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 SERD or SERM inhibitor, along with pharmaceutically acceptable salts of any of the foregoing.

Description

[Technical Field]

[0001] Incorporation by reference of any priority application For example, all applications for which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 62 / 951,991, filed December 20, 2019.

[0002] 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 2019, approximately 1.8 million people were diagnosed with cancer in the United States, and an estimated 606,880 people died from cancer. Therefore, there remains a need for effective cancer treatments. Summary of the Invention

[0004] Some embodiments described herein relate to a combination of compounds, which may include an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.

[0005] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B) or a pharmaceutically acceptable salt thereof.

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

[0007] [Figure 1-1] Examples of SERD inhibitors are provided. [Figure 1-2] Examples of SERD inhibitors are provided. [Figure 2] Examples of SERM inhibitors are provided. [Figure 3-1] Examples of compound (A) are provided below. [Figure 3-2] Examples of compound (A) are provided below. [Figure 4] 1 shows the results of a combination study of compound (1A) and compound 11 in an MCF-7 breast cancer tumor model. [Figure 5] 1 shows the results of a combination study of compound (1A) and compound 13 in an MCF-7 breast cancer tumor model. [Figure 6] 1 shows the results of a combination study of Compound (1A) and Compound 3 in an MCF-7 breast cancer tumor model. DETAILED DESCRIPTION OF THE INVENTION

[0008] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0009] Whenever a group is described as being "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are specified, it means that the specified "optionally substituted" or "substituted" group may be substituted with one or more 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).

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

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

[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, isopropyl, sec-butyl, t-butyl, and the like. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms. (Whenever appearing herein, a numerical range such as "1 to 30" refers to each integer within the given range; for example, "1 to 30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 30 carbon atoms; however, this definition also encompasses the case 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.

[0014] 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.

[0015] 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.

[0016] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As 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 the 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, and the two rings are not joined by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the rings, 3 to 20 atoms in the rings, 3 to 10 atoms in the rings, 3 to 8 atoms in the rings, or 3 to 6 atoms in the rings. Cycloalkyl groups can be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0017] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the rings, 3 to 8 atoms in the rings, or 3 to 6 atoms in the rings. When composed of more than one ring, the rings may be connected together in a fused, bridged, or spiro fashion. Cycloalkenyl groups can be unsubstituted or substituted.

[0018] As used herein, "carbocyclyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion, as described herein. A carbocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A carbocyclyl group can be unsubstituted or substituted. Examples of carbocyclyl groups include, but are in no way limited to, cycloalkyl and cycloalkenyl groups, as defined herein, and the non-aromatic moieties of 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0019] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10 The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0020] 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 rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), 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 in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. 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.

[0021] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms and one to five heteroatoms together comprise said ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a fully delocalized π-electron system does not occur throughout all rings. 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 define them 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 that share one bond with two atoms. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which the 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 are not joined by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). For example, 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; 2 carbon atoms and 3 heteroatoms; 1 carbon atom and 4 heteroatoms; 3 carbon atoms and 1 heteroatom; or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in the heteroalicyclic ring may be quaternized.A heterocyclyl or heteroalicyclic group may be substituted or unsubstituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, and imidazolidine. , isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (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.

[0022] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected as a substituent via a lower alkylene group. The lower alkylene and aryl groups of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0023] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.

[0024] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group connected as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include tetrahydro-2H-pyran-4-yl(methyl), Examples include, but are not limited to, piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0025] As used herein, a "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group is also a cycloalkyl group (e.g.,

[0026] [ka] ) by replacing one or more hydrogens on a lower alkylene group and / or by replacing both hydrogens on the same carbon.

[0027] As used herein, the term "hydroxy" refers to an --OH group.

[0028] 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 can be substituted or unsubstituted.

[0029] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0030] A "cyano" group refers to a "-CN" group.

[0031] 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.

[0032] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

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

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

[0039] The "S-sulfonamide" group is defined as "-SO2N(R A R B ) group, where R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0040] The "N-sulfonamide" group is "RSO2N(R A )-" group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0041] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxy can be substituted or unsubstituted.

[0042] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0043] A "nitro" group refers to a "-NO2" group.

[0044] 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.

[0045] 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.

[0046] A "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0047] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl can be substituted or unsubstituted.

[0048] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0049] As used herein, the term "amino" refers to the group --NH.sub.2.

[0050] 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 may be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0051] A "disubstituted amine" group is defined as "-NR A R B " group, where R A and R B R may independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A and R B may be independently substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -N(methyl), -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0052] As used herein, an "amine(alkyl)" group refers to a -(alkylene)-NRR'R" group, where R' and R" are independently hydrogen or alkyl, as defined herein. Amine(alkyl) groups can be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CHNHNH(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.

[0053] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0054] As used herein, a radical refers to a species having a single unpaired electron such that the radical-containing species can be covalently bonded to another species. Thus, in this context, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule. The term "radical" may be used interchangeably with the term "group."

[0055] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, 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, e.g., an ammonium salt, an alkali metal salt, e.g., sodium, potassium, or lithium salt, an alkaline earth metal salt, e.g., calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt with an organic base, e.g., 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 recognize that when a salt is formed by protonation of a nitrogen-based group (e.g., NH), the nitrogen-based group may be associated with a positive charge (e.g., NH becomes NH3). + ), and the positive charge can be a negatively charged counterion (Cl - Understand that balance can be achieved by

[0056] 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, diastereomerically pure, diastereomerically enriched, 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 independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0057] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0058] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0059] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, 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 unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0060] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0061] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring" and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood to imply that a particular feature is critical, essential, or even important to its structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be synonymous with the phrases "having at least" or "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0062] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art will readily convert from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. The various singular / plural permutations may be expressly stated herein for the sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope.

[0063] compound Some embodiments disclosed herein relate to the use of a combination of compounds to treat a disease or condition, the combination may include an effective amount of compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of compound (B), or a pharmaceutically acceptable salt thereof, wherein compound (A) has the following structure:

[0064] [ka] In the formula, R 1 may be selected from hydrogen, halogen, and substituted or unsubstituted C1-C6 alkyl; ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl; ring B may be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl; R 2 teeth,

[0065] [ka] m may be 0, 1, 2, or 3; R 3 may be selected from halogen and substituted or unsubstituted C1-C6 alkyl, and X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1~6-amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl; Y may be CH or N; 1 is CR 4A or N, and Y 2 is CR 4B or N, and ring C may be a substituted or unsubstituted C to C 10 aryl, substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl, substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl, substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and substituted or unsubstituted 7- to 10-membered bicyclic heterocyclyl; R 4A and R 4B are independently hydrogen, halogen, and unsubstituted C 1~4 alkyl, and R 5 may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl, and one or more of the compounds (B) are selected from SERD compounds and SERM compounds, or pharmaceutically acceptable salts of any of the above. good.

[0066] In some embodiments, R 1 may be selected from halogen and substituted or unsubstituted C1-C6 alkyl. In some embodiments, ring A may be selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring B may be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl. In some embodiments, R 2 teeth,

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

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

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

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

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

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

[0073] In some embodiments,

[0074] [ka] teeth,

[0075] [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments,

[0076] [ka] is substituted or unsubstituted

[0077] [ka] In some embodiments,

[0078] [ka] is substituted or unsubstituted

[0079] [ka] wherein ring A is unsubstituted. In other embodiments,

[0080] [ka] is substituted or unsubstituted

[0081] [ka] , substituted or unsubstituted

[0082] [ka] , and substituted or unsubstituted

[0083] [ka] As described herein,

[0084] [ka] The Ring A portion of may be unsubstituted.

[0085] In some embodiments, Ring B may be selected from substituted or unsubstituted 5- to 7-membered monocyclic carbocyclyl and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.

[0086] In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl. In some embodiments, ring B can be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In other embodiments, ring B can be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In still other embodiments, ring B can be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0087] In some embodiments,

[0088] [ka] teeth,

[0089] [ka] wherein each of the foregoing groups is substituted or unsubstituted.

[0090] In some embodiments, Ring B is a substituted or unsubstituted monocyclic 5-7 membered heterocyclyl. In some embodiments, Ring B can be a substituted or unsubstituted monocyclic 5-membered heterocyclyl. In other embodiments, Ring B can be a substituted or unsubstituted monocyclic 6-membered heterocyclyl. In still other embodiments, Ring B can be a substituted or unsubstituted monocyclic 7-membered heterocyclyl.

[0091] In some embodiments,

[0092] [ka] teeth,

[0093] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH groups.

[0094] In some embodiments, ring B is

[0095] [ka] wherein each of the foregoing groups is substituted or unsubstituted, including any -NH group. In some embodiments, Ring B is substituted or unsubstituted

[0096] [ka] It may be.

[0097] In some embodiments, when ring B is substituted, it can be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-linked amido (e.g., —NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyl (e.g., as described herein), and substituted or unsubstituted C1-C6 alkyl (e.g., as described herein). In some embodiments, when ring B is substituted, it can be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, amino, unsubstituted N-linked amido (e.g., —NHC(O)C1-C6 alkyl), and substituted or unsubstituted C1-C6 alkyl (e.g., as described herein). In some embodiments, ring B can be substituted with 1, 2, or 3 substituents independently selected from fluoro, hydroxy, amino, unsubstituted —NHC(O)C1-C6 alkyl, unsubstituted C1-C6 haloalkyl (e.g., as described herein), and unsubstituted C1-C6 alkyl (e.g., as described herein). In some embodiments, ring B can be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy-CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0098] In some embodiments,

[0099] [ka] teeth,

[0100] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH groups.

[0101] In some embodiments,

[0102] [ka] teeth,

[0103] [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments,

[0104] [ka] teeth,

[0105] [ka] wherein each of the foregoing groups is substituted or unsubstituted. In some embodiments,

[0106] [ka] is substituted or unsubstituted

[0107] [ka] In some embodiments,

[0108] [ka] may be substituted, or

[0109] [ka] It may be.

[0110] Both Ring A and Ring B can be substituted or unsubstituted. In some embodiments,

[0111] [ka] Ring A and ring B of the formula (I) may be independently substituted or unsubstituted.

[0112] [ka] Ring A and ring B of the formula (I) may both be unsubstituted. In some embodiments,

[0113] [ka] Ring A and ring B of the formula (I) may both be independently substituted. In some embodiments,

[0114] [ka] wherein ring A is optionally substituted;

[0115] [ka] Ring B of the formula (I) may be unsubstituted. In some embodiments,

[0116] [ka] Ring A may be unsubstituted;

[0117] [ka] Ring B of the formula (I) may be substituted. In some embodiments,

[0118] [ka] Ring A may be unsubstituted;

[0119] [ka] Ring B of the formula (I) may be substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, and substituted or unsubstituted C1-C6 alkyl (such as those described herein).

[0120] [ka] Ring A may be unsubstituted;

[0121] [ka] Ring B of the formula (I) 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,

[0122] [ka] Ring A may be unsubstituted;

[0123] [ka] Ring B may be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy, amino, -CF3, -CHF2, -CF2CH3, unsubstituted methyl, unsubstituted ethyl, and -NHC(O)CH3.

[0124] In some embodiments, R 2 teeth,

[0125] [ka] In some embodiments, R 2 teeth,

[0126] [ka] In some embodiments, R 2 teeth,

[0127] [ka] It may be.

[0128] In some embodiments, Y can be CH or N (nitrogen). In some embodiments, Y can be CH. In some embodiments, Y can be N (nitrogen).

[0129] In some embodiments, R 3 may be selected from halogen and substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3 may be halogen. In some embodiments, R 3 may be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, R 3 can be an unsubstituted C1-C6 alkyl (such as those described herein).

[0130] In some embodiments, m can be 0, 1, 2, or 3. In some embodiments, m can be 0. In some embodiments, m can be 1. In some embodiments, m can be 2. In some embodiments, m can be 3. When m is 2 or 3, R 3 The groups may be the same or different from one another.

[0131] In some embodiments, X is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6 -amine, monosubstituted amine, disubstituted amine, amino, substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy (straight or branched chain), or hexoxy (straight or branched chain)), substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy), substituted or unsubstituted (C1-C6 alkyl)acyl, substituted or unsubstituted C-amido, substituted or unsubstituted N-amido, substituted or unsubstituted C-carboxy, substituted or unsubstituted O-carboxy, substituted or unsubstituted O-carbamyl, and substituted or unsubstituted N-carbamyl.

[0132] In some embodiments, X can be hydrogen. In other embodiments, X can be halogen. In some embodiments, X can be fluoro. In some embodiments, X can be chloro. In still other embodiments, X can be hydroxy. In still yet other embodiments, X can be cyano. In some embodiments, X can be amino.

[0133] In some embodiments, X can be an unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, X can be an unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In some embodiments, X can be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, X can be an unsubstituted C1-C6 haloalkyl (such as a C1-C6 fluoroalkyl, a C1-C6 chloroalkyl, or a C1-C6 chlorofluoroalkyl). In some embodiments, X can be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, X can be an unsubstituted C1-C6 hydroxyalkyl (such as a C1-C6 monohydroxyalkyl or a C1-C6 dihydroxyalkyl). In some embodiments, X can be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3). In some embodiments, X can be an unsubstituted C1-C6 cyanoalkyl (such as a C1-C6 monocyanoalkyl or a C1-C6 dicyanoalkyl).

[0134] [ka] In some embodiments, X may be selected from the group consisting of unsubstituted C1-C6 alkoxy groups. In some embodiments, X may be alkyl (such as C1-C6 monoalkoxyalkyl or C1-C6 dialkoxyalkyl).

[0135] [ka] In some embodiments, -a may be selected from:

[0136] [ka] It may be a substituted C1-C6 alkyl selected from:

[0137] In some embodiments, X can be an unsubstituted C1-C6 alkoxy (such as those described herein). In some embodiments, X can be an unsubstituted methoxy, unsubstituted ethoxy, or unsubstituted isopropoxy. In some embodiments, X can be a substituted C1-C6 alkoxy (such as those described herein). In some embodiments, X can be a C1-C6 alkoxy substituted with one, two, or three substituents independently selected from halogen, amino, a monosubstituted amine (such as those described herein), and a disubstituted amine (such as those described herein). In some embodiments, X can be a C1-C6 alkoxy substituted with one substituent selected from halogen, amino, a monosubstituted amine (such as those described herein), and a disubstituted amine (such as those described herein).

[0138] In some embodiments, X is

[0139] [ka] may be selected from:

[0140] In some embodiments, X can be a substituted C3-C6 cycloalkoxy (such as those described herein). In some embodiments, X can be an unsubstituted C3-C6 cycloalkoxy (such as those described herein).

[0141] In some embodiments, X can be substituted (C1-C6 alkyl) acyl, such as substituted -(CO)-CH3. In some embodiments, X can be unsubstituted (C1-C6 alkyl) acyl, such as unsubstituted -(CO)-CH3.

[0142] In some embodiments, X can be a substituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be an unsubstituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be selected from azetidine, oxetane, diazetidine, azaoxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, and dioxane, and any of the above groups. Each is substituted or unsubstituted, including an optional -NH group. In some embodiments, X is

[0143] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH groups.

[0144] In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl (such as those described herein) substituted with one or two substituents independently selected from halogen, substituted or unsubstituted C1-C6 alkyl (such as those described herein), monosubstituted amine (such as those described herein), disubstituted amine (such as those described herein), amino, substituted or unsubstituted amine(C1-C6 alkyl), and substituted or unsubstituted (C1-C6 alkyl)acyl. In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl substituted with one or two substituents independently selected from fluoro, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, -CH2OH, and -N(CH3)2. In some embodiments, X can be

[0145] [ka] may be selected from:

[0146] In some embodiments, X can be a substituted amine(C1-C6 alkyl). In some embodiments, X can be an unsubstituted amine(C1-C6 alkyl). In some embodiments, X can be

[0147] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH groups.

[0148] In some embodiments, X is a substituted -NH-(CH) 1-6 In some embodiments, X is an unsubstituted —NH—(CH) 1-6 In some embodiments, X may be an amine.

[0149] [ka] Each of the aforementioned groups may be substituted or unsubstituted, including any -NH groups.

[0150] In some embodiments, X can be a monosubstituted amine. In some embodiments, the substituent of the monosubstituted amine is an unsubstituted C1-C6 alkyl (such as those described herein) or an unsubstituted C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0151] In some embodiments, X can be a disubstituted amine, in which the two substituents of the disubstituted amine are independently selected from unsubstituted C1-C6 alkyl (such as those described herein) and unsubstituted C3-C6 cycloalkyl (such as those described herein).

[0152] In some embodiments, X is

[0153] [ka] may be selected from:

[0154] In some embodiments, X may be substituted or unsubstituted C-amido. In some embodiments, X may be substituted or unsubstituted N-amido. In some embodiments, X may be substituted or unsubstituted C-carboxy. In some embodiments, X may be substituted or unsubstituted O-carboxy. In some embodiments, X may be substituted or unsubstituted O-carbamyl. In some embodiments, X may be substituted or unsubstituted N-carbamyl. In some embodiments, X may be monosubstituted with unsubstituted C1-C6 hydroxyalkoxy (such as those described herein).

[0155] In some embodiments, Y 1 is CR 4A or N (nitrogen). In some embodiments, Y 1 is CR 4A In some embodiments, Y 1 may be N (nitrogen).

[0156] In some embodiments, Y 2 is CR 4B or N (nitrogen). In some embodiments, Y 2 is CR 4B In some embodiments, Y 2 may be N (nitrogen).

[0157] In some embodiments, Y 1 and Y 2 may each be N (nitrogen). In some embodiments, Y 1 is CR 4A and Y 2 is CR 4B In some embodiments, Y 1 is CR 4A and Y 2may be N (nitrogen). In some embodiments, Y 1 may be N (nitrogen), and Y 2 is CR 4B It may be.

[0158] In some embodiments, R 4A may be hydrogen. In some embodiments, R 4A may be halogen. In some embodiments, R 4A is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0159] In some embodiments, R 4B may be hydrogen. In some embodiments, R 4B may be halogen. In some embodiments, R 4B is the unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0160] In some embodiments, R 4A and R 4B and R may each be hydrogen. 4A and R 4B and R may each be a halogen (wherein the halogens may be the same or different from one another). In some embodiments, R 4A and R 4B are unsubstituted C 1~4 Alkyl (such as those described herein, where C 1~4 In some embodiments, R 4A and R 4B may be hydrogen, and R 4A and R 4B The other of R may be halogen. 4A and R 4B may be hydrogen, and R 4A and R 4BThe other is unsubstituted C 1~4 In some embodiments, R 4A and R 4B One of R may be halogen; 4A and R 4B The other is unsubstituted C 1~4 It may be alkyl (such as those described herein).

[0161] In some embodiments, R 2 teeth,

[0162] [ka] For example, R 2 teeth,

[0163] [ka] R 2 but

[0164] [ka] In some embodiments, when 5 may be a substituted 5- to 7-membered monocyclic heterocyclyl. 5 R may be an unsubstituted 5- to 7-membered monocyclic heterocyclyl. 5 Exemplary groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azepanyl. When substituted, R 5 Leading the way Possible substituents include unsubstituted C 1~4 Alkyl, halogen, hydroxy, and unsubstituted C 1~4 Haloalkyl is an example.

[0165] In some embodiments, ring C is a substituted or unsubstituted C-C10 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.

[0166] In some embodiments, ring C is a substituted C-C 10 In some embodiments, ring C is an unsubstituted C-C aryl. 10 In some embodiments, ring C may be substituted C aryl. In some embodiments, ring C may be unsubstituted C aryl.

[0167] In some embodiments, ring C can be a substituted 5-10 membered heteroaryl. In some embodiments, ring C can be an unsubstituted 5-10 membered heteroaryl. In some embodiments, ring C can be a substituted 5-6 membered heteroaryl. In some embodiments, ring C can be an unsubstituted 5-6 membered heteroaryl. In some embodiments, ring C can be selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, benzimidazole, indole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, quinoline, isoquinoline, quinazoline, and quinoxaline, each of the foregoing groups being substituted or unsubstituted, including any -NH group.

[0168] In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 6-membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 7-membered carbocyclyl.

[0169] In some embodiments, Ring C can be Ring C and can be a substituted or unsubstituted 5-membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 6-membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 7-membered monocyclic heterocyclyl. In some embodiments, Ring C can be selected from imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, tetrahydropyran, azepine, oxepine, and diazepine, each of the foregoing groups being substituted or unsubstituted, including any -NH group.

[0170] In some embodiments, Ring C can be a substituted or unsubstituted 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiroheterocyclyl). In some embodiments, Ring C can be selected from pyrrolizidine, indoline, 1,2,3,4 tetrahydroquinoline, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane, each of the foregoing groups being substituted or unsubstituted, including any -NH groups.

[0171] In some embodiments, Ring C can be substituted with one or more substituents independently selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl. In some embodiments, Ring C can be substituted with one substituent selected from unsubstituted C1-C6 alkyl (as described herein) and unsubstituted (C1-C6 alkyl) acyl.

[0172] In some embodiments, R 2 teeth,

[0173] [ka] and each of the foregoing groups may be substituted or unsubstituted.

[0174] In some embodiments, Compound (A), or a pharmaceutically acceptable salt thereof, can be used in combination with a SERD inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound (A), or a pharmaceutically acceptable salt thereof, can be used in combination with a SERM inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound (A), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (B1), which has the structure:

[0175] [ka] In the formula, b 1 is N or Cb 8 b 8 may be H, halogen, or OCH3; b 2 is N or Cb 9 b 9 may be H or halogen, b 4 is N or Cb 10 b 10 may be H or halogen, b 5 is N or Cb11 b 11 may be H, halogen, or OCH3; b 6 may be H, F, or OH, b 7 may be unsubstituted lower alkyl; b 8 may be substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; b 3 teeth,

[0176] [ka] , -O-(CH2)2-N(a 1 )[(CH2) m -F],

[0177] [ka] m may be 2 or 3, n1, n2, n3, or n4 may independently be 1 or 2, and a 1 may be H or CH3, provided that the compound of formula (B1) 1 and b 5 is CF, b 2 and b 4 are CH, b 6 H, b 7 is CH3, b 8 but

[0178] [ka] , and b 3 but

[0179] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, 8 is a substitution C 1~6In other embodiments, b may be alkyl. 8 is the unsubstituted C 1~6 In other embodiments, b may be alkyl. 8 In still other embodiments, b can be substituted cycloalkyl. 8 In some embodiments, cycloalkyl is a monocyclic C 3~8 In some embodiments, b may be a monocyclic cycloalkyl, such as a cycloalkyl. 8 In other embodiments, b may be substituted aryl. 8 may be unsubstituted aryl. An example of a suitable aryl is phenyl. In some embodiments, b 1 is Cb 8 b 2 is Cb 9 b 4 is Cb 10 b 5 is Cb 11 In other embodiments, b 1 , b 2 , b 4 and b 5 At least one of b may be N. In some embodiments, 3 teeth,

[0180] [ka] In other embodiments, b 3 is -O-(CH2)2-N(a 1 )[(CH2) m -F]. In yet another embodiment, b 3 teeth,

[0181] [ka] In still other embodiments, b 3 teeth,

[0182] [ka] In some embodiments, b 3 teeth,

[0183] [ka] It may be.

[0184] A non-limiting list of SERD and SERM inhibitors is described herein and includes those provided in Figures 1 and 2. Additional SERD and / or SERM inhibitors are disclosed in WO 95 / 12383, WO 96 / 19997, WO 97 / 21440, WO 97 / 37653, WO 97 / 40823, WO 98 / 11902, WO 2004 / 058682, WO 2012 / 037410, WO 2014 / 130310, WO 2014 / 191726, WO 2016 / 097071, WO 2016 / 09 No. 7072, No. 2016 / 196337, No. 2016 / 19634, No. 2016 / 202161, No. 2017 / 059139, No. 2017 / 080338, No. 2017 / 100 No. 712, No. 2017 / 100715, No. 2017 / 107754, No. 2017 / 136688, No. 2017 / 172957, No. 2017 / 182493, No. 2017 / 182 No. 495, No. 2017 / 216279, No. 2017 / 216280, No. 2018 / 001232, No. 2018 / 019793, No. 2018 / 077260, No. 2018 / 081 No. 168, No. 2018 / 091153, No. 2018 / 102725, No. 2018 / 130123, No. 2018 / 130124, No. 2018 / 138303, No. 2018 / 148 576, 2019 / 066692, 2019 / 223715, 2017 / 059139, U.S. Patent Application Publication Nos. 2020 / 0017516, 2018 / 0072711, and WO 2020 / 014440, each of which is incorporated by reference herein for the limited purpose of disclosing compounds that are SERD and / or SERM inhibitors.

[0185] Examples of compounds (A) include:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka] or a pharmaceutically acceptable salt of any of the foregoing.

[0191] Compound (A), along with its pharmaceutically acceptable salts, can be prepared as described herein and in WO 2019 / 173082, the entire contents of which are incorporated herein by reference. As described in WO 2019 / 173082, Compound (A) is a WEE1 inhibitor.

[0192] Table 1 provides embodiments of combinations of Compound (A) and Compound (B), including any of the pharmaceutically acceptable salts described above. The numbers in Table 1 represent the compounds provided in Figures 1 to 3. For example, in Table 1, the combination represented as 1:5A is a combination of fulvestrant and Compound (B), including any of the pharmaceutically acceptable salts described above.

[0193] [ka] corresponds to the combination of

[0194] [Table 1-1]

[0195] [Table 1-2]

[0196] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A), including its pharmaceutically acceptable salts and salt forms, may be administered before all of compound (B) or its pharmaceutically acceptable salts. In other embodiments, compound (A), including its pharmaceutically acceptable salts and salt forms, may be administered before at least one dose of compound (B) or its pharmaceutically acceptable salts. In still other embodiments, compound (A), including its pharmaceutically acceptable salts and salt forms, may be administered simultaneously with all of compound (B) or its pharmaceutically acceptable salts. In still yet other embodiments, compound (A), including its pharmaceutically acceptable salts and salt forms, may be administered following the administration of at least one dose of compound (B) or its pharmaceutically acceptable salts. In some embodiments, compound (A), including its pharmaceutically acceptable salts and salt forms, may be administered following the administration of all of compound (B) or its pharmaceutically acceptable salts.

[0197] There may be several advantages to using the combinations of compounds described herein. For example, combining compounds that simultaneously attack multiple pathways may be more effective in treating cancers such as those described herein compared to when the combined compounds are used as monotherapy.

[0198] In some embodiments, the combination of one or more of Compound (A), including pharmaceutically acceptable salts thereof, described herein with Compound (B), or a pharmaceutically acceptable salt thereof, can reduce the number and / or severity of side effects that can be attributed to a compound, such as Compound (B), or a pharmaceutically acceptable salt thereof, described herein.

[0199] The use of the combinations of compounds described herein can result in additive, synergistic, or potentially synergistic effects. The combinations of compounds described herein can result in effects that are not antagonistic.

[0200] In some embodiments, the combination of compound (A), including a pharmaceutically acceptable salt thereof, and one or more of compound (B) or a pharmaceutically acceptable salt thereof, as described herein, may provide an additive effect. In some embodiments, the combination of compound (A), including a pharmaceutically acceptable salt thereof, and one or more of compound (B) or a pharmaceutically acceptable salt thereof, as described herein, may provide a synergistic effect. In some embodiments, the combination of compound (A), including a pharmaceutically acceptable salt thereof, and one or more of compound (B) or a pharmaceutically acceptable salt thereof, as described herein, may provide a strong synergistic effect. In some embodiments, the combination of compound (A), including a pharmaceutically acceptable salt thereof, and one or more of compound (B) or a pharmaceutically acceptable salt thereof, as described herein, is not antagonistic.

[0201] As used herein, the term "antagonistic" means that the activity of a combination of compounds is less than the sum of the activities of each compound in the combination when the activity of each compound is measured individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of a combination of compounds is greater than the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually. As used herein, the term "additive" means that the activity of a combination of compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually.

[0202] A potential advantage of utilizing the combinations described herein may be a reduction in the amount of compound required to be effective for treating a disease condition disclosed herein compared to when each compound is administered as a monotherapy. For example, the amount of compound (B) or a pharmaceutically acceptable salt thereof used in the combinations described herein may be less than the amount of compound (B) or a pharmaceutically acceptable salt thereof required to achieve the same reduction in a disease marker (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 pose 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 include little or no cross-resistance between the compounds of the combinations described herein, different excretion routes for the compounds of the combinations described herein, and / or different combinations of the compounds described herein. It may be noted that there is little or no overlapping toxicity between the compounds in the combination.

[0203] Pharmaceutical Composition Compound (A), including its pharmaceutically acceptable salt, can be provided in a pharmaceutical composition. Similarly, compound (B), including its pharmaceutically acceptable salt, can be provided in a pharmaceutical composition.

[0204] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate 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.

[0205] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0206] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity but may be pharmaceutically 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.

[0207] 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.

[0208] In some embodiments, compound (B) may be provided in a pharmaceutical composition comprising compound (A) with a pharmaceutically acceptable salt thereof, hi other embodiments, compound (B) may be administered in a pharmaceutical composition separate from the pharmaceutical composition comprising compound (A) with a pharmaceutically acceptable salt thereof.

[0209] The pharmaceutical compositions described herein can be administered to human patients either 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 selected route of administration. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0210] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0211] These include oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. Multiple techniques for administering compounds, salts, and / or compositions exist in the art, including, but not limited to, compound (A), including its pharmaceutically acceptable salt, can be administered orally. In some embodiments, compound (A), including its pharmaceutically acceptable salt, can be provided to a subject by the same route of administration as compound (B), along with its pharmaceutically acceptable salt. In other embodiments, compound (A), including its pharmaceutically acceptable salt, can be provided to a subject by a different route of administration than compound (B), along with its pharmaceutically acceptable salt.

[0212] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compound directly into the affected area, often as a depot or sustained-release formulation. Additionally, 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.

[0213] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have associated with it a notice on the container in a format prescribed by a government agency regulating the manufacture, use, or sale of drugs, which notice reflects the agency's approval of the drug form for human or animal administration. Such notice may, for example, be the label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the compounds and / or salts described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0214] Uses and Treatment Methods As provided herein, in some embodiments, a disease or condition can be treated using a combination of compounds comprising an effective amount of Compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B) or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the disease or condition can be selected from breast cancer, cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, vulvar cancer, brain cancer, cervical cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, lung cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, Wilms' carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. In other embodiments, the disease or condition can be selected from breast cancer, cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0216] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0217] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily imply a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Furthermore, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0218] The term "effective amount" is used to refer to the amount of an active compound or agent that elicits the indicated biological or medical response. 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 the signs or symptoms of the disease or condition being treated. Determining an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be tailored to achieve the desired effect, depending on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical field would recognize.

[0219] 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.

[0220] Various types of breast cancer are known. In some embodiments, the breast cancer may be ER-positive breast cancer. In some embodiments, the breast cancer may be ER-positive, HER2-negative breast cancer. In some embodiments, the breast cancer may be localized breast cancer (as used herein, "localized" breast cancer means that the cancer has not spread to other areas of the body). In some embodiments, the cancer may be metastatic breast cancer. The subject may have breast cancer that has not been previously treated.

[0221] In some cases, following breast cancer treatment, a subject may experience a relapse or recurrence of breast cancer. As used herein, the terms "relapse" and "recurrence" are used in their ordinary sense as understood by those skilled in the art. Thus, the breast cancer may be recurrent breast cancer. In some embodiments, the subject has relapsed after a previous treatment for breast cancer. For example, the subject has relapsed after receiving one or more treatments with a SERM, a SERD, and / or an aromatase inhibitor, such as those described herein.

[0222] Several amino acid mutations have been identified within ESR1. Mutations in ESR1 have been proposed to play a role in resistance. Several therapies exist to inhibit the estrogen receptor, including selective ER modulators (SERMs), selective ER degraders (SERDs), and aromatase inhibitors. One problem that can arise from the aforementioned cancer therapies is the development of resistance to cancer therapies. Acquired resistance to cancer therapies, such as endocrine therapy, has been found in nearly one-third of women treated with tamoxifen and other endocrine therapies. Alluri et al. See al., "Estrogen receptor mutations and their role in breast cancer progression," Breast Cancer Research (2014) 16:494. Researchers believe that mutations in the estrogen receptor are one of the reasons for acquired resistance to cancer therapies, such as endocrine therapy. Therefore, there is a need for compounds that can treat breast cancers that harbor one or more mutations in ESR1.

[0223] Some embodiments disclosed herein relate to the use of a combination of compounds comprising an effective amount of compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of compound (B) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof, wherein the breast cancer has at least one point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). Other embodiments disclosed herein relate to the use of a combination of compounds comprising an effective amount of compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of compound (B) or a pharmaceutically acceptable salt thereof, for treating breast cancer in a subject in need thereof, wherein the breast cancer has at least one point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). Yet other embodiments disclosed herein relate to methods of treating breast cancer in a subject in need thereof with a combination of compounds comprising an effective amount of Compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B) or a pharmaceutically acceptable salt thereof, wherein the breast cancer has at least one point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα).

[0224] In some embodiments, the mutations may be in the ligand binding domain (LBD) of ESR1. In some embodiments, the one or more mutations may be A593, S576, G557, R555, L549, A546, E542, L540, D538, Y537, L536, P535, V534, V533, N532, K531, C530, H524, E523, M522, R503, L497, K481, V478, R477, E471, S463, F461, S432, G420, V41 In some embodiments, the one or more mutations may be at an amino acid selected from D538, Y537, L536, P535, V534, S463, V392, and E380. In some embodiments, the one or more mutations may be at an amino acid selected from D538 and Y537.

[0225] In some embodiments, the one or more mutations are K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N, K481N, K531E, L370F, L453F, L46 6Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K, P147Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D and Y537H.

[0226] Some embodiments disclosed herein relate to the use of a combination of compounds comprising an effective amount of Compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof, wherein the breast cancer does not contain at least one point mutation (e.g., a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα)). Other embodiments disclosed herein relate to the use of an effective amount of Compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of Compound (B), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof. (B) or one or more pharmaceutically acceptable salts thereof, wherein the breast cancer does not contain at least one point mutation, such as a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). Still other embodiments disclosed herein relate to methods of treating breast cancer in a subject in need thereof with a combination of compounds comprising an effective amount of compound (A), including a pharmaceutically acceptable salt thereof, and an effective amount of one or more of compound (B) or a pharmaceutically acceptable salt thereof, wherein the breast cancer does not contain at least one point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα) (e.g., a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα)).

[0227] As provided herein, several studies have shown that a potential cause of resistance in ER-positive breast cancer is due to acquired mutations in ESR1 from endocrine therapy. In some embodiments, the subject has previously been treated with one or more selective ER modulators. For example, the subject has previously been treated with one or more selected ER modulators selected from tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and lasofoxifene, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the subject has previously been treated with one or more selected ER modulators selected from fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl )-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brilanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4 (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide (H3B-6545), (E)- 3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (rintodestrant, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (giredestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-( The subject has previously been treated with one or more selective ER degraders, such as [(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250, and LY3484356, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the subject has previously been treated with one or more aromatase inhibitors. The aromatase inhibitor may be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor. For example, the one or more aromatase inhibitors may be selected from exemestane (a steroidal aromatase inhibitor), testolactone (a steroidal aromatase inhibitor), anastazole (a non-steroidal aromatase inhibitor), and letrazole (a non-steroidal aromatase inhibitor) (including pharmaceutically acceptable salts of any of the foregoing).

[0228] In some embodiments, the subject may have breast cancer and may be female. As a woman approaches middle age, she may enter menopause. In some embodiments, the subject may be a premenopausal woman. In other embodiments, the subject may be a peri-menopausal woman. In yet other embodiments, the subject may be a menopausal woman. In yet other embodiments, the subject may be a post-menopausal woman. In other embodiments, the subject may have breast cancer and may be male. The subject's serum estradiol concentration may vary. In some embodiments, the subject's serum estradiol concentration (E2) may be in the range of greater than 15 pg / mL to 350 pg / mL. In other embodiments, the subject's serum estradiol concentration (E2) may be 15 pg / mL or less. In other embodiments, the subject's serum estradiol concentration (E2) may be 10 pg / mL or less.

[0229] The amount of compound, salt, and / or composition required for therapeutic use will vary not only with the particular compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges set forth herein to effectively and aggressively treat, particularly advanced diseases or conditions.

[0230] As will be readily apparent to those skilled in the art, useful in vivo dosages and specific methods of administration will vary depending on the age, weight, severity of the affliction, and mammalian species being treated, the particular compound used, and the particular application for which these compounds are being used. Determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired result, 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 pharmaceutically acceptable salts of either of the foregoing, can be determined by comparing their in vitro and in vivo activity in animal models. Such comparisons can be made by comparison with established drugs, such as cisplatin and / or gemcitabine.

[0231] Dosage amount and interval may be adjusted individually to provide plasma concentrations sufficient to maintain the active moiety's modulatory effect or minimal effective concentration (MEC). The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to measure plasma concentrations. Dosage intervals can 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 drug may not be related to plasma concentration.

[0232] It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and the route of administration. The severity of the disease or condition may, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose, and perhaps the frequency of administration, will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above may be used in veterinary medicine.

[0233] 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 particularly humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, dog, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, those skilled in the art can use the state of the art as a guide to select an appropriate model, dose, route of administration, and / or regimen. [Example]

[0234] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below.

[0235] Xenograft tumor model MCF-7 breast cancer tumor cells were cultured in vitro in DMEM medium supplemented with 15% fetal bovine serum at 37°C under a 5% CO2 atmosphere in air. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation. MCF-7 tumor cells (1.5 × 10 cells) in 100 μL of DMEM:Matrigel (1:1) were inoculated into the second right mammary fat pad of BALB / c nude mice. 7 The tumor was subcutaneously implanted. 3 When the tumor size reached 100 mg / kg, animals were randomly assigned to treatment groups of 8 animals each. Single-agent treatment groups received daily oral administration of vehicle, 80 mg / kg Compound (1A), 30 mg / kg Compound 3, 1 mg / kg Compound 11, and 5 mg / kg Compound 13. Combination treatment groups received 80 mg / kg Compound (1A) along with 30 mg / kg Compound 3, 1 mg / kg Compound 11, or 5 mg / kg Compound 13 for the durations indicated in Figures 4-6. Additionally, estradiol benzoate injections were administered sc (40 μg / 20 μL, twice weekly). Additionally, estradiol benzoate injections were administered sc (40 μg / 20 μL, twice weekly). Tumor volume was assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: TGI = (1 - (Td - T0) / (Cd - C0)) x 100%, where 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 study.

[0236] As shown in Figure 4, 80 mg / kg of Compound (1A) and Compound 11 exhibited antitumor activity with TGI values ​​of 152.5% and 133.5%, respectively. In Figure 4, the top line (circle) represents vehicle data, and the second line (circle) from the bottom represents data for Compound (1A) (80 mg / kg). The combination of 80 mg / kg of Compound (1A) and 1 mg / kg of Compound 11 exhibited significant antitumor activity with a TGI of 174%.

[0237] As shown in Figure 5, 80 mg / kg of Compound (1A) and Compound 13 exhibited antitumor activity with TGI values ​​of 152.5% and 133%, respectively. In Figure 5, the top line (circle) represents vehicle data, and the second line (circle) from the bottom represents data for Compound (1A) (80 mg / kg). The combination of 80 mg / kg of Compound (1A) and 5 mg / kg of Compound 13 exhibited significant antitumor activity with a TGI of 169.5%.

[0238] As shown in Figure 6, 80 mg / kg of Compound (1A) and Compound 3 exhibited antitumor activity with TGI values ​​of 152.5% and 120.5%, respectively. In Figure 5, the top line (circle) represents the vehicle data, and the second line (circle) from the bottom represents the data for Compound (1A) (80 mg / kg). The combination of Compound 3 demonstrated significant antitumor activity with a TGI of 169%. The data provided herein demonstrate that a combination of a WEE1 inhibitor with a SERD / SERM inhibitor described herein can be used to treat the diseases or conditions described herein. Table 2 provides the antitumor activity of the different treatment groups at 28 days.

[0239] [Table 2]

[0240] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made thereto without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A pharmaceutical combination of compounds, said pharmaceutical combination being for treating breast cancer, said combination comprising an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of compound (B) or a pharmaceutically acceptable salt thereof; The compound (A) has the following structure: 【Chemistry 1】 The compound (B) is (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indo N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), or a pharmaceutically acceptable salt of any of the foregoing; A pharmaceutical composition, wherein the compound (A) or a pharmaceutically acceptable salt thereof and the compound (B) or a pharmaceutically acceptable salt thereof are administered as a single pharmaceutical composition or separate pharmaceutical compositions.

2. The compound (A) or a pharmaceutically acceptable salt thereof is the compound (B) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered before administration of a therapeutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the compound (A) or a pharmaceutically acceptable salt thereof is administered simultaneously with the compound (B) or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the compound (A) or a pharmaceutically acceptable salt thereof is administered after the compound (B) or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical agent according to any one of claims 1 to 4, wherein the breast cancer does not contain any point mutation ER mutation.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the breast cancer is ER-positive breast cancer.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the breast cancer is ER-positive / HER2-negative breast cancer.

8. The method of any one of claims 1 to 7, wherein the breast cancer has been previously treated with endocrine therapy.

9. The method of claim 8, wherein the treatment was a selective ER modulator (SERM).

10. The method of claim 8, wherein the treatment was a selective ER degrader (SERD).

11. The pharmaceutical composition of claim 8, wherein the treatment is an aromatase inhibitor.

12. The method of claim 11, wherein the aromatase inhibitor is a steroidal aromatase inhibitor.

13. The pharmaceutical composition according to claim 11, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.

14. The method of any one of claims 1 to 7, wherein the breast cancer has not been previously treated.

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