.

[0138] In some implementations, a combination of compound (A) as described herein (including its pharmaceutically acceptable salt) with one or more compounds (B) or their pharmaceutically acceptable salts may reduce the number and / or severity of side effects attributable to the compound described herein (such as compound (B)) or its pharmaceutically acceptable salts.

[0139] The combinations of compounds described herein can produce additive, synergistic, or strong synergistic effects. The combinations of compounds described herein can also produce non-antagonistic effects.

[0140] In some embodiments, a combination of compound (A) as described herein (including its pharmaceutically acceptable salt) with one or more compounds (B) or their pharmaceutically acceptable salts may produce an additive effect. In some embodiments, a combination of compound (A) as described herein (including its pharmaceutically acceptable salt) with one or more compounds (B) or their pharmaceutically acceptable salts may produce a synergistic effect. In some embodiments, a combination of compound (A) as described herein (including its pharmaceutically acceptable salt) with one or more compounds (B) or their pharmaceutically acceptable salts may produce a strong synergistic effect. In some embodiments, a combination of compound (A) as described herein (including its pharmaceutically acceptable salt) with one or more compounds (B) or their pharmaceutically acceptable salts is non-antagonistic.

[0141] As used herein, the term "antagonistic" means that when the activity of each compound is determined individually (i.e., as a single compound), the activity of the combination of compounds is smaller than the sum of the activities of the compounds in the combination. As used herein, the term "synergistic" means that when the activity of each compound is determined individually, the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination. As used herein, the term "cumulative" means that when the activity of each compound is determined individually, the activity of the combination of compounds is approximately equal to the sum of the individual activities of the compounds in the combination.

[0142] A potential advantage of using combinations as described herein is that it reduces the amount of compound required to effectively treat the disease symptoms disclosed herein compared to when each compound is administered as a monotherapy. For example, the amount of compound (B) or its pharmaceutically acceptable salt required to achieve the same reduction in disease markers (e.g., tumor size) when administered as a monotherapy can be less than the amount of compound (B) or its pharmaceutically acceptable salt required to achieve the same reduction. Another potential advantage of using combinations as described herein is that using two or more compounds with different mechanisms of action can create a greater barrier to the development of resistance compared to when compounds are administered as a monotherapy. Additional advantages of using combinations as described herein may include: little or no cross-resistance between the compounds in the combinations; different elimination pathways for the compounds in the combinations; and / or little or no overlapping toxicity between the compounds in the combinations.

[0143] Pharmaceutical Composition

[0144] Compound (A) (including its pharmaceutically acceptable salts) may be provided in the pharmaceutical composition. Similarly, compound (B) (including its pharmaceutically acceptable salts) may be provided in the pharmaceutical composition.

[0145] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are typically formulated according to a specific intended route of administration.

[0146] As used herein, "carrier" refers to a compound that facilitates the binding of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0147] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that does not have significant pharmaceutical activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of a potent pharmaceutical product whose mass is too small to manufacture and / or administer. It can also be a liquid used to dissolve a pharmaceutical product intended for administration by injection, ingestion, or inhalation. Common forms of diluents in the art are buffered aqueous solutions, such as, but not limited to, phosphate-buffered saline solutions with pH and isotonicity that mimic human blood.

[0148] As used herein, "excipient" refers to a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelator. "Diluent" is a type of excipient.

[0149] In some embodiments, compound (B) and its pharmaceutically acceptable salt may be provided in a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt). In other embodiments, compound (B) and its pharmaceutically acceptable salt may be administered in a pharmaceutical composition separate from a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt).

[0150] The pharmaceutical compositions described herein may be administered to human patients themselves, or to compositions wherein the pharmaceutical composition is mixed with other active ingredients (as in combination therapy), or with carriers, diluents, excipients, or combinations thereof. The appropriate formulation depends on the chosen route of administration. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0151] The pharmaceutical compositions disclosed herein can be manufactured in ways known per se, such as by conventional mixing, dissolving, granulation, pill preparation, grinding, emulsification, encapsulation, embedding, or tableting processes. Furthermore, they contain an active ingredient in an amount effective to achieve their intended use. Many compounds used in the pharmaceutical compositions disclosed herein can be provided as salts having pharmaceutically compatible counterions.

[0152] Various techniques exist in the art for administering compounds, salts, and / or compositions, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery (including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, and intraocular injection). In some embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered orally. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered to a subject via the same route of administration as compound (B) and its pharmaceutically acceptable salts. In other embodiments, compound (A) (including its pharmaceutically acceptable salts) may be administered to a subject via a different route of administration than compound (B) and its pharmaceutically acceptable salts.

[0153] Compounds, salts, and / or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound into the affected area in the form of a reservoir or sustained-release formulation. Furthermore, compounds can be administered in targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. The liposomes will target the organ and be selectively taken up by it. For example, intranasal or pulmonary delivery to target respiratory diseases or conditions may be desirable.

[0154] The composition may (if desired) be present in a packaging or dispenser device that may include one or more unit dose forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification associated with the container form as prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the form of the drug for human or veterinary use. For example, such notification may be a label or approved product insert approved by the U.S. Food and Drug Administration for prescription drugs. Compositions that may contain the compounds and / or salts described herein formulated in a compatible drug carrier may also be prepared, placed, and labeled for the treatment of the indicated condition in a suitable container.

[0155] Uses and treatments

[0156] As provided herein, in some embodiments, a combination of compounds comprising an effective amount of compound (A) (including a pharmaceutically acceptable salt thereof) and an effective amount of one or more compounds (B) or a pharmaceutically acceptable salt thereof may be used to treat a disease or condition.

[0157] Examples of diseases or conditions that can be treated by combination of compounds and pharmaceutically acceptable salts include malignancies, cancers, and syndromes (such as those described herein). In some embodiments, the disease or condition can be a hematologic malignancy. Exemplary hematologic malignancies include leukemia, lymphoma, or myeloma. In some embodiments, the hematologic malignancy can be refractory. In some embodiments, the disease or condition can be leukemia, including but not limited to: acute myeloid leukemia (AML) (including its subtypes, such as subtype TP53 wild-type AML, TP53 mutant AML, refractory AML, acute promyelocytic leukemia, acute basophilic leukemia, and treatment-associated AML), chronic lymphocytic leukemia (CLL) (including but not limited to hairy cell leukemia and small lymphocytic lymphoma), acute lymphoblastic leukemia (ALL) (including but not limited to specializations targeting B cells, T cells, and ETP), and chronic myeloid leukemia (CML) (chronic myeloid leukemia).

[0158] In some implementations, the disease or condition may be myelodysplastic syndrome. In some implementations, the disease or condition may be myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET).

[0159] As described herein, combinations of compounds can be used to treat and / or improve lymphomas. Exemplary lymphomas include, but are not limited to, non-Hodgkin lymphoma (NHL) (including, but not limited to, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), peripheral T-cell lymphoma, cutaneous T-cell lymphoma, NK lymphoma, Burkitt lymphoma, and Waldenström macroglobulinemia). Combinations of compounds (including their pharmaceutically acceptable salts) can also be used to treat myeloma. Examples of treatable myeloma include, but are not limited to, multiple myeloma (MM) (including, but not limited to, translocation (11;14) and non-translocation (11;14)). As described herein, combinations of compounds can be used to treat and / or improve systemic mastocytosis and blastic plasmacytoid dendritic cell tumors.

[0160] The diseases or conditions described herein may be in adult or pediatric subjects. In some embodiments, subjects with a disease or condition (such as those described herein) may be pediatric subjects. In some embodiments, the disease or condition may be a pediatric hematologic malignancy, such as pediatric AML and / or pediatric ALL.

[0161] The combinations of compounds described herein can be used to treat and / or improve solid tumors. For example, in some embodiments, the solid tumor may be selected from Ewing sarcoma and Wilms' cancer. Additional examples of solid tumors that can be treated by combinations of the compounds described herein (including their pharmaceutically acceptable salts) are bladder cancer, brain cancer, breast cancer (including but not limited to ER+ breast cancer and triple-negative breast cancer), cervical cancer, choriocarcinoma, cervical brain cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder / choleduct cancer, head and neck cancer (including oral cancer), hepatocellular carcinoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), mesothelioma, ovarian cancer, osteosarcoma, pancreatic cancer, penile cancer, anal cancer, prostate cancer, small cell carcinoma, gastric cancer, rectal cancer, renal pelvis / ureter cancer, skin cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thyroid cancer, endometrial cancer, and cervical cancer. In some embodiments, the disease or condition may be a cancer expressing the BCL-2 protein.

[0162] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles, and especially mammals. "Mammalian" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates (e.g., monkeys, chimpanzees, and apes), and especially humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, such as a feverish child or infant. In other embodiments, the subject may be an adult.

[0163] As used herein, the terms “treat,” “treating,” “treatment,” and “therapeutic” do not necessarily mean the complete cure or elimination of a disease or condition. Any degree of relief from any undesirable sign or symptom of a disease or condition may be considered a treatment and / or therapy. Furthermore, treatment may include behaviors that may worsen a subject’s overall feeling of health or appearance.

[0164] The term "effective amount" is used to indicate the amount of an active compound or agent that elicits the indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt, or composition may be the amount required to prevent, alleviate, or improve symptoms of a disease or condition, or to prolong the survival of a treated subject. This response can occur in tissues, systems, animals, or humans and includes the reduction of signs or symptoms of the treated disease or condition. Based on the disclosure provided herein, the determination of the effective amount is entirely within the capabilities of those skilled in the art. The effective amount of the compounds disclosed herein as a dosage will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal under consideration. The dosage may be modulated to achieve the desired effect, but this dosage will depend on factors such as body weight, diet, concomitant drug treatments, and other factors that a person skilled in the medical field will recognize.

[0165] For example, an effective amount of a compound or radiation is an amount that results in: (a) a reduction, alleviation, or disappearance of one or more symptoms caused by cancer; (b) a reduction in tumor size; (c) elimination of the tumor; and / or (d) long-term disease stabilization (growth arrest) of the tumor.

[0166] The amount of compounds, salts, and / or compositions required for treatment will vary not only with the specific compound or salt chosen, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, and the patient's age and condition, and will ultimately be determined by the attending physician or clinician. In the case of administering pharmaceutically acceptable salts, the dosage can be calculated using the free base. As those skilled in the art will understand, in some cases it may be necessary to administer the compounds disclosed herein in amounts exceeding or even far exceeding the dosage range described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.

[0167] As will be apparent to those skilled in the art, the available in vivo dose and specific administration method will vary depending on age, weight, severity of pain, species of the mammal being treated, the specific compound used, and the specific purpose for which the compound is used. The determination of the effective dose level (i.e., the dose level necessary to achieve the desired outcome) can be performed by those skilled in the art using conventional methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, the available dose of a pharmaceutically acceptable salt of compounds (A) and / or (B) or any of the foregoing can be determined by comparing their in vitro and in vivo activities in animal models. Such comparisons can be made by comparing with established drugs such as cisplatin and / or gemcitabine.

[0168] The dosage and interval can be individually adjusted to provide plasma levels sufficient to maintain the modulating effect or minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated based on in vivo and / or in vitro data. The dosage necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or bioassays can be used to determine plasma concentrations. The MEC value can also be used to determine the dosing interval. The composition should be administered using a regimen that maintains plasma levels at 10% to 90% above the MEC, preferably between 30% and 90%, and most preferably between 50% and 90%. In cases of local application or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0169] It should be noted that in cases of toxicity or organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust administration. Conversely, in cases of insufficient clinical response (excluding toxicity), the attending physician will also know to adjust treatment to a higher level. The dosage administered in the management of the disorder of interest will vary depending on the severity of the disease or condition being treated and the route of administration. For example, the severity of the disease or condition can be assessed in part by standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on age, weight, and individual patient response. Procedures equivalent to those discussed above are available in veterinary medicine.

[0170] The efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subset of such compounds (sharing certain chemical components) can be established by determining its in vitro toxicity to cell lines, such as mammalian and preferably human cell lines. Results of such studies typically predict toxicity in animals, such as mammals or more specifically humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models, such as mice, rats, rabbits, dogs, or monkeys. Several recognized methods, such as in vitro methods, animal models, or human clinical trials, can be used to establish the efficacy of a particular compound. When selecting a model to determine efficacy, a person skilled in the art can follow existing techniques to select an appropriate model, dosage, route of administration, and / or regimen.

[0171] Example

[0172] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0173] CTG determination

[0174] Using CellTiter- A luminescent cell viability assay measures cell proliferation. This assay involves the application of a single reagent (CellTiter- The reagent was added directly to the cells cultured in serum-supplemented medium. DMS-53 (ATCC CRL-2062) cells were cultured according to ATCC recommendations, with 20,000 cells seeded per well.

[0175] Each compound evaluated was prepared as a DMSO stock solution (10 mM). The compounds were tested repeatedly on each plate using the concentrations shown in Table 2. Cells were treated with the compound at 10 times the stock concentration (10.0 μL). The plates were incubated at 37 °C and 5% CO2 for 72 h, and then equilibrated at room temperature for approximately 30 min. An equal volume of CellTiter- was added to each well. Reagent (100 μL). The plate was mixed on a track-shaking device for 2 minutes to induce cell lysis, and then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence was recorded using a SpectraMAX, M5e plate reader according to the CellTiter-Glo protocol. The inhibition percentage was calculated using the following formula: Inhibition % = (RLU * 100 / (RLU of cell background)). Figure 3 Table 2 shows the combined effects of adding compound 3 to compound 1a (also referred to as "compound 1A" throughout the specification and figures).

[0176] Table 2

[0177]

[0178] xenograft tumor model

[0179] MV4-11 cells were cultured in vitro in IMDM medium supplemented with 10% fetal bovine serum at 37°C under a 5% CO2 atmosphere. Cells growing in the exponential growth phase were collected and counted for tumor inoculation. Mice were subepithelially inoculated with MV4-11 cells—95% viable tumor cells (1×10⁻⁶)—on the right flank. 7 A single-cell suspension in 100 μL of serum-free IMDM was used for tumorigenesis. When the average tumor size reached approximately 230 mm... 3 Treatment began at that time, with individual tumor sizes ranging from 200-260 mm. 3 Animals were randomly assigned to treatment groups of 10 animals each and administered the drugs orally for 21 days as follows: the same volume of the medium as single-agent treatment; 60 mg / kg of compound 1a, 25 mg / kg of compound 3; and combination treatment of compound 1a (60 mg / kg) and compound 3 (25 mg / kg). Tumor volume was assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following equation: TGI = (1 - (Td – T0) / (Cd – C0)) × 100%. Td and Cd are the mean tumor volumes in the treated and control animals, and T0 and C0 are the mean tumor volumes in the treated and control animals at the start of the experiment. Figure 4 Mild tumor growth inhibition (20%) was demonstrated with single-agent treatment of compound 1a at 60 mg / kg, and approximately (50%) with single-agent treatment of compound 3. Figure 4 In the table, the bottom row (squares) represents data for the combination of compound 3 (25 mg / kg) and compound 1a (60 mg / kg), and the third-to-last row (squares) represents data for compound 1a (60 mg / kg). The combination of compound 3 (25 mg / kg) and compound 1a (60 mg / kg) exhibited a significant TGI on day 22, suggesting that the combination of the Bcl-2 inhibitor and WEE1 inhibitor described herein may be used to treat the disease or condition described herein.

[0180] Furthermore, although the foregoing has provided some detailed description by way of illustration and example for the purpose of clarity and understanding, those skilled in the art will understand that many and various modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the form of the disclosure herein is merely illustrative and is not intended to limit the scope of this disclosure, but rather to cover all modifications and alternatives consistent with the true scope and spirit of this disclosure.

Claims

1. Use of the compound combination in the preparation of a medicament for treating hematologic malignancies or small cell lung cancer, wherein the hematologic malignancy is acute myeloid leukemia (AML), and wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, wherein: The compound (A) has the following structure: （A） and The compound (B) is a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof; The Bcl-2 inhibitor mentioned above is: Venetok (ABT-199) Or, or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein: Apply compound (A) or a pharmaceutically acceptable salt thereof before or after the application of compound (B) or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, wherein: Compound (A) or a pharmaceutically acceptable salt thereof may be administered concurrently with compound (B) or a pharmaceutically acceptable salt thereof.

4. The use according to claim 1, wherein: Compound (B) or a pharmaceutically acceptable salt thereof is provided in a pharmaceutical composition comprising compound (A) or a pharmaceutically acceptable salt thereof.

5. The use according to claim 1, wherein: Compound (B) or a pharmaceutically acceptable salt thereof is provided in a pharmaceutical composition separate from a pharmaceutical composition comprising compound (A) or a pharmaceutically acceptable salt thereof.

6. The use according to any one of claims 1 to 5, wherein the drug is used to treat acute myeloid leukemia (AML).

7. The use according to any one of claims 1 to 5, wherein the drug is used to treat small cell lung cancer.

Images