combination

Abstract

Disclosed herein are combinations of compounds for treating a disease or condition, such as cancer. The combinations of compounds for treating a disease or condition can include a WEE1 inhibitor and a Bcl-2 inhibitor, along with pharmaceutically acceptable salts of any of the foregoing.

Description

[Technical field]

[0001] (Incorporation by reference of any priority application) For example, any application in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application is incorporated by reference herein under 37 CFR 1.57 and 4.18 and 20.6, including U.S. Provisional Application No. 62 / 952,039, filed December 20, 2019.

[0002] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are combination therapies and methods of treating diseases and / or conditions using the combination therapies described herein. [Background technology]

[0003] Cancer is a family of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Today's cancer treatments include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary depending on the type of cancer and the stage at which the cancer is diagnosed. In the United States, it is estimated that approximately 1.8 million people will be diagnosed with cancer and 606,880 people will die from cancer in 2019. Thus, there remains a need for effective cancer treatments. Summary of the Invention

[0004] Some embodiments described herein relate to a compound combination that may include an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of one or more of compounds (B), or a pharma- ceutically acceptable salt thereof.

[0005] Some embodiments described herein relate to the use of a combination of compounds comprising an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of one or more of compound (B), or a pharma- ceutically acceptable salt thereof, for treating a disease or condition. 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 pharma- ceutically acceptable salt thereof, and an effective amount of one or more of compound (B), or a pharma- ceutically acceptable salt thereof.

[0006] In some embodiments, the disease may be a cancer as described herein. [Brief description of the drawings]

[0007] [Figure 1-1] An example of compound (A) is provided. [Figure 1-2] An example of compound (A) is provided. [Figure 1-3] An example of compound (A) is provided. [Figure 1-4] An example of compound (A) is provided. [Figure 2-1] An example of compound (B) is provided. [Figure 2-2] An example of compound (B) is provided. [Diagram 3] Shows inhibition of monotherapy and combination therapy against RS4;11, DMS053, MV4-11, and Toledo cell lines. [Figure 4] 1 shows inhibition of monotherapy and combination therapy against MCF-7 cell line. [Diagram 5] 1 shows tumor volume in response to monotherapy and combination therapy in an HL-60 (AML) mouse model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Definition of Compound (A) and its Pharmacologically Acceptable Salts Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise stated.

[0009] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it means the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups 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, haloalkoxy, amino, monosubstituted amine group, disubstituted amine group, monosubstituted amine(alkyl) group, and disubstituted amine(alkyl).

[0010] As used herein, "C a ~C b" (where "a" and "b" are integers) refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified, the broadest ranges described by these definitions are intended to be assumed.

[0011] When two "R" groups are described as being "together," the R groups and the atom to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic ring. For example, and without limitation, NR a R b R in the group a and R b When and are shown to be "together", it is meant that they are covalently linked to each other to form a ring.

[0012] [ka]

[0013] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched chain alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms (wherever it appears in this specification, a numerical range such as "1 to 30" refers to each integer within the given range, e.g., "1 to 30"). "carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 30 carbon atoms, although this definition also extends to the occurrence of the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0014] As used herein, the term "alkylene" refers to a divalent, fully saturated, straight-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. An alkylene group is:

[0015] [ka] , followed by the number of carbon atoms, followed by " * ". For example,

[0016] [ka] represents ethylene. The alkylene group may have 1 to 30 carbon atoms (whenever it appears in this specification, a numerical range such as "1 to 30" refers to each integer within the given range, e.g., "1 to 30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 30 carbon atoms, but this definition also extends to the appearance of the term "alkylene" where no numerical range is specified). The alkylene group may also be a medium-sized alkyl having 1 to 12 carbon atoms. The alkylene group may also be a lower alkyl having 1 to 4 carbon atoms. The alkylene group may be substituted or unsubstituted. For example, a lower alkylene group may be C 3~6Monocyclic cycloalkyl groups, such as

[0017] [ka] ) may be substituted by replacing one or more hydrogens on a lower alkylene group, and / or by replacing both hydrogens on the same carbon.

[0018] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing a carbon double bond, 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.

[0019] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing a carbon triple bond, including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, etc. Alkynyl groups can be unsubstituted or substituted.

[0020] As used herein, "cycloalkyl" refers to a group that is fully saturated (with no double bonds or triple bonds). Cycloalkyl refers to a monocyclic (without double bonds) or polycyclic (such as bicyclic) hydrocarbon ring system. When composed of more than one ring, the rings may be fused, bridged, or joined together in a spiro fashion. As used herein, the term "fused" refers to two rings sharing one bond with two atoms. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings sharing one atom, where the two rings are not joined by a bridge. Cycloalkyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0021] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic (such as bicyclic) hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). Cycloalkenyl groups can contain 3-10 atoms in a ring, 3-8 atoms in a ring, or 3-6 atoms in a ring. When composed of more than one ring, the rings may be connected together in a fused, bridged, or spiro fashion. Cycloalkenyl groups may be unsubstituted or substituted.

[0022] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic (such as bicyclic) aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, aryl groups include those having C6 to C7 14 Aryl groups, C6-C 10 It may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0023] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (such as bicyclic) aromatic ring system (a ring system having a fully delocalized pi-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring, such as 9 carbon atoms and 1 heteroatom; 8 carbon atoms and 2 heteroatoms; 7 carbon atoms and 3 heteroatoms; 8 carbon atoms and 1 heteroatom; 7 carbon atoms and 2 heteroatoms; 6 carbon atoms and 3 heteroatoms; 5 carbon atoms and 4 heteroatoms; 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; or 2 carbon atoms and 3 heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, in which two rings share at least one chemical bond. Examples of heteroaryl rings include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzox ... Heteroaryl groups include, but are not limited to, thazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0024] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms and one to five heteroatoms together constitute said ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned such that a fully delocalized pi-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to be defined as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or joined together in a spiro fashion. As used herein, the term "fused" refers to two rings sharing one bond with two atoms. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which a heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings sharing one atom, where the two rings are not joined by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. For example, 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; 2 carbon atoms and 3 heteroatoms; 1 carbon atom and 4 heteroatoms; 3 carbon atoms and 1 heteroatom; or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in a heteroalicyclic ring may be quaternized. A heterocyclyl or heteroalicyclic group can be unsubstituted or substituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 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, isopropyl alcohol ... These include, but are not limited to, soxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane. .

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

[0026] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected as a substituent through a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl 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 connected as a substituent through a lower alkylene group. The lower alkylene and heterocyclyl of (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-thiazinane-4-yl(methyl).

[0028] As used herein, the term "hydroxy" refers to an --OH group.

[0029] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy may be substituted or unsubstituted.

[0030] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0031] A "cyano" group refers to a "-CN" group.

[0032] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0033] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0034] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

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

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

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

[0038] A "C-amide" group is defined as -C(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

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

[0040] The "S-sulfonamide" group is "-SO2N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

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

[0042] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0043] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R may be the same as defined for O-carboxy. Ester and C-carboxy may be substituted or unsubstituted.

[0044] A "nitro" group refers to a "-NO2" group.

[0045] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Sulfenyl can be substituted or unsubstituted.

[0046] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0047] A "sulfonyl" group refers to a "SO2R" group, where R may be the same as defined for sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0048] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl can be substituted or unsubstituted.

[0049] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0050] As used herein, the terms "amino" and "unsubstituted amino" refer to the group --NH.

[0051] The "monosubstituted amine" group is defined as "-NHR A " group, where R A R may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A may be substituted or unsubstituted. Examples of the mono-substituted amine group include a mono-alkylamine group, a mono-C1 to C6 alkylamine group, a mono-arylamine group, a mono-C6 to C7 alkylamine group, a mono-arylamine group, a mono-C6 to C8 alkylamine group, a mono-aryl ... 10 Examples of monosubstituted amine groups include - Examples include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0052] A "disubstituted amine" group is defined as "-NR A R B " group, where R A and R B R may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A and R B may be independently substituted or unsubstituted. Examples of the disubstituted amine group include a di-alkylamine group, a di-C1 to C6 alkylamine group, a di-arylamine group, a di-C6 to C 10 Examples of disubstituted amine groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0053] As used herein, a "monosubstituted amine(alkyl)" group refers to a monosubstituted amine linked as a substituent via a lower alkylene group, as provided herein. The monosubstituted amine(alkyl) may be substituted or unsubstituted. Examples of the monosubstituted amine(alkyl) group include mono-alkylamine(alkyl) groups, mono-C1-C6 alkylamine(C1-C6 alkyl) groups, mono-arylamine(alkyl) groups, mono-C6-C8 alkylamine(C1-C8 ... 10 Examples of monosubstituted amine (alkyl) groups include, but are not limited to, -CHNH(methyl), -CHNH(phenyl), -CHCHNH(methyl), -CHCHNH(phenyl), and the like.

[0054] As used herein, a "disubstituted amine(alkyl)" group refers to a disubstituted amine, as provided herein, linked as a substituent via a lower alkylene group. The disubstituted amine(alkyl) may be substituted or unsubstituted. Disubstituted amine(alkyl) groups include, for example, dialkylamine(alkyl) groups, di-C1-C6 alkylamine(C1-C6 alkyl) groups, di-arylamine(alkyl) groups, di-C6-C8 alkyl ... 10 Arylamine (C1-C6 alkyl) groups and the like can be included. Disubstituted amine (alkyl) groups include, but are not limited to, -CH2N(methyl)2, -CH2N(phenyl)(methyl), -NCH2(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl), and the like.

[0055] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

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

[0057] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, etc. , nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting the compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt with an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. Those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 becomes NH3). + ), and the positive charge can be a negatively charged counterion (Cl - Understand that the benefits of these measures may be offset by other measures such as:

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

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

[0060] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced required dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a 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). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

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

[0062] When a range of values ​​is provided, the upper and lower limits, as well as any intervening values ​​between the upper and lower limits of the range, It is understood that each of the values ​​is encompassed within the embodiments.

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

[0064] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0065] Compound (A) Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, which combination may include an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of one or more of compounds (B), or pharma- ceutically acceptable salts thereof, where compound (A) has the structure:

[0066] [ka] In the formula, R 1 can be selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, unsubstituted mono-C1-C6 alkylamine, and unsubstituted di-C1-C6 alkylamine; each R 2 may be independently selected from the group consisting of halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C6 cycloalkyl, or when m is 2 or 3, each R 2 can be independently selected from halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C6 cycloalkyl, or two R 2groups, together with the atoms to which they are attached, can form a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; R 4 is NO2, S(O)R 6 , SO2R 6 , halogen, cyano, and unsubstituted C1-C6 haloalkyl; R 5 -X 1 -(Alk 1 ) n -R 7 It may be Alk 1 can be selected from unsubstituted C1-C4 alkylene and C1-C4 alkylene substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, unsubstituted C1-C3 alkyl, and unsubstituted C1-C3 haloalkyl; R 6 can be selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C6 cycloalkyl; R 7 is a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C3-C 10 X may be selected from cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, hydroxy, amino, substituted or unsubstituted mono-substituted amine group, substituted or unsubstituted di-substituted amine group, substituted or unsubstituted N-carbamyl, substituted or unsubstituted C-amido, and substituted or unsubstituted N-amido; m may be 0, 1, 2, or 3; n may be selected from 0 and 1; X may be selected from 0, 1, 2, or 3; 1 can be selected from -O-, -S-, and -NH-.

[0067] In some embodiments, R 1 can be, for example, a halogen, such as fluoro, chloro, bromo, or iodo. In some embodiments, R 1 may be fluoro. In some embodiments, R 1 may be chloro. In some embodiments, R 1 may be hydrogen.

[0068] In some embodiments, R 1 may be a substituted or unsubstituted C1-C6 alkyl. For example, in some embodiments, R 1 may be a substituted C1-C6 alkyl. In other embodiments, R 1 may be an unsubstituted C1-C6 alkyl. Examples of suitable C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and hexyl (branched and straight chain). In some embodiments, R 1 may be unsubstituted methyl or unsubstituted ethyl.

[0069] In some embodiments, R 1 may be a substituted or unsubstituted C1-C6 haloalkyl, such as a substituted or unsubstituted mono-haloC1-C6 alkyl, a substituted or unsubstituted di-haloC1-C6 alkyl, a substituted or unsubstituted tri-haloC1-C6 alkyl, a substituted or unsubstituted tetra-haloC1-C6 alkyl, or a substituted or unsubstituted penta-haloC1-C6 alkyl. 1 may be unsubstituted -CHF2, -CF3, -CH2CF3, or -CF2CH3.

[0070] In some embodiments, R 1 may be a substituted or unsubstituted monocyclic or bicyclic C-C cycloalkyl. For example, in some embodiments, R 1 may be a substituted monocyclic C-C cycloalkyl. In other embodiments, R 1 may be an unsubstituted monocyclic C3-C6 cycloalkyl. Examples of suitable monocyclic or bicyclic C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, [1.1. 1] Bicyclopentyl, and cyclohexyl.

[0071] In some embodiments, R 1may be a substituted or unsubstituted C1-C6 alkoxy. For example, in some embodiments, R 1 may be a substituted C1-C6 alkoxy. 1 may be an unsubstituted C1-C6 alkyl. Examples of suitable C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight chain), and hexoxy (branched and straight chain). In some embodiments, R 1 may be unsubstituted methoxy or unsubstituted ethoxy.

[0072] In some embodiments, R 1 may be an unsubstituted mono-C1-C6 alkylamine, such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, tert-butylamine, pentylamine (branched and straight chain), and hexylamine (branched and straight chain). 1 may be methylamine or ethylamine.

[0073] In some embodiments, R 1 may be an unsubstituted di-C1-C6 alkylamine. In some embodiments, each C1-C6 alkyl in the di-C1-C6 alkylamine is the same. In other embodiments, each C1-C6 alkyl in the di-C1-C6 alkylamine is different. Examples of suitable di-C1-C6 alkylamine groups include, but are not limited to, di-methylamine, di-ethylamine, (methyl)(ethyl)amine, (methyl)(isopropyl)amine, and (ethyl)(isopropyl)amine.

[0074] In some embodiments, m may be 0. When m is 0, the skilled artisan will recognize that R 2is attached is unsubstituted. In some embodiments, m can be 1. In some embodiments, m can be 2. In some embodiments, m can be 3.

[0075] In some embodiments, one R 2 may be unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and hexyl (branched and straight chain)), and any other R 2 When present, each R can be independently selected from halogen (e.g., fluoro or chloro), substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 haloalkyl (such as those described herein), and substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl (such as those described herein). 2 may be independently selected from unsubstituted C1-C6 alkyl, such as those described herein.

[0076] In some embodiments, m can be 2, and each R 2 In some embodiments, m can be 2 and each R 2 In some embodiments, m can be 2, and each R 2 In some embodiments, m can be 2 and each R 2 may be geminal unsubstituted methyl.

[0077] In some embodiments, two R 2 The groups, together with the atom to which they are attached, can form a substituted or unsubstituted monocyclic C3-C6 cycloalkyl. For example, in some embodiments, two R 2 The groups, together with the atom to which they are attached, form a substituted monocyclic C3-C6 cycloalkyl, such as those described herein. In another embodiment, two R 2 The groups, together with the atom to which they are attached, can form an unsubstituted monocyclic C3-C6 cycloalkyl, such as those described herein. In some embodiments, two R 2 The groups, together with the atom to which they are attached, can form an unsubstituted cyclopropyl.

[0078] In some embodiments, two R 2 The groups, together with the atom to which they are attached, can form a substituted or unsubstituted monocyclic 3-6 membered heterocyclyl. For example, in some embodiments, two R 2 The groups, together with the atoms to which they are attached, can form a substituted monocyclic 3- to 6-membered heterocyclyl. In other embodiments, two R 2 The groups, together with the atoms to which they are attached, can form an unsubstituted monocyclic 3- to 6-membered monocyclic heterocyclyl. In some embodiments, the substituted monocyclic 3- to 6-membered heterocyclyl can be substituted on one or more nitrogen atoms. Examples of suitable substituted or unsubstituted monocyclic 3- to 6-membered heterocyclyl groups include azidirine, oxy, phenyl ... These include, but are not limited to, orane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, and dioxane.

[0079] In some embodiments, R 4 may be NO2. In some embodiments, R 4 may be cyano. In some embodiments, R 4 may be a halogen.

[0080] In some embodiments, R 4 may be an unsubstituted C1-C6 haloalkyl, such as those described herein. In some embodiments, R 4may be -CF3.

[0081] In some embodiments, R 4 is S(O)R 6 In some embodiments, R 4 is SO2R 6 In some embodiments, R 4 may be SO2CF3.

[0082] In some embodiments, R 6 may be a substituted or unsubstituted C1-C6 alkyl. For example, in some embodiments, R 6 may be a substituted C1-C6 alkyl, such as those described herein. In other embodiments, R 6 may be an unsubstituted C1-C6 alkyl, such as those described herein.

[0083] In some embodiments, R 6 may be a substituted or unsubstituted monocyclic or bicyclic C-C cycloalkyl. For example, in some embodiments, R 6 may be a substituted monocyclic or bicyclic C-C cycloalkyl. In other embodiments, R 6 may be an unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl. Examples of suitable monocyclic or bicyclic C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, [1.1.1]bicyclopentyl, and cyclohexyl.

[0084] In some embodiments, R 6 may be a substituted or unsubstituted C1-C6 haloalkyl, such as those described herein. In some embodiments, R 6 may be -CF3.

[0085] In some embodiments, R 5 -X 1 -(Alk 1 )n -R 7 In some embodiments, X 1 may be -O-. In some embodiments, X 1 may be -S-. In some embodiments, X 1 may be -NH-.

[0086] In some embodiments, Alk 1 is the unsubstituted -(CH2) 1~4 - * It may be " * " is R 7 In some embodiments, Alk 1 teeth,

[0087] [ka] may be also possible.

[0088] In some embodiments, Alk 1 is replaced

[0089] [ka] It may be " * " is R 7 For example, in some embodiments, Alk 1 may be a substituted methylene, a substituted ethylene, a substituted propylene, or a substituted butylene. In some embodiments, Alk 1 may be mono-, di-, or trisubstituted. In some embodiments, Alk 1 may be monosubstituted with halogen (such as fluoro or chloro) or unsubstituted C1-C3 alkyl, such as those described herein. 1 may be monosubstituted with unsubstituted C1-C3 haloalkyl, such as those described herein. In some embodiments, Alk 1may be monosubstituted with fluoro or unsubstituted methyl. In some embodiments, Alk 1 may be disubstituted with one fluoro and one unsubstituted C1-C3 alkyl, such as those described herein. In other embodiments, Alk 1 may be disubstituted with one unsubstituted C1-C3 haloalkyl, such as those described herein, and one unsubstituted C1-C3 alkyl, such as those described herein. In some embodiments, Alk 1 is optionally disubstituted with one fluoro and one unsubstituted methyl. In some embodiments, Alk 1 may be disubstituted with two independently selected unsubstituted C1-C3 alkyl groups, such as those described herein. In some embodiments, Alk 1 may be disubstituted with unsubstituted methyl.

[0090] In some embodiments, Alk 1 teeth,

[0091] [ka] may be selected from:

[0092] In some embodiments, n may be 0. When n is 0, the skilled artisan will recognize that X 1 Directly R 7 In some embodiments, n may be 1.

[0093] In some embodiments, R 7 may be a substituted or unsubstituted mono-substituted amine group. For example, R 7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C6-C 10Aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl, substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl (unsubstituted C1-C6 alkyl), substituted or unsubstituted monocyclic or bicyclic C6-C 10 The amino group may be mono-substituted with aryl (unsubstituted C1-C6 alkyl), substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl (unsubstituted C1-C6 alkyl), or substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl (unsubstituted C1-C6 alkyl). Examples of suitable mono-substituted amine groups include, but are not limited to, -NH(methyl), -NH(isopropyl), -NH(cyclopropyl), -NH(phenyl), -NH(benzyl), and -NH(pyridin-3-yl).

[0094] In some embodiments, R 7 may be a substituted or unsubstituted disubstituted amine group. For example, R 7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C6-C 10 Aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl, substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl (unsubstituted C1-C6 alkyl), substituted or unsubstituted monocyclic or bicyclic C6-C 10The amino group may be substituted with two substituents independently selected from aryl (unsubstituted C1-C6 alkyl), substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl (unsubstituted C1-C6 alkyl), or substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl (unsubstituted C1-C6 alkyl). In some embodiments, the two substituents may be the same. In other embodiments, the two substituents may be different. Examples of suitable disubstituted amine groups include, but are not limited to, -N(methyl)2, -N(ethyl)2, -N(isopropyl)2, -N(benzyl)2, -N(ethyl)(methyl), -N(isopropyl)(methyl), -N(ethyl)(isopropyl), -N(phenyl)(methyl), and -N(benzyl)(methyl).

[0095] In some embodiments, R 7 may be selected from substituted or unsubstituted N-carbamyl, substituted or unsubstituted C-amido, and substituted or unsubstituted N-amido.

[0096] In some embodiments, R 7 is a substituted or unsubstituted C3-C 10 In some embodiments, R 7 is a substituted or unsubstituted monocyclic C3-C 10 In another embodiment, R 7 is a substituted or unsubstituted bicyclic C 10 Cycloalkyl, e.g., bridged, fused, or spiro C-C 10 Cycloalkyl may be used. Suitable substituted or unsubstituted monocyclic or bicyclic C3-C 10Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3.3]heptyl, spiro[2.3]hexyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[2.5]octyl, spiro[3.5]nonyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, Examples include, but are not limited to, decahydronaphthalenyl, octahydro-1H-indenyl, octahydropentalenyl, bicyclo[4.2.0]octyl, bicyclo[2.1.0]pentyl, and bicyclo[3.2.0]heptyl.

[0097] In some embodiments, R 7 is a substituted or unsubstituted C6-C 10 In some embodiments, R 7 is the substituted C6-C 10 In another embodiment, R 7 is unsubstituted C6-C 10 In some embodiments, R 7may be substituted or unsubstituted -cyclopropyl-cyclobutyl spiroalkyl, -cyclopropyl-cyclopentyl spiroalkyl, -cyclopropyl-cyclohexyl spiroalkyl, -cyclopropyl-cycloheptyl spiroalkyl, -cyclopropyl-cyclooctyl spiroalkyl, -cyclobutyl-cyclopropyl spiroalkyl, -cyclobutyl-cyclobutyl spiroalkyl, -cyclobutyl-cyclopentyl spiroalkyl, -cyclobutyl-cyclohexyl spiroalkyl, -cyclobutyl-cycloheptyl spiroalkyl, -cyclopentyl-cyclopropyl spiroalkyl, -cyclopentyl-cyclobutyl spiroalkyl, -cyclopentyl-cyclopentyl spiroalkyl, cyclopentyl-cyclohexyl spiroalkyl, -cyclohexyl-cyclopropyl spiroalkyl, -cyclohexyl-cyclobutyl spiroalkyl, -cyclohexyl-cyclopentyl spiroalkyl, -cycloheptyl-cyclopropyl spiroalkyl, -cyclohexyl-cyclobutyl spiroalkyl, -cyclohexyl-cyclopentyl spiroalkyl, -cycloheptyl-cyclopropyl spiroalkyl, -cycloheptyl-cyclobutyl spiroalkyl, or -cyclooctyl-cyclopropyl spiroalkyl.

[0098] In some embodiments, R 7 may be a substituted or unsubstituted 3- to 10-membered heterocyclyl. In some embodiments, R 7 may be a substituted 3- to 10-membered heterocyclyl. 7 may be an unsubstituted 3- to 10-membered heterocyclyl. In some embodiments, R 7 may be a substituted or unsubstituted monocyclic 3- to 10-membered heterocyclyl. 7 may be a substituted or unsubstituted bicyclic 5-10 membered heterocyclyl, for example a fused, bridged, or spiro 5-10 membered heterocyclyl. Suitable substituted or unsubstituted 3-10 membered heterocyclyl groups include azidirine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imine, Examples of heterocyclic rings include, but are not limited to, dazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, dioxane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl can be connected to the remainder of the molecule through a nitrogen atom. In other embodiments, a substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl can be attached to the remainder of the molecule via a carbon atom. In some embodiments, a substituted monocyclic or bicyclic 3-10 membered heterocyclyl can be substituted on one or more nitrogen atoms.

[0099] In some embodiments, R 7 may be a substituted or unsubstituted 6-10 membered spiroheterocyclyl. In some embodiments, R 7 may be a substituted 6- to 10-membered spiroheterocyclyl. In other embodiments, R 7 may be an unsubstituted 6-10 membered spiroheterocyclyl. In some embodiments, R 7 is a substituted or unsubstituted azaspirohexane, azaspiroheptane, azaspirooctane, oxaspirohexane, oxaspiroheptane, oxaspirooctane, diazaspirohexane, diazaspiroheptane, diazaspirooctane, dioxaspirohexane, dioxaspiroheptane, dioxaspirooctane, oxa-azaspirohexane, oxa-azaspiroheptane, or oxa It may be 3-azaspirooctane. Suitable substituted or unsubstituted 3-10 membered heterocyclyl groups include, but are not limited to, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the substituted or unsubstituted 6-10 membered spiroheterocyclyl can be attached to the remainder of the molecule through a nitrogen atom. In other embodiments, a substituted or unsubstituted 6- to 10-membered spiroheterocyclyl can be attached to the remainder of the molecule via a carbon atom. In some embodiments, a substituted 6- to 10-membered spiroheterocyclyl can be substituted on one or more nitrogen atoms.

[0100] In some embodiments, R 7 may be hydroxy or amino.

[0101] In some embodiments, R 7 In other embodiments, R 7 may be substituted. In some embodiments, R 7 is optionally substituted with one or two substituents independently selected from unsubstituted C1-C6 alkyl (such as those described herein), unsubstituted C1-C6 alkoxy (such as those described herein), fluoro, chloro, hydroxy, and -SO2- (unsubstituted C1-C6 alkyl). For example, R 7 C1-C6 alkoxy, C3-C 10 The cycloalkyl, 3- to 10-membered heterocyclyl, mono-substituted amine group, di-substituted amine group, N-carbamyl, C-amido, and N-amido groups may be substituted with one or two substituents independently selected from any of the above-mentioned substituents.

[0102] In some embodiments, R7 teeth,

[0103] [ka] may be also possible.

[0104] In some embodiments, R 7 teeth,

[0105] [ka] may be also possible.

[0106] In some embodiments, R 7 teeth,

[0107] [ka] For example, in some embodiments, R 7 teeth,

[0108] [ka] In some embodiments, R 7 teeth,

[0109] [ka] For example, in some embodiments, R 7 teeth,

[0110] [ka] In some embodiments, R 7 teeth,

[0111] [ka] In some embodiments, R 7 teeth,

[0112] [ka] For example, in some embodiments, R 7 teeth,

[0113] [ka] In some embodiments, R 7 teeth,

[0114] [ka] For example, in some embodiments, R 7 teeth,

[0115] [ka] for example,

[0116] [ka] may be also possible.

[0117] In some embodiments, compound (A), or a pharma- ceutically acceptable salt thereof, is a compound of formula (AA), formula (BB), formula (CC), and formula (DD):

[0118] [ka] or a pharma- ceutically acceptable salt of any of the foregoing.

[0119] A non-limiting list of Bcl-2 inhibitors of Compound (A) are described herein and include those provided in FIG.

[0120] Examples of compound (A) include:

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka] Or a pharma- ceutically acceptable salt of any of the foregoing.

[0128] Compound (A), together with its pharma- ceutically acceptable salts, can be prepared as described herein and in WO 2019 / 139902, WO 2019 / 139900, WO 2019 / 139907, and WO 2019 / 139899, ​​each of which is incorporated herein by reference in its entirety. As described in WO 2019 / 139902, WO 2019 / 139900, WO 2019 / 139907, and WO 2019 / 139899, ​​compound (A) is a Bcl-2 inhibitor.

[0129] Definition of Compound (B) and its Pharmacologically Acceptable Salts Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise stated.

[0130] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amine group, disubstituted amine group, and amine(C1-C6 alkyl).

[0131] As used herein, "C a ~C b " (where "a" and "b" are integers) refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified, the broadest ranges described by these definitions are intended to be assumed.

[0132] When two "R" groups are described as being "together," the R groups and the atom to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic ring. For example, and without limitation, NR a R b Group R a and R b When and are shown as being "together," it is meant that they are covalently linked to each other to form a ring.

[0133] [ka]

[0134] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears in this specification, a numerical range such as "1 to 30" refers to each integer within the given range, e.g., "1 to 30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., or may consist of up to 30 carbon atoms, but this definition also extends to the occurrence of the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium-sized alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0135] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing a carbon double bond, 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.

[0136] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms containing a carbon triple bond, including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, etc. Alkynyl groups can be unsubstituted or substituted.

[0137] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings that share one bond with two atoms. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom, where the two rings are not joined by a bridge. Cycloalkyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Cycloalkyl groups can be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0138] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). Cycloalkenyl groups can contain 3-10 atoms in a ring, 3-8 atoms in a ring, or 3-6 atoms in a ring. When composed of more than one ring, the rings may be connected together in a fused, bridged, or spiro fashion. Cycloalkenyl groups may be unsubstituted or substituted.

[0139] As used herein, "carbocyclyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be fused, bridged, or joined together in a spiro fashion as described herein. A carbocyclyl group can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. A carbocyclyl group may be unsubstituted or substituted. Examples of carbocyclyl groups include, but are in no way limited to, cycloalkyl and cycloalkenyl groups, as defined herein, and the non-aromatic moieties of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0140] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, aryl groups include those having C6 to C7 14 Aryl groups, C6-C 10 It may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0141] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring, such as 9 carbon atoms and 1 heteroatom; 8 carbon atoms and 2 heteroatoms; 7 carbon atoms and 3 heteroatoms; 8 carbon atoms and 1 heteroatom; 7 carbon atoms and 2 heteroatoms; 6 carbon atoms and 3 heteroatoms; 5 carbon atoms and 4 heteroatoms; 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; or 2 carbon atoms and 3 heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, where two rings share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0142] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms and one to five heteroatoms together constitute said ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized pi-electron system does not occur throughout all rings. Heteroatoms include oxygen, Heterocycles are elements other than carbon, including, but not limited to, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups to define them to include oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or linked together in a spiro fashion. As used herein, the term "fused" refers to two rings that share one bond with two atoms. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which a heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom, and the two rings are not linked by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring, 3 to 20 atoms in the ring, 3 to 10 atoms in the ring, 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring. For example, 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; 2 carbon atoms and 3 heteroatoms; 1 carbon atom and 4 heteroatoms; 3 carbon atoms and 1 heteroatom; or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in the heteroalicyclic ring may be quaternized. The heterocyclyl or heteroalicyclic group may be unsubstituted or substituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 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, isopropyl alcohol ... These include, but are not limited to, soxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

[0143] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected as a substituent through a lower alkylene group. The lower alkylene and aryl groups of an aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0144] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, as well as benzo-fused analogs thereof. Not limited to.

[0145] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group connected as a substituent through a lower alkylene group. The lower alkylene and heterocyclyl of (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-thiazinane-4-yl(methyl).

[0146] As used herein, a "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCH-). A lower alkylene group is also included in cycloalkyl groups, such as

[0147] [ka] ) may be substituted by replacing one or more hydrogens on a lower alkylene group, and / or by replacing both hydrogens on the same carbon.

[0148] As used herein, the term "hydroxy" refers to an --OH group.

[0149] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy may be substituted or unsubstituted.

[0150] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0151] A "cyano" group refers to a "-CN" group.

[0152] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0153] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0154] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B)" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0155] The "N-carbamyl" group is ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0156] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0157] The "N-thiocarbamyl" group is ROC(=S)N(R A )-" group, where R and R Amay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0158] A "C-amide" group is defined as -C(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0159] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0160] The "S-sulfonamide" group is "-SO2N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0161] The "N-sulfonamide" group is A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0162] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0163] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R may be the same as defined for O-carboxy. Ester and C-carboxy may be substituted or unsubstituted.

[0164] A "nitro" group refers to a "-NO2" group.

[0165] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Sulfenyl can be substituted or unsubstituted.

[0166] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0167] A "sulfonyl" group refers to a "SO2R" group, where R may be the same as defined for sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0168] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl can be substituted or unsubstituted.

[0169] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0170] As used herein, the term "amino" refers to the group --NH.

[0171] The "monosubstituted amine" group is defined as "-NHR A " group, where R AR may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A can be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0172] A "disubstituted amine" group is defined as "-NR A R B " group, where R A and R B is independent, R may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A and R B may be independently substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0173] As used herein, an "amine(alkyl)" group refers to a -(alkylene)-NR'R" group, where R' and R" are independently hydrogen or alkyl as defined herein. Amine(alkyl) groups can be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CHNH(methyl), -CHNH(phenyl), -CHCHNH(methyl), -CHCHNH(phenyl), -CHN(methyl), -CHN(phenyl)(methyl), -NCH(ethyl)(methyl), -CHCHN(methyl), -CHCHN(phenyl)(methyl), -NCHCH(ethyl)(methyl), and the like.

[0174] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0175] As used herein, a radical refers to a species that has a single unpaired electron such that the species containing the radical can be covalently bonded to another species. Thus, in this regard, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule. The term "radical" may be used interchangeably with the term "group."

[0176] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt with an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. One skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 becomes NH3). + ), and the positive charge can be a negatively charged counterion (Cl - Understand that the benefits of these measures may be offset by other measures such as:

[0177] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, or mixtures thereof. It may be a stereoisomeric mixture, a diastereomerically enriched compound, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0178] When the compounds disclosed herein have unsatisfied valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0179] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced required dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a 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). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0180] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in nonsolvated forms. Solvates contain either stoichiometric or nonstoichiometric amounts of solvent, and may be formed during the crystallization process with pharma-ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in nonsolvated as well as solvated forms. In general, solvated forms are considered equivalent to nonsolvated forms for the purposes of the compounds and methods provided herein.

[0181] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0182] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended, and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" is synonymous with the phrases "having at least" and "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0183] With respect to the use of substantially any plural and / or singular term herein, a person skilled in the art may convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope thereof.

[0184] Compound (B) As described herein, some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, which combination may include an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof (as described herein), and an effective amount of one or more of compound (B), or a pharma- ceutically acceptable salt thereof, wherein compound (B) has the structure:

[0185] [ka] In the formula, R 1a can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl; ring Aa can be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; ring Ba can be selected from substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R 2a teeth,

[0186] [ka] ma may be 0, 1, 2, or 3; R 3acan be selected from halogen and substituted or unsubstituted C1-C6 alkyl, and Xa is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1~6 -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted Y may be selected from O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y may be CH or N; 1-a CR 4A-a or N, Y 2-a CR 4B-a or N, and the ring Ca may be a substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R 4A-a and R 4B-a are independently hydrogen, halogen, and unsubstituted C 1~4 alkyl, R 5-a may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

[0187] In some embodiments, R 1a can be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, ring Aa can be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, ring Ba can be selected from substituted or unsubstituted 5-7 membered monocyclic carbocyclyl and substituted or unsubstituted 5-7 membered monocyclic heterocyclyl. In some embodiments, R2a teeth,

[0188] [ka] In some embodiments, ma may be 0, 1, 2, or 3. R 3a can be selected from halogen and substituted or unsubstituted C1-C6 alkyl. In some embodiments, Xa is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1~6 -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl. In some embodiments, Ya may be CH or N. In some embodiments, Y 1-a CR 4A-a or N. In some embodiments, Y 2-a CR 4B-a or N. In some embodiments, the ring Ca may be a substituted or unsubstituted C6-C 10 In some embodiments, R may be selected from aryl, substituted or unsubstituted monocyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, and substituted or unsubstituted 7-10 membered bicyclic heterocyclyl. 4A-a and R 4B-a are independently hydrogen, halogen, and unsubstituted C 1~4 is selected from alkyl.

[0189] In some embodiments, R 1acan be selected from hydrogen, halogen, and C1-C6 alkyl. In some embodiments, R 1a may be hydrogen. In other embodiments, R 1a may be a halogen. In some embodiments, R 1a In yet other embodiments, R 1a may be an unsubstituted C1-C6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl (straight or branched chain), or hexyl (straight or branched chain). In some embodiments, R 1a may be unsubstituted methyl. In some embodiments, R 1a may be substituted, such as those described herein. In some embodiments, R 1a may be an unsubstituted C1-C6 haloalkyl (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, R 1a may be -CHF2, -CF3, -CF2CH3, or -CH2CF3.

[0190] In some embodiments, ring Aa can be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered monocyclic heteroaryl.

[0191] In some embodiments, ring Aa can be a substituted phenyl. In other embodiments, ring A can be an unsubstituted phenyl.

[0192] In some embodiments, ring Aa may be a substituted 5-6 membered monocyclic heteroaryl. In some embodiments, ring Aa may be an unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, ring Aa 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.

[0193] When substituted, ring Aa may be substituted with one or more substituents selected from halogen, unsubstituted C1-C4 haloalkyl, and unsubstituted C1-C4 alkyl, in some embodiments, ring Aa is mono-substituted with halogen (e.g., fluoro).

[0194] In some embodiments,

[0195] [ka] teeth,

[0196] [ka] wherein each of the aforementioned groups is substituted or unsubstituted. In some embodiments,

[0197] [ka] is substituted or unsubstituted

[0198] [ka] In some embodiments,

[0199] [ka] is substituted or unsubstituted

[0200] [ka] wherein ring Aa is unsubstituted. In other embodiments,

[0201] [ka] is substituted or unsubstituted

[0202] [ka] Substituted or unsubstituted

[0203] [ka] and substituted or unsubstituted

[0204] [ka] As described herein,

[0205] [ka] The ring Aa portion of may be unsubstituted.

[0206] In some embodiments, ring Ba can be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

[0207] In some embodiments, ring Ba may be a substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl. In some embodiments, ring Ba may be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In other embodiments, ring Ba may be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In yet other embodiments, ring Ba may be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0208] In some embodiments,

[0209] [ka] teeth,

[0210] [ka] wherein each of the aforementioned groups is substituted or unsubstituted.

[0211] In some embodiments, ring Ba may be a substituted or unsubstituted monocyclic 5- to 7-membered heterocyclyl. In some embodiments, ring Ba may be a substituted or unsubstituted monocyclic 5-membered heterocyclyl. In other embodiments, ring Ba may be a substituted or unsubstituted monocyclic 6-membered heterocyclyl. In yet other embodiments, ring Ba may be a substituted or unsubstituted monocyclic 7-membered heterocyclyl.

[0212] In some embodiments,

[0213] [ka] teeth,

[0214] [ka] wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0215] In some embodiments, ring Ba is

[0216] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH group. In some embodiments, ring Ba may be substituted or unsubstituted

[0217] [ka] may be also possible.

[0218] In some embodiments, when ring Ba is substituted, ring Ba may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-linked amido (e.g., -NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, when ring Ba 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)C1-C6 alkyl), and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring Ba may be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted -NHC(O)C1-C6 alkyl, unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring Ba may be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy-CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0219] In some embodiments,

[0220] [ka] teeth,

[0221] [ka] wherein each of the above groups is substituted or unsubstituted, including any -NH group.

[0222] In some embodiments,

[0223] [ka] teeth,

[0224] [ka] wherein each of the aforementioned groups is substituted or unsubstituted. In some embodiments,

[0225] [ka] teeth,

[0226] [ka] wherein each of the aforementioned groups is substituted or unsubstituted. In some embodiments,

[0227] [ka] is substituted or unsubstituted

[0228] [ka] In some embodiments,

[0229] [ka] may be substituted, or

[0230] [ka] may be also possible.

[0231] Both ring Aa and ring Ba can be substituted or unsubstituted. In some embodiments,

[0232] [ka] Ring Aa and ring Ba in the formula (I) may be independently substituted or unsubstituted.

[0233] [ka] Ring Aa and ring Ba in the formula (I) may both be unsubstituted.

[0234] [ka] Both ring Aa and ring Ba of the formula (I) are independently optionally substituted.

[0235] [ka] Ring Aa may be substituted;

[0236] [ka] Ring B of the formula may be unsubstituted. In some embodiments,

[0237] [ka] Ring Aa may be unsubstituted;

[0238] [ka] The ring Ba in may be substituted. In some embodiments,

[0239] [ka] Ring Aa may be unsubstituted;

[0240] [ka] Ring Ba may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, and substituted or unsubstituted C1-C6 alkyl (such as those described herein).

[0241] [ka] Ring Aa may be unsubstituted;

[0242] [ka] Ring Ba of may be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted N-linked amido (e.g., -NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments,

[0243] [ka] Ring Aa may be unsubstituted;

[0244] [ka] Ring Ba may be substituted with one or two substituents independently selected from fluoro, hydroxy, amino, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0245] In some embodiments, R 2a teeth,

[0246] [ka] In some embodiments, R 2a teeth,

[0247] [ka] In some embodiments, R 2a teeth,

[0248] [ka] may be also possible.

[0249] In some embodiments, Ya can be CH or N (nitrogen). In some embodiments, Ya can be CH. In some embodiments, Ya can be N (nitrogen).

[0250] In some embodiments, R 3a may be selected from halogen and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3a may be a halogen. In some embodiments, R 3a may be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3a may be unsubstituted C1-C6 alkyl (such as those described herein).

[0251] In some embodiments, ma may be 0, 1, 2, or 3. In some embodiments, ma may be 0. In some embodiments, ma may be 1. In some embodiments, ma may be 2. In some embodiments, ma may be 3. When ma is 2 or 3, R 3a The groups may be the same or different.

[0252] In some embodiments, Xa is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1~6 -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 alkoxy (such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy, pentoxy (straight or branched chain), or hexoxy (straight or branched chain)), substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy), substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl.

[0253] In some embodiments, Xa may be hydrogen. In other embodiments, Xa may be halogen. In some embodiments, Xa may be fluoro. In some embodiments, Xa may be chloro. In still other embodiments, Xa may be hydroxy. In still yet other embodiments, Xa may be cyano. In some embodiments, Xa may be amino.

[0254] In some embodiments, Xa may be an unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Xa may be an unsubstituted methyl, unsubstituted ethyl, or unsubstituted iso-propyl. In some embodiments, Xa may be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, Xa may be an unsubstituted C1-C6 haloalkyl (such as a C1-C6 fluoroalkyl, a C1-C6 chloroalkyl, or a C1-C6 chlorofluoroalkyl). In some embodiments, Xa may be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, Xa may be an unsubstituted C1-C6 hydroxyalkyl (such as a C1-C6 monohydroxyalkyl or a C1-C6 dihydroxyalkyl). In some embodiments, Xa may be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3)2. In some embodiments, Xa can be an unsubstituted C1-C6 cyanoalkyl (such as a C1-C6 monocyanoalkyl or a C1-C6 dicyanoalkyl).

[0255] [ka] In some embodiments, Xa can be selected from: In some embodiments, Xa can be an unsubstituted C1-C6 alkoxyalkyl (such as a C1-C6 monoalkoxyalkyl or a C1-C6 dialkoxyalkyl). In some embodiments, Xa can be selected from:

[0256] [ka] In some embodiments, Xa can be selected from:

[0257] [ka] It may be a substituted C1-C6 alkyl selected from the following:

[0258] In some embodiments, Xa may be an unsubstituted C1-C6 alkoxy (such as those described herein). In some embodiments, Xa may be an unsubstituted methoxy, unsubstituted ethoxy, or unsubstituted iso-propoxy. In some embodiments, Xa may be a substituted C1-C6 alkoxy (such as those described herein). In some embodiments, Xa may be a C1-C6 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, Xa may be a C1-C6 alkoxy substituted with 1 substituent independently selected from halogen, amino, monosubstituted amine (such as those described herein), and disubstituted amine (such as those described herein).

[0259] In some embodiments, Xa is

[0260] [ka] You can choose from.

[0261] In some embodiments, Xa can be a substituted C3-C6 cycloalkoxy (such as those described herein). In some embodiments, Xa can be an unsubstituted C3-C6 cycloalkoxy (such as those described herein).

[0262] In some embodiments, Xa may be a substituted (C1-C6 alkyl) acyl, e.g., a substituted -(CO)-CH3. In some embodiments, Xa is an unsubstituted (C1-C6 alkyl) acyl, e.g., an unsubstituted -(CO)-CH3. This is also fine.

[0263] In some embodiments, Xa may be a substituted 4-6 membered monocyclic heterocyclyl. In some embodiments, Xa may be an unsubstituted 4-6 membered monocyclic heterocyclyl. In some embodiments, Xa 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, Xa is

[0264] [ka] wherein each of the above groups is substituted or unsubstituted, including the optional -NH group.

[0265] In some embodiments, Xa may be a 4-6 membered monocyclic heterocyclyl (such as those described herein) substituted with one or two substituents independently selected from halogen, substituted or unsubstituted C1-C6 alkyl (such as those described herein), monosubstituted amine (such as those described herein), disubstituted amine (such as those described herein), amino, substituted or unsubstituted amine (C1-C6 alkyl), and substituted or unsubstituted (C1-C6 alkyl) acyl. In some embodiments, Xa may be a 4-6 membered monocyclic heterocyclyl substituted with one or two substituents independently selected from fluoro, unsubstituted methyl, unsubstituted ethyl, unsubstituted iso-propyl, -CH2OH, and -N(CH3)2. In some embodiments, Xa may be

[0266] [ka] You can choose from.

[0267] In some embodiments, Xa may be a substituted amine (C1-C6 alkyl). In some embodiments, Xa may be an unsubstituted amine (C1-C6 alkyl). In some embodiments, Xa is

[0268] [ka] wherein each of the above groups is substituted or unsubstituted, including the optional -NH group.

[0269] In some embodiments, Xa is a substituted -NH-(CH) 1~6 In some embodiments, Xa is an unsubstituted -NH-(CH) 1~6 In some embodiments, Xa may be

[0270] [ka] wherein each of the above groups is substituted or unsubstituted, including the optional -NH group.

[0271] In some embodiments, Xa 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).

[0272] In some embodiments, Xa may be a disubstituted amine. In some embodiments, the two substituents of the disubstituted amine are independently selected from unsubstituted C1-C6 alkyl (such as those described herein) and unsubstituted C3-C6 cycloalkyl (such as those described herein).

[0273] In some embodiments, Xa is

[0274] [ka] You can choose from.

[0275] In some embodiments, Xa may be substituted or unsubstituted C-amide. In some embodiments, Xa may be substituted or unsubstituted N-amide. In some embodiments, Xa may be substituted or unsubstituted C-carboxy. In some embodiments, Xa may be substituted or unsubstituted O-carboxy. In some embodiments, Xa may be substituted or unsubstituted O-carbamyl. In some embodiments, Xa may be substituted or unsubstituted N-carbamyl. In some embodiments, Xa may be mono-substituted with unsubstituted C1-C6 hydroxyalkyl (such as those described herein).

[0276] In some embodiments, Y 1-a CR 4A-a or N (nitrogen). In some embodiments, Y 1-a CR 4A-a In some embodiments, Y 1-a may be N (nitrogen).

[0277] In some embodiments, Y 2-a CR 4B-a or N (nitrogen). In some embodiments, Y 2-a CR 4B-a In some embodiments, Y 2-a may be N (nitrogen).

[0278] In some embodiments, Y 1-a and Y 2-a Each may be N (nitrogen). In some embodiments, Y 1-a is CR 4A-a and Y 2-a is CR 4B-aIn some embodiments, Y 1-a is CR 4A-a and Y 2-a may be N (nitrogen). In some embodiments, Y 1-a may be N (nitrogen), and Y 2-a is CR 4B-a may be also possible.

[0279] In some embodiments, R 4A-a may be hydrogen. In some embodiments, R 4A-a may be a halogen. In some embodiments, R 4A-a is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0280] In some embodiments, R 4B-a may be hydrogen. In some embodiments, R 4B-a may be a halogen. In some embodiments, R 4B-a is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0281] In some embodiments, R 4A-a and R 4B-a Each may be hydrogen. In some embodiments, R 4A-a and R 4B-a Each of R may be a halogen (the halogens may be the same or different from each other). In some embodiments, R 4A-a and R 4B-a are unsubstituted C 1~4 may be alkyl (such as those described herein and in which 1~4 (The alkyls may be the same or different from each other.) In some embodiments, R 4A-a and R 4B-a may be hydrogen, and R 4A-a and R 4B-a The other of R may be halogen. 4A-a and R4B-a may be hydrogen, and R 4A-a and R 4B-a The other is unsubstituted C 1~4 In some embodiments, R 4A-a and R 4B-a One of R may be halogen; 4A-a and R 4B-a The other is unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0282] In some embodiments, R 2a teeth,

[0283] [ka] For example, R 2a teeth,

[0284] [ka] R 2a but

[0285] [ka] In some embodiments, when 5-a may be a substituted 5- to 7-membered monocyclic heterocyclyl. 5-a R may be an unsubstituted 5- to 7-membered monocyclic heterocyclyl. 5-a Exemplary groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azepanyl. When substituted, R 5-a The substituents that can be introduced include unsubstituted C 1~4 Alkyl, halogen, hydroxy, and unsubstituted C 1~4 Haloalkyl is mentioned.

[0286] In some embodiments, the ring Ca is a substituted or unsubstituted C6-C 10 It may be selected from aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl.

[0287] In some embodiments, the ring Ca is a substituted C-C 10 In some embodiments, the ring Ca is an unsubstituted C-C 10 In some embodiments, the ring Ca may be a substituted C6 aryl. In some embodiments, the ring Ca may be an unsubstituted C6 aryl.

[0288] In some embodiments, ring Ca may be a substituted 5-10 membered heteroaryl. In some embodiments, ring Ca may be an unsubstituted 5-10 membered heteroaryl. In some embodiments, ring Ca may be a substituted 5-6 membered heteroaryl. In some embodiments, ring Ca may be an unsubstituted 5-6 membered heteroaryl. In some embodiments, ring Ca 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.

[0289] In some embodiments, ring Ca may be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In some embodiments, ring Ca may be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In some embodiments, ring Ca may be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0290] In some embodiments, ring Ca may be a substituted or unsubstituted 5-membered monocyclic heterocyclyl. In some embodiments, ring Ca may be a substituted or unsubstituted 6-membered monocyclic heterocyclyl. In some embodiments, ring Ca 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.

[0291] In some embodiments, Ring Ca can be a substituted or unsubstituted seven-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, ring Ca may be a substituted or unsubstituted 8-membered bicyclic heterocyclyl, such as a fused, bridged, or spiroheterocyclyl. In some embodiments, ring Ca may be a substituted or unsubstituted 9-membered bicyclic heterocyclyl (e.g., a fused, bridged, or spiroheterocyclyl). In some embodiments, ring Ca may be a substituted or unsubstituted 10-membered bicyclic heterocyclyl, such as a fused, bridged, or spiroheterocyclyl. In some embodiments, Ring Ca can be selected from pyrrolizidine, indoline, 1,2,3,4 tetrahydroquinoline, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane, each of the foregoing groups being substituted or unsubstituted, including any -NH group.

[0292] In some embodiments, ring Ca may be substituted with one or more substituents independently selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl. In some embodiments, ring Ca may be substituted with one substituent selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl.

[0293] In some embodiments, R 2a teeth,

[0294] [ka] and each of the aforementioned groups may be substituted or unsubstituted.

[0295] A non-limiting list of WEE1 inhibitors of compound (B) are described herein and include those provided in FIG.

[0296] Examples of compounds (B) include:

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka]

[0301] [ka] Or a pharma- ceutically acceptable salt of any of the foregoing.

[0302] Compound (B), together with its pharma- ceutically acceptable salts, can be prepared as described herein and in WO 2019 / 173082, the entireties of which are incorporated herein by reference. As described in WO 2019 / 173082, compound (B) is a WEE1 inhibitor.

[0303] Embodiments of combinations of Compound (A) and Compound (B) (including pharma- ceutically acceptable salts of any of the foregoing) are provided in Table 1. The numbers in Table 1 represent the compounds provided in Figures 1 and 2. For example, in Table 1, the combination represented by 1:4A is

[0304] [ka] (including pharma- ceutically acceptable salts of any of the foregoing).

[0305] [Table 1]

[0306] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be administered before all of the compounds (B), or their pharma- ceutically acceptable salts. In other embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be administered before at least one compound (B), or its pharma- ceutically acceptable salts. In still other embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be administered simultaneously with compound (B), or its pharma- ceutically acceptable salts. In still yet other embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be administered after administration of at least one compound (B), or its pharma- ceutically acceptable salts. In some embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be administered after administration of all of the compounds (B), or their pharma- ceutically acceptable salts.

[0307] There may be some advantages to using the combination of compounds described herein.For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers such as those described herein compared to when the combination compounds are used as monotherapy.

[0308] In some embodiments, the combination of Compound (A) (including pharma- ceutically acceptable salts thereof) with one or more of Compound (B), or a pharma- ceutically acceptable salt thereof, as described herein, may reduce the number and / or severity of side effects that may be attributable to a compound described herein, such as Compound (B), or a pharma- ceutically acceptable salt thereof.

[0309] The use of the combinations of compounds described herein may result in additive, synergistic, or potentially synergistic effects. The combinations of compounds described herein may result in effects that are not antagonistic.

[0310] In some embodiments, the combination of compound (A) (including its pharma- ceutically acceptable salts) with one or more of compound (B), or pharma- ceutically acceptable salts thereof, as described herein, may produce an additive effect. In some embodiments, the combination of compound (A) (including its pharma- ceutically acceptable salts) with one or more of compound (B), or pharma- ceutically acceptable salts thereof, as described herein, may produce a synergistic effect. In some embodiments, the combination of compound (A) (including its pharma- ceutically acceptable salts) with one or more of compound (B), or pharma- ceutically acceptable salts thereof, as described herein, may produce a strongly synergistic effect. In some embodiments, the combination of compound (A) (including its pharma- ceutically acceptable salts) with one or more of compound (B), or pharma- ceutically acceptable salts thereof, as described herein, is not antagonistic.

[0311] As used herein, the term "antagonism" means that the activity of the combination of compounds is less than the sum of the activities of the combined compounds when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term "synergy" means that the activity of the combination of compounds is greater than the sum of the individual activities of the combined compounds when the activity of each compound is determined individually. As used herein, the term "additive effect" means that the activity of the combination of compounds is approximately equal to the sum of the individual activities of the combined compounds when the activity of each compound is determined individually.

[0312] A potential advantage of utilizing the combinations described herein may be a reduction in the amount of the compounds required to be effective in treating the disease conditions disclosed herein, compared to when each compound is administered as a monotherapy. For example, the amount of compound (B), or a pharma- ceutically acceptable salt thereof, used in the combinations described herein may be less than the amount of compound (B), or a pharma- ceutically acceptable salt thereof, required to achieve the same reduction in disease markers (e.g., tumor size) when administered as a monotherapy. Another potential advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action may result in a higher barrier to the development of resistance, compared to when the compounds are administered as a monotherapy. Additional advantages of utilizing the combinations described herein may include little or no cross-resistance between the compounds of the combinations described herein, different pathways for eliminating the compounds of the combinations described herein, and / or little or no overlapping toxicity between the compounds of the combinations described herein.

[0313] Pharmaceutical Compositions Compound (A) (including its pharma- ceutically acceptable salts) may be provided in a pharmaceutical composition. Similarly, compound (B) (including its pharma- ceutically acceptable salts) may be provided in a pharmaceutical composition.

[0314] The term "pharmaceutical composition" refers to a pharmaceutical composition containing one or more compounds and / or salts disclosed herein, preferably Pharmaceutical compositions refer to mixtures of compounds with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0315] As used herein, "carrier" refers to a compound that facilitates the incorporation 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 cells or tissues of a subject.

[0316] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0317] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0318] In some embodiments, compound (B) together with a pharma- ceutically acceptable salt thereof can be provided in a pharmaceutical composition comprising compound (A) (including a pharma- ceutically acceptable salt thereof. In other embodiments, compound (B) together with a pharma- ceutically acceptable salt thereof can be administered in a pharmaceutical composition that is separate from the pharmaceutical composition comprising compound (A) (including a pharma- ceutically acceptable salt thereof).

[0319] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0320] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, encapsulating or tabletting processes. In addition, the active ingredient is contained in an effective amount to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharma-ceutical compatible counterions.

[0321] Multiple techniques of administering compounds, salts, and / or compositions exist in the art, including, but not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, compound (A) (including pharmaceutically acceptable salts thereof) may be administered orally. In some embodiments, compound (A) (including pharmaceutically acceptable salts thereof) may be provided to a subject by the same route of administration along with compound (B) and pharmaceutically acceptable salts thereof. In other embodiments, compound (A) (including pharmaceutically acceptable salts thereof) may be provided to a subject by the same route of administration along with compound (B) and pharmaceutically acceptable salts thereof. Together with the acceptable salts, they may be provided to the subject by different routes of administration.

[0322] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compounds directly into the affected area, often as a depot or sustained release formulation.Furthermore, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies.The liposomes are targeted to and taken up selectively by organs.For example, intranasal or intrapulmonary delivery may be desirable to target respiratory diseases or conditions.

[0323] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a format prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, which notice reflects the approval by the agency of the drug form for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compounds and / or salts described herein, formulated in a compatible pharmaceutical carrier, and may also be prepared, placed in an appropriate container, and labeled for the treatment of the indicated condition.

[0324] Methods of Use and Treatment As provided herein, in some embodiments, a combination of compounds comprising an effective amount of Compound (A), including a pharma- ceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharma- ceutically acceptable salt thereof, can be used to treat a disease or condition.

[0325] Examples of diseases or conditions that may be treated by the combination of compounds with pharma- ceutically acceptable salts include malignancies, cancers, and syndromes, such as those described herein. In some embodiments, the disease or condition may be a hematological malignancy. Exemplary hematological malignancies are leukemia, lymphoma, or myeloma. In some embodiments, the hematological malignancy may be refractory. In some embodiments, the disease or condition may be a leukemia, including but not limited to, acute myeloid leukemia (AML) (including subtypes thereof such as subtypes TP53 wild-type AML, TP53 mutant AML, refractory AML, acute promyelocytic leukemia, acute basophilic leukemia, and therapy-related 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 B cell, T cell, and ETP specialization), and chronic myeloid leukemia (CML) (chronic myelogenous leukemia).

[0326] In some embodiments, the disease or condition may be myelodysplastic syndrome. In some embodiments, the disease or condition may be polycythemia vera (PV), myelofibrosis, The tumor may be a myeloproliferative neoplasm (MPN), such as myelofibrosis (MF), and essential thrombocythemia (ET).

[0327] As described herein, the combinations of compounds described herein can be used to treat and / or ameliorate lymphomas. Exemplary lymphomas include non-Hodgkin's lymphoma (NHL), including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and leukemia (LE). Follicular lymphoma (FL), marginal zone lymphoma (MZ) L), peripheral T-cell lymphoma, cutaneous T-cell lymphoma, NK lymphoma, Burkitt's lymphoma, and Waldenstrom's macroglobulinemia. The combination of compounds (including pharmaceutically acceptable salts thereof) can also be used to treat myeloma. Examples of myelomas that can be treated include, but are not limited to, multiple myeloma (MM) (including, but not limited to, translocation (11;14) and non-translocation (11;). As described herein, the combination of compounds described herein can be used to treat and / or ameliorate systemic mastocytosis, and blastic plasmacytoid dendritic cell neoplasm.

[0328] The diseases or conditions described herein may be in adult or pediatric subjects. In some embodiments, a subject suffering from a disease or condition such as those described herein may be a pediatric subject. In some embodiments, the disease or condition may be a pediatric hematological malignancy, such as pediatric AML and / or pediatric ALL.

[0329] The combination of compounds described herein can be used to treat and / or ameliorate solid tumors. For example, in some embodiments, the solid tumor can be selected from Ewing's tumor and Wilms' carcinoma. Additional examples of solid tumors that can be treated by the combination of compounds described herein (including pharmaceutically acceptable salts thereof) include bladder cancer, brain cancer, breast cancer (including, but not limited to, ER+ breast cancer and triple-negative breast cancer), cervical cancer, choriocarcinoma, cervicocerebral cancer, and ovarian cancer. Intestinal cancer, endometrial cancer, esophageal cancer, gallbladder / bile duct cancer, head and neck cancer (including oral cancer), hepatocellular carcinoma, lung cancer (including non-small cell carcinoma 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, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and uterocervical cancer. In some embodiments, the disease or condition may be a cancer that expresses a BCL-2 protein.

[0330] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and 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 child or infant with a fever. In other embodiments, the subject may be an adult.

[0331] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0332] The term "effective amount" is used to indicate an amount of an active compound or agent that elicits a biological or medical response as indicated. For example, an effective amount of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in view of the disclosure provided herein. The amount required as a dose is generally within the range of 100 mg / kg / day of administration. The effective amount of the compounds disclosed herein depends on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. The dosage can be tailored to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medication, and other factors that will be recognized by those skilled in the medical field.

[0333] For example, an effective amount of a compound or radiation is an amount that results in (a) reduction, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of the tumor, and / or (d) long-term disease stabilization (cessation of growth) of the tumor.

[0334] The amount of compound, salt, and / or composition required for use in treatment will vary not only with the specific compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as a free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly progressive, diseases or conditions.

[0335] Various dosages of Compound (A) and Compound (B) (together with their pharma- ceutically acceptable salts) may be used in the combinations described herein. In some embodiments, Compound (A), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 20 to 500 mg / day. In some embodiments, Compound (B), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 20 to 500 mg / day. For example, compound (A) and / or compound (B) (including pharma- ceutically acceptable salts thereof) may be administered at a dose of about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 210 mg / day, about 220 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, about 500 mg / day, about 510 mg / day, about 520 mg / day, about 530 mg / day, about 540 mg / day, about 550 mg / day, about 560 mg / day, about 570 mg / day, about 5 g / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, or about 500 mg / day. In some embodiments, compound (A), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 200 to 400 mg / day. In some embodiments, compound (B), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 200 to 400 mg / day.

[0336] Various dosages of Compound (A) and Compound (B) (together with their pharma- ceutically acceptable salts) may be used in the combinations described herein. In some embodiments, Compound (A), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 20 to 500 mg. In some embodiments, Compound (B), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 20 to 500 mg. For example, Compound (A) and / or Compound (B) (including their pharma- ceutically acceptable salts) may be administered in an amount ranging from about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 50 ... 0mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 3 20mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about In some embodiments, compound (A), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 200 to 400 mg. In some embodiments, compound (B), or a pharma- ceutically acceptable salt thereof, may be administered in an amount ranging from 200 to 400 mg.

[0337] As will be readily apparent to those skilled in the art, the useful in vivo dosages and the specific administration methods administered will vary depending on the age, weight, severity of the affliction, and mammalian species being treated, the specific compounds used, and the specific applications for which these compounds are used. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of compounds (A) and / or (B), or pharma-ceutically acceptable salts of 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 comparison with established drugs, such as cisplatin and / or gemcitabine).

[0338] Dosage amount and interval are adjusted individually to provide plasma concentrations of the active moiety sufficient to maintain the modulating effect or minimal effective concentration (MEC). The MEC may be determined by the method of the present invention. The MEC varies for each compound but may be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. However, HPLC assays or bioassays may be used to measure plasma concentrations. Dosage intervals may also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma concentrations above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0339] It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The size of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps the number of doses will also vary with the age, weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0340] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a certain chemical moiety can be established by evaluating in vitro toxicity on cell lines, such as mammalian and preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, a person skilled in the art can be guided by the state of the art in selecting the appropriate model, dose, route of administration, and / or regimen. EXAMPLES

[0341] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the following examples.

[0342] CTG assay Cell proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability assay. This assay involved the direct addition of a single reagent (CellTiter-Glo® Reagent) to cells cultured in serum-supplemented medium. RS4;11 (ATC, CRL-1873) cells were cultured according to ATCC recommendations and seeded at 50,000 cells per well. MV4-11 (ATCC, CRL-9591), Toledo (ATCC, CRL-2631), MCF-7 (ATCC, HTB-22), and DMS-53 (ATCC, CRL-2062) cells were cultured according to ATCC recommendations and seeded at 20,000 cells per well.

[0343] Compound 5 (free base) and compound 1a (free base) were prepared as DMSO stock solutions (10 mM). The compounds were assayed for the RS4;11, MV4-11, Toledo, and DMS-53 cell lines at their respective IC values ​​as shown in Table 1. 50 Concentrations were used and tested in triplicate. MCF-7 combination assays were performed in duplicate with 10-point serial dilution curves (1:3 dilution) for compounds 5 and 1a, and 10-point serial dilution curves (1:5 dilution) when treated in combination. The highest compound concentration was 10 μM, and the final DMSO concentration was 0.1%. Plates were incubated at 37° C., 5% CO2 for 72 hours, then equilibrated at room temperature for approximately 30 minutes. An equal volume of CellTiter-Glo® Reagent (100 μL) was added to each well. Plates were mixed on an orbital shaker for 2 minutes to induce cell lysis, and then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence (relative light units, RLU) was measured according to the CellTiter-Glo protocol The inhibition rates were recorded using a SpectraMAX, M5e plate reader according to the method described above. The percent inhibition was calculated using the following formula: % inhibition = (RLU * 100 / (cell background RLU). IC of each compound 50 , using nonlinear regression analysis in GraphPad Calculations were performed using Prism.

[0344] Figures 3 and 4, along with Tables 2 and 3, show that the addition of compound 5 to compound 1a (alternatively referred to as "compound 1A" throughout this specification and figures) resulted in combination efficacy.

[0345] [Table 2]

[0346] [Table 3]

[0347] Xenograft tumor models Mice were cultured with 95% viable tumor cells (1 × 10 ) in 100 μL of serum-free IMDM-Matrigel mixture (1:1 ratio) for tumor development. 7 HL-60 cells were inoculated subcutaneously into the right flank as a single-cell suspension of 100 μg / ml of HL-60 cells. The average tumor size was approximately 215 mm. 3 Treatment was initiated when the individual tumors reached a size of 185–245 mm 3 The doses ranged from 0.01 mg / kg to 0.1 mg / kg. Animals were randomly assigned to treatment groups of 10 animals each and dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figure 5 and Table 4. Compound 5 was dosed as the free base and Compound 1a was dosed as the free base. In Figure 5, the bottom line (indicated by diamonds) represents data for Compound 5 (50 mg / kg) + Compound 1a (80 mg / kg), the second line from the bottom (indicated by triangles) represents data for Compound 5 (50 mg / kg) + Compound 1a (60 mg / kg), and the third line from the bottom (indicated by diamonds) represents data for Compound 5 (50 mg / kg). Tumor volumes were 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 evaluated twice weekly to calculate tumor volume over time and mice were weighed twice weekly as a surrogate for signs of toxicity. The TGI was calculated using the following formula: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the experiment. Tumor regression was defined as the individual tumor volume (TV) reduction (end TV compared to initial TV). Tumor regression rate was calculated using the following formula: (1-(Td / T0))×100%. Figure 5 and Table 4 illustrate that single treatment with compound 1a at 60 or 80 mg / kg did not result in tumor growth inhibition, and single treatment with compound 5 resulted in marginal efficacy (30%). The combination of compound 5 (50 mg / kg) and compound 1a (60 mg / kg) showed significant TGI, resulting in complete regression of 8 of 10 tumors at day 18. The combination of Compound 5 (50 mg / kg) and Compound 1a (80 mg / kg) demonstrated significant TGI, resulting in complete regression of 9 of 10 tumors at day 18. The data provided herein demonstrate that a combination of a Bcl-2 inhibitor and a WEE1 inhibitor as described herein can be used to treat the diseases or conditions described herein.

[0348] [Table 4]

[0349] Moreover, although the above has been described in some detail with reference to the figures and examples for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It is to be expressly understood that no limitation to the scope of the disclosure is intended, but on the contrary, all modifications and alternative forms consistent with the true scope and spirit of the invention are encompassed.

Claims

1. A pharmaceutical composition for treating a disease or condition, the composition comprising an effective amount of compound (A) and an effective amount of compound (B), or a pharma- ceutically acceptable salt thereof; The compound (A) has the following structure: 【Chemistry 1】 During the ceremony, R １ is hydrogen, halogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C １ ~C ６ Haloalkyl, substituted or unsubstituted C ３ ~C ６ Cycloalkyl, substituted or unsubstituted C １ ~C ６ Alkoxy, unsubstituted mono-C １ ~C ６ Alkylamines and unsubstituted di-C １ ~C ６ selected from the group consisting of alkylamines, Each R ２ are independently halogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C １ ~C ６ Haloalkyl, and substituted or unsubstituted C ３ ~C ６ cycloalkyl; or When m is 2 or 3, each R ２ are independently halogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C １ ~C ６ Haloalkyl, and substituted or unsubstituted C ３ ~C ６ cycloalkyl, or two R ２ The groups, together with the atoms to which they are attached, are substituted or unsubstituted C ３ ~C ６ forming a cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl; R ４ No. ２ , S(O)R ６ , S.O. ２ R ６ , halogen, cyano, and unsubstituted C １ ~C ６ haloalkyl; R ５ is -X １ -(Alk １ ) ｎ -R ７ and Alk １ is unsubstituted C １ ~C ４ Alkylene, as well as fluoro, chloro, unsubstituted C １ ~C ３ Alkyl and unsubstituted C １ ~C ３ C substituted with 1, 2, or 3 substituents independently selected from haloalkyl １ ~C ４ alkylene; R ６ is a substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C １ ~C ６ Haloalkyl, and substituted or unsubstituted C ３ ~C ６ cycloalkyl; R ７ is a substituted or unsubstituted C １ ~C ６ Alkoxy, substituted or unsubstituted C ３ ~C １０ selected from cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, hydroxy, amino, substituted or unsubstituted mono-substituted amine groups, substituted or unsubstituted di-substituted amine groups, substituted or unsubstituted N-carbamyl, substituted or unsubstituted C-amido, and substituted or unsubstituted N-amido; m is 0, 1, 2, or 3; n is selected from the group consisting of 0 and 1; X １ is selected from the group consisting of -O-, -S-, and -NH-; The compound (B) has the following structure: 【Chemistry 2】 During the ceremony, R １ａ is hydrogen, halogen, and substituted or unsubstituted C １ ~C ６ is selected from the group consisting of alkyl, Ring A-a is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; Ring Ba is selected from the group consisting of substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R ２ａ teeth, 【Chemistry 3】 is selected from the group consisting of m-a is 0, 1, 2, or 3; R ３ａ is a halogen, and a substituted or unsubstituted C １ ~C ６ is selected from the group consisting of alkyl, X-a is hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4- to 6-membered monocyclic ring Tetracyclyl, 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 substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y-a is CH or N; Y １－ａ is CR ４Ａ－ａ or N, Y ２－ａ is CR ４Ｂ－ａ or N, Ring C-a is selected from the group consisting of substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R ４Ａ－ａ and R ４Ｂ－ａ are independently hydrogen, halogen, and unsubstituted C １～４ is selected from the group consisting of alkyl, R ５－ａ is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; A pharmaceutical composition, wherein the compound (A) or a pharma- ceutically acceptable salt thereof, and the compound (B) or a pharma- ceutically acceptable salt thereof are provided as a single pharmaceutical composition or separate pharmaceutical compositions.

2. The compound (A) is 【Chemistry 4】 or a pharma- ceutical acceptable salt thereof.

3. The compound (A), 【Chemistry 5】 or a pharma- ceutical acceptable salt thereof.

4. The compound (A), 【Chemistry 6】 or a pharma- ceutical acceptable salt thereof.

5. The compound (A), 【Chemistry 7】 or a pharma- ceutical acceptable salt thereof.

6. The compound (A), 【Chemistry 8】 or a pharma- ceutical acceptable salt thereof.

7. The compound (A), 【Chemistry 9】 or a pharma- ceutical acceptable salt thereof.

8. The compound (A) is 【Chemistry 10】 or a pharma- ceutical acceptable salt thereof.

9. The compound (A) is 【Chemistry 11】 or a pharma- ceutical acceptable salt thereof.

10. The compound (A) is 【Chemistry 12】 or a pharma- ceutical acceptable salt thereof.

11. The compound (B) 【Chemistry 13】 The pharmaceutical agent according to any one of claims 1 to 10, which is a pharma- ceutical acceptable salt thereof.

12. The compound (B) 【Chemistry 14】 The pharmaceutical agent according to any one of claims 1 to 10, which is either one of the above or a pharma- ceutically acceptable salts thereof.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound (A) or a pharma- ceutically acceptable salt thereof is provided before the compound (B) or a pharma- ceutically acceptable salt thereof.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound (A) or a pharma- ceutically acceptable salt thereof is provided simultaneously with the compound (B) or a pharma- ceutically acceptable salt thereof.

15. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound (A) or a pharma- ceutically acceptable salt thereof is provided subsequent to the compound (B) or a pharma- ceutically acceptable salt thereof.

16. The pharmaceutical according to any one of claims 1 to 15, wherein the disease or condition is a hematological malignancy.

17. 17. The pharmaceutical of claim 16, wherein the hematological malignancy is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

18. The method of claim 16, wherein the hematological malignancy is non-Hodgkin's lymphoma.

19. The method of claim 16, wherein the hematological malignancy is selected from the group consisting of multiple myeloma and blastic plasmacytoid dendritic cell neoplasm.

20. The disease or condition is bladder cancer, brain cancer, breast cancer, cervical cancer, The pharmaceutical agent according to any one of claims 1 to 15, which is selected from the group consisting of choriocarcinoma, cervicocerebral cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder / bile duct cancer, head and neck cancer (including oral cancer), hepatocellular carcinoma, lung cancer, non-small cell carcinoma, mesothelioma, ovarian cancer, osteosarcoma, pancreatic cancer, penile cancer, anal cancer, prostate cancer, testicular cancer, small cell carcinoma, small cell lung cancer, gastric cancer, rectal cancer, renal pelvis / ureter cancer, skin cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and cervical cancer.

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