Monotherapy and combination therapy

Abstract

The objective is to provide compounds and combinations of compounds for treating diseases or conditions such as cancer. [Solution] To solve the above problem, a combination of compounds is disclosed herein, which may contain an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, and one or more effective amounts of compound (B) or a pharmaceutically acceptable salt of any of the above.

Description

[Technical Field]

[0001] (Incorporation by referencing any priority application) For example, any foreign or domestic priority claim confirmed in the application data sheet or claims filed with this application, including U.S. Provisional Application No. 63 / 025,490 filed on 15 May 2020, No. 63 / 040,832 filed on 18 June 2020, No. 63 / 089,419 filed on 8 October 2020, No. 63 / 160,325 filed on 12 March 2021, and No. 63 / 161,828 filed on 16 March 2021, are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6.

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

[0003] Cancer is a group of diseases characterized by abnormal cell proliferation 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 it is diagnosed. In 2019, approximately 1.8 million people in the United States were diagnosed with cancer, and an estimated 606,880 people died from it. Therefore, the need for effective cancer treatment remains. [Overview of the project]

[0004] Some embodiments described herein relate to compound combinations that may comprise an effective amount of compound (A), or a pharmaceutically acceptable salt thereof, and one or more of compound (B), or a pharmaceutically acceptable salt of any of the foregoing.

[0005] Some embodiments described herein relate to the use of combinations of compounds for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and one or more of compound (B) or a pharmaceutically acceptable salt of any of the foregoing. Other embodiments described herein relate to the use of combinations of compounds in the manufacture of a drug for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and one or more of compound (B) or a pharmaceutically acceptable salt of any of the foregoing.

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

[0007] [Figure 1-1] Figure 1 shows examples of chemotherapeutic agents. [Figure 1-2] Continuation of Figure 1 [Figure 1-3] Continuation of Figure 1 [Figure 1-4] Continuation of Figure 1 [Figure 2-1] Figure 2 provides an example of a PARP inhibitor. [Figure 2-2] Continuation of Figure 2 [Figure 3] Examples of PD-1 inhibitors are provided. [Figure 4] Examples of PD-L1 inhibitors are provided. [Figure 5-1] Figure 5 provides an example of compound (A). [Figure 5-2] Continuation of Figure 5 [Figure 6] The results of studies on compounds containing or not containing thalazoparib (1A) in the TOV112D cell line are shown. [Figure 7] The results of studies on compounds containing or not containing niraparib (1A) in the MDA-MB-436 cell line are shown. [Figure 8]The results of studies on compounds containing or not containing carboplatin (1A) in the TOV21G xenograft model are presented. [Figure 9] The results of studies on gemcitabine-containing and gemcitabine-free compounds (1A) in the SJSA-1 xenograft model are presented. [Figure 10] The results of studies on compounds containing or not containing thalazoparib (1A) in an OVCAR3 xenograft model are presented. [Figure 11] The results of studies on compounds containing or not containing anti-PD-1 (1A) in the MC38 syngeneic tumor model are shown. [Figure 12] The results of studies on compounds containing or not containing anti-PD-1 (1A) in the MC38 syngeneic tumor model are shown. [Figure 13] The results of the efficacy study of compound (1A) as a monotherapy in the A427 NSCLC xenograft model are shown. [Figure 14] The results of an efficacy study of compound (1A) as a monotherapy in the H1755 NSCLC tumor model are presented. [Figure 15] This paper presents the results of an efficacy study of compound (1A) as a monotherapy agent in the SKUT-1 uterine leiomyosarcoma tumor model. [Figure 16] The results of an efficacy study of compound (1A) as a monotherapy in an OVCAR3 ovarian tumor model are presented. [Figure 17] This paper presents the results of an efficacy study of compound (1A) as a monotherapy in the MDA-MB-468 TNBC (triple-negative breast cancer) tumor model. [Figure 18] This paper presents the results of efficacy studies of compound (1A) and niraparib, either as a monotherapy or in combination, in an x2 MDA-MB-468 TNBC (triple-negative breast cancer) tumor model. [Figure 19] This paper presents the results of efficacy studies of the compound (1A) and radiation, either as a monotherapy or in combination, in a Fadu head and neck tumor model. [Figure 20]The study demonstrated inhibition of cell proliferation in UWB1.289 cells by a compound (1A) combined with hydroxyurea (HU), with data expressed in relative light units (RLU). [Figure 21] This study demonstrates the inhibition of cell proliferation in UWB1.289 cells by compound (1A) combined with hydroxyurea (HU). The data are expressed as normalized relative luminescence units (RLU) for each hydroxyurea concentration to show the synergistic effect of the HU-combination of compound (1A). [Figure 22] The study demonstrated inhibition of cell proliferation in OVCAR3 cells by a compound (1A) combined with hydroxyurea (HU), with data expressed in relative luminescence units (RLU). [Figure 23] This study demonstrates the inhibition of cell proliferation in OVCAR3 cells by compound (1A) combined with hydroxyurea (HU). The data are expressed as normalized relative luminescence units (RLU) for each hydroxyurea concentration to show the synergistic effect of the HU-combination with compound (1A). [Figure 24] The combination of compound (1A) and gemcitabine in the KMS-12-BM cell line is shown. [Figure 25] The combination of compound (1A) and gemcitabine in the OPM-2 cell line is shown. [Figure 26] The combination of compound (1A) and gemcitabine in the MOLP-8 cell line is shown. [Figure 27] This paper presents the results for the near-optimal doses of compound (1A) and triapin, both as monotherapy and in combination, in A427 cell proliferation studies. [Figure 28] The results of an efficacy study of compound (1A) in combination with doxorubicin in an OVCAR3 ovarian tumor model are presented. [Modes for carrying out the invention]

[0008] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated in their entirety by reference unless otherwise specified. If there are multiple definitions for any term herein, the definition in this section shall prevail unless otherwise specified.

[0009] Whenever a group is described as being "optionally substituted," that group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituent may be selected from one or more of the indicated substituents. If no substituent is specified, it means that the specified "optionally substituted" or "substituted" group may be substituted with one or more groups (e.g., one, two, or three 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-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amine groups, disubstituted amine groups, and amines (C1-C6 alkyl).

[0010] As used herein, "a" and "b" are integers. a ~C b" refers to the number of carbon atoms in the group. The indicated group can contain "a" to "b" carbon atoms (including a and b). Therefore, for example, the "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified, the broadest range described in those definitions is assumed.

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

[0012] [ka]

[0013] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl group may be branched or linear. Examples of branched alkyl groups include Examples of linear alkyl groups include, but are not limited to, isopropyl, sec-butyl, and t-butyl. Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl. Alkyl groups may have 1 to 30 carbon atoms (wherever they appear herein, numerical ranges such as "1 to 30" refer to each integer within a given range; for example, "1 to 30 carbon atoms" means that an alkyl group may consist of up to 30 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition also includes the case where the term "alkyl" does not specify a numerical range). Alkyl groups may also be intermediate-sized alkyl groups having 1 to 12 carbon atoms. Alkyl groups may also be lower alkyl groups having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted.

[0014] As used herein, the term "alkenyl" refers to a monovalent linear or branched radical 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, and 2-butenyl. The alkenyl group may be unsubstituted or substituted.

[0015] As used herein, the term "alkynyl" refers to a monovalent linear or branched radical of 2 to 20 carbon atoms containing a carbon triple bond, including but not limited to 1-propynyl, 1-butynyl, and 2-butynyl. The alkynyl group may be unsubstituted or substituted.

[0016] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. If it consists of two or more rings, the rings may be joined together by condensation, bridging, or spiro. As used herein, the term “condensation” refers to two rings sharing two atoms and one bond. As used herein, the term “bridging 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 sharing one atom, where the two rings are not joined by bridging. Cycloalkyl groups may contain 3 to 30 atoms, 3 to 20 atoms, 3 to 10 atoms, 3 to 8 atoms, or 3 to 6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of condensed cycloalkyl groups include decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of cross-linked cycloalkyl groups include 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, but if there are two or more, the double bonds cannot form a completely delocalized π-electron system across the entire ring (otherwise, the group is an “aryl” as defined herein). A cycloalkenyl group may contain 3 to 10 atoms in the ring, 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring. If it consists of two or more rings, the rings may be joined together by condensation, bridging, or spiro. A cycloalkenyl group may be unsubstituted or substituted.

[0018] As used herein, "carbocykrill" refers to non-aromatic monocyclic or polycyclic carbides. This refers to an elementary cyclic system. If it consists of two or more rings, the rings may be joined together by condensation, crosslinking, or spiro as described herein. A carbocyclyl group may contain 3 to 30 atoms, 3 to 20 atoms, 3 to 10 atoms, 3 to 8 atoms, or 3 to 6 atoms in the ring. The carbocyclyl group may be unsubstituted or substituted. Examples of carbocyclyl groups include, as defined herein, cycloalkyl and cycloalkenyl groups, as well as 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, but are not limited to these.

[0019] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) that has a completely delocalized π-electron system throughout the entire ring. The number of carbon atoms in an aryl group can vary. For example, an aryl group may have C6~C 14 Aryl group, C6~C 10 The 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 completely delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms, 5 to 10 atoms, or 5 to 6 atoms in the ring, such as 9 carbon atoms and 1 heteroatom; 8 carbon atoms and 2 heteroatoms; 7 carbon atoms and 3 heteroatoms; 8 carbon atoms and 1 heteroatom; 7 carbon atoms and 2 heteroatoms; 6 carbon atoms and 3 heteroatoms; 5 carbon atoms and 4 heteroatoms; 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; or 2 carbon atoms and 3 heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems 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, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0021] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to monocyclic, bicyclic, and tricyclic ring systems of 3, 4, 5, 6, 7, 8, 9, 10, and up to 18 members, in which a carbon atom and 1 to 5 heteroatoms together constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds in such positions, but a completely delocalized π-electron system does not arise throughout the entire ring. Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen, as are elements other than carbon. Heterocycles include lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. To define the group as including so-type and thio-type groups, it may further contain one or more carbonyl or thiocarbonyl functional groups. If it consists of two or more rings, the rings may be joined together in a condensed, cross-linked, or spiro-type manner. As used herein, the term “condensed” refers to two rings sharing two atoms and one bond. As used herein, the terms “cross-linked heterocyclyl” or “cross-linked heteroalicyl” refer to a compound in which the heterocyclyl or heteroalicyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings sharing one atom, and the two rings are not joined by cross-linking. Heterocyclyl and heteroalicyl groups may contain 3 to 30 atoms in the ring, 3 to 20 atoms in the ring, 3 to 10 atoms in the ring, 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring. For example, 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; 2 carbon atoms and 3 heteroatoms; 1 carbon atom and 4 heteroatoms; 3 carbon atoms and 1 heteroatom; or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in heteroalicyclic is quaternized. It may be done. The heterocyclyl or heteroalicyl group may be substituted or unsubstituted. Examples of such "heterocyclyl" or "heteroalicyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxatian, 1,4-oxathian, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiaidine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, i Examples include, but are not limited to, sooxazolines, isoxazolidines, oxazolines, oxazolidines, oxazolidinones, thiazolines, thiazolidinones, morpholines, oxirans, piperidine N-oxides, piperidines, piperazines, pyrrolidines, azepanes, pyrrolidones, pyrrolidiones, 4-piperidones, pyrazolines, pyrazolidines, 2-oxopyrrolidines, tetrahydropyrans, 4H-pyrans, tetrahydrothiopyrans, thiamorpholines, thiamorpholine sulfoxides, thiamorpholine sulfones, and their benzo-condensed analogs (e.g., benzimidazolidinones, tetrahydroquinolines, and / or 3,4-methylenedioxyphenyls). Examples of spiroheterotic 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 aryl groups attached as substituents via lower alkylene groups. The lower alkylene and aryl groups of aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl groups.

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

[0024] "Heteroallicyryl(alkyl)" and "heterolicyryl(alkyl)" refer to a heteroallicyryl or heteroallicyryl group connected as a substituent via a lower alkylene group. The lower alkylene and heterolicyryl of (heteroallicyryl)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidine-4-yl(ethyl), piperidine-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiadinan-4-yl(methyl).

[0025] As used herein, “lower alkylene group” refers to a linear -CH2-linking group that forms a bond to connect molecular fragments via its terminal carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). Lower alkylene groups are cycloalkyl groups (e.g.,

[0026] [ka] ) may be substituted by replacing one or more hydrogens of the 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 alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzyloxy. Alkoxy may 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 via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl. Acyl may be substituted or unsubstituted.

[0030] The "cyano" group refers to the "-CN" group.

[0031] As used herein, the term "halogen atom" or "halogen" means any one of the radiation-stable atoms in column 7 of the periodic table of the elements such as fluorine, chlorine, bromine, and iodine.

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

[0033] The "O-carbamyl" group is "-OC(=O)N(R AR B )" refers to the group, and in the formula, R A Reach biR B O-carbamyl 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 )-" refers to the group, in the formula, R and R A N-carbamyl 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 "-OC(=S)-N(R A R B )" refers to the group, and in the formula, R A and R B O-thiocarbamyl 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 )-" refers to the group, and in the formula, R and R AN-thiocarbamyl may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0037] The "C-amide" group is "-C(=O)N(R) A R B )" refers to the group, and in the formula, R A and R B This can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The C-amide may be substituted or unsubstituted.

[0038] The "N-amide" group is "RC(=O)N(R A )-" refers to the group, and in the formula, R and R A This can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-amide may be substituted or unsubstituted.

[0039] The "S-sulfonamide" group is "-SO2N(R A R B )" refers to the group, and in the formula, R A and R B This can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The S-sulfonamide may be substituted or unsubstituted.

[0040] The "N-sulfonamide" group is "RSO2N(R A )-" refers to the group, and in the formula, R and R A This can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-sulfonamide may be substituted or unsubstituted.

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

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

[0043] The "nitro" group refers to the "-NO2" group.

[0044] The "sulfenyl" group refers to the "-SR" group, where R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Sulfenyl may be substituted or unsubstituted.

[0045] The "sulfinyl" group refers to the "-S(=O)-R" group, where R may be the same as that defined for sulfenyl. Sulfinyl may be substituted or unsubstituted.

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

[0047] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyls may be substituted or unsubstituted.

[0048] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxys may be substituted or unsubstituted.

[0049] As used herein, the term "amino" refers to the -NH2 group.

[0050] The "monosubstituted amine" group is "-NHR A " refers to the base, and in the formula, R AR may be an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A The amino group may be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH (methyl) and -NH (phenyl).

[0051] The "disubstituted amine" group is "-NR A R B " refers to the base, and in the formula, R A and R B These are, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), as defined herein. It may be an aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A and R B These can be independently substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), and -N(ethyl)(methyl).

[0052] As used herein, the “amine(alkyl)” group refers to the -(alkylene)-NR'R” radical, where R' and R” are independently hydrogen or alkyl as defined herein. The amine(alkyl) group may be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CH2NH(methyl), -CH2NH(phenyl), -CH2CH2NH(methyl), -CH2CH2NH(phenyl), -CH2N(methyl)2, -CH2N(phenyl)(methyl), -NCH2(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), and -NCH2CH2(ethyl)(methyl).

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

[0054] As used herein, a radical refers to a species having a single unpaired electron such that a species containing the radical can be covalently bonded to another species. Therefore, in this regard, a radical is not necessarily a free radical. Rather, a radical refers to a specific part 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 the organism to which it is administered and does not negate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. A pharmaceutically acceptable salt is a salt of a compound that has been added to an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and It can be obtained by reacting the compound with phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting compounds with bases to form salts, e.g., ammonium salts, alkali metal salts, e.g., sodium, potassium, or lithium salts, alkaline earth metal salts, e.g., calcium or magnesium salts, carbonate salts, bicarbonate salts, organic base salts, e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts having amino acids such as arginine and lysine. Those skilled in the art will know that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may associate with a positive charge (e.g., NH2 becomes NH3). + (It can become), a positive charge has a counterion with a negative charge (Cl - Understand that balance can be achieved through factors such as [examples of factors].

[0056] In any compound described herein having one or more chiral centers, if absolute stereochemistry is not explicitly shown, it is understood that each center may independently be in an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomerically mixed compounds. It is acceptable. In addition, 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 herein, all tautomers are also intended to be included.

[0057] If a compound disclosed herein has an unfilled valence, it should be understood that this valence is filled with hydrogen or its isotopes, such as hydrogen-1 (practium) and hydrogen-2 (deuterium).

[0058] It is understood that the compounds described herein may be labeled with isotopes. Substitution with isotopes such as deuterium may result in certain therapeutic benefits due to greater metabolic stability, such as an increased in vivo half-life or a reduced required dose. Each chemical element represented in the compound structure may contain any isotope of that element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (practium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein encompass all possible isotopic forms unless the context explicitly indicates otherwise.

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

[0060] If a range of values ​​is provided, it is understood that the upper and lower limits, as well as the values ​​interposing between the upper and lower limits of that range, are included within the embodiment.

[0061] The terms and phrases used in this application, and their variations, particularly those in the appended claims, should be construed as non-limiting, not limiting, unless otherwise specified. For example, the term “including” should be construed as meaning “including without limitation,” “including, but not limited to,” etc. Where used herein, the term “equipped with” is synonymous with “including,” “containing,” or “characterizing,” and is comprehensive or non-limiting, not excluding additional unlisted elements or steps of the method. 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 a thorough or limiting list of the items under consideration. The use of terms such as “preferred,” “desired,” or “desirable,” and words with similar meanings, should not be understood as implying that certain features are critical, essential, or even important to their structure or function, but rather are intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “to have” shall be interpreted as synonymous with the phrases “to have at least” or “to include at least” when used in the context of compounds, compositions, or devices. In this context, the term “to include” means that the compound, composition, or device includes at least the listed features or components, but may also include additional features or components.

[0062] With regard to substantially any use of plural and / or singular terms herein, a person skilled in the art can appropriately convert from plural to singular and / or singular to plural depending on the context and / or use. Various singular / plural substitutions may be expressly described herein for clarity. The indefinite article "a" or "an" does not exclude the plural. The mere fact that certain means are enumerated in different dependent claims does not imply that combinations of these means cannot be used for benefit. No reference numeral in a claim should be construed as limiting its scope.

[0063] compound Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, the combination may comprise 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 of any of the foregoing, wherein compound (A) has the following structure:

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

[0065] [ka] m may be selected from, and m may be 0, 1, 2, or 3, R 3X may be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups, where X is hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocycline, substituted or unsubstituted amine (C1-C6 alkyl), or substituted or unsubstituted -NH-(CH2) 1~6 -amines, monosubstituted amines, disubstituted amines, aminos, substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C3-C6 cycloalkyls, substituted or unsubstituted (C1-C6 alkyl)acyls, substituted or unsubstituted C-amides, substituted or unsubstituted N-amides, substituted or unsubstituted C-carboxys, substituted or unsubstituted O-carboxys, substituted Alternatively, Y may be selected from unsubstituted O-carbamyl and substituted or unsubstituted N-carbamyl, where Y may be CH or N. 1 CR 4A Or it may be N, Y 2 CR 4B Or it may be N, and the ring C is substituted or unsubstituted C6~C 10 R may be selected from aryls, substituted or unsubstituted monocyclic 5-10 member heteroaryls, substituted or unsubstituted monocyclic 5-7 member carbocyclils, substituted or unsubstituted 5-7 member monocyclic heterocyclils, and substituted or unsubstituted 7-10 member bicyclic heterocyclils. 4A and R 4B These are, independently, hydrogen, halogen, and unsubstituted C 1~4 Alkyl can be selected, R 5 (B) may be a substituted or unsubstituted 5- to 7-membered monocyclic heterocycline, and one or more of compound (B) may be a PARP inhibitor, a PD-L1 inhibitor, a chemotherapeutic agent, or a pharmaceutically acceptable salt of any of the above.

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

[0067] [ka] It may be selected from the following. In some embodiments, m may be 0, 1, 2, or 3. In some embodiments, R 3 X may be selected from halogens and substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, X is hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted 4-6 membered monocyclic heterocyclines, substituted or unsubstituted amines (C1-C6 alkyl groups), or substituted or unsubstituted -NH-(CH2) 1~6 -amines, monosubstituted amines, disubstituted amines, aminos, substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C1-C6 alkoxys, substituted or unsubstituted C3-C6 cycloalkoxys, substituted or unsubstituted (C1-C6 alkyl)acyls, substituted or unsubstituted C-amides, substituted or unsubstituted N-amides, substituted or unsubstituted C-carboxys, substituted or unsubstituted O-carboxys, substituted or unsubstituted O-carbamyls, and substituted or unsubstituted N-carbamyls may be selected. In some embodiments, Y may be CH or N. In some embodiments, Y 1 CR 4A Or it may be N. In some embodiments, Y 2 CR 4B Or it may be N. In some embodiments, the ring C is substituted or unsubstituted C6~C 10The following may be selected: aryl, substituted or unsubstituted monocyclic 5-10 member heteroaryl, substituted or unsubstituted monocyclic 5-7 member carbocyclyl, substituted or unsubstituted 5-7 member monocyclic heterocyclyl, and substituted or unsubstituted 7-10 member bicyclic heterocyclyl. In some embodiments, R 4A and R 4B These are, independently, hydrogen, halogen, and unsubstituted C 1~4 Selected from alkyl groups.

[0068] In some embodiments, R 1 R may be selected from hydrogen, halogens, and C1-C6 alkyl groups. In some embodiments, 1 R may be hydrogen. In other embodiments, R 1 R may be a halogen. In some embodiments, 1 R may be fluoro. In yet another embodiment, R 1 R may be an unsubstituted C1-C6 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (linear or branched), or hexyl (linear or branched)). In some embodiments, R 1 R may be an unsubstituted methyl group. In some embodiments, R 1 R may be a substituted C1-C6 alkyl, for example, those described herein. In some embodiments, R 1 R may be an unsubstituted C1-C6 haloalkyl (such as a C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, R 1 This can 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 heteroaryls.

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

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

[0072] If substituted, ring A may be substituted with one or more substituents selected from halogens, unsubstituted C1-C4 haloalkyls, and unsubstituted C1-C4 alkyls. In some embodiments, ring A is monosubstituted with a halogen (e.g., fluoro).

[0073] In some embodiments,

[0074] [ka] teeth,

[0075] [ka] The following may be selected, and each of the above bases may be substituted or non-substituted. Several implementations In terms of form,

[0076] [ka] is a substitution or non-substitution

[0077] [ka] This may be the case. In some embodiments,

[0078] [ka] is a substitution or non-substitution

[0079] [ka] This may be the case, where ring A is unsubstituted. In other embodiments,

[0080] [ka] is a substitution or non-substitution

[0081] [ka] Substitution or non-substitution

[0082] [ka] and substitution or non-substitution

[0083] [ka] You may choose from the following. As described herein,

[0084] [ka] The ring A portion may be non-substituted.

[0085] In some embodiments, ring B may be selected from substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyls and substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyls.

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

[0087] In some embodiments,

[0088] [ka] teeth,

[0089] [ka] The following can be selected, and each of the above-mentioned groups may be substituted or non-substituted.

[0090] In some embodiments, ring B may be a substituted or unsubstituted monocyclic 5- to 7-membered heterocycline. In some embodiments, ring B may be a substituted or unsubstituted monocyclic 5-membered heterocycline. In other embodiments, ring B may be a substituted or unsubstituted monocyclic 6-membered heterocycline. In yet another embodiment, ring B may be a substituted or unsubstituted monocyclic 7-membered heterocycline.

[0091] In some embodiments,

[0092] [ka] teeth,

[0093] [ka] The following may be selected, and each of the above groups may be substituted or unsubstituted, containing any -NH group.

[0094] In some embodiments, ring B is

[0095] [ka] The above groups may be selected from, and each of the above groups may be substituted or unsubstituted, containing any -NH group. In some embodiments, ring B may be substituted or unsubstituted

[0096] [ka] That's fine.

[0097] In some embodiments, if ring B is substituted, ring B may be substituted with one, two, or three substituents independently selected from halogens, hydroxy, amino, unsubstituted N-bonded amides (e.g., -NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyls (as described herein), and substituted or unsubstituted C1-C6 alkyls (as described herein). In some embodiments, ring B may be substituted with one, two, or three substituents independently selected from fluoro, hydroxy, amino, unsubstituted -NHC(O)C1-C6 alkyl, unsubstituted C1-C6 haloalkyl (such as those described herein), and unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, ring B may be substituted with one or two 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] The following may be selected, and each of the above groups may be substituted or unsubstituted, containing any -NH group.

[0101] In some embodiments,

[0102] [ka] teeth,

[0103] [ka] The following may be selected, and each of the above-mentioned groups may be substituted or non-substituted. In some embodiments,

[0104] [ka] teeth,

[0105] [ka] The following may be selected, and each of the above-mentioned groups may be substituted or non-substituted. In some embodiments,

[0106] [ka] is a substitution or non-substitution

[0107] [ka] This may be the case. In some embodiments,

[0108] [ka] may be substituted, or

[0109] [ka] That's fine.

[0110] Rings A and B may both be substituted or unsubstituted. In some embodiments,

[0111] [ka] Rings A and B may independently be substituted or unsubstituted. In some embodiments,

[0112] [ka] Rings A and B may both be unsubstituted. In some embodiments,

[0113] [ka] Rings A and B may both be substituted independently. In some embodiments,

[0114] [ka] Ring A may be substituted,

[0115] [ka] Ring B may be unsubstituted. In some embodiments,

[0116] [ka] Ring A may be non-substituted,

[0117] [ka] Ring B may be substituted. In some embodiments,

[0118] [ka] Ring A may be non-substituted,

[0119] [ka] Ring B may be substituted with one, two, or three substituents independently selected from halogens, hydroxyls, and substituted or unsubstituted C1-C6 alkyls (such as those described herein). In some embodiments,

[0120] [ka] Ring A may be non-substituted,

[0121] [ka] Ring B may be substituted with one, two, or three substituents independently selected from fluoro, hydroxy, amino, unsubstituted N-bonded amides (e.g., -NHC(O)C1-C6 alkyl), unsubstituted C1-C6 haloalkyls (as described herein), and unsubstituted C1-C6 alkyls (as described herein). In some embodiments,

[0122] [ka] Ring A may be non-substituted,

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

[0124] In some embodiments, R 2 teeth,

[0125] [ka] It may be selected from. In some embodiments, R 2 teeth,

[0126] [ka] It may be R 2 teeth,

[0127] [ka] That's fine.

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

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

[0130] In some embodiments, m may be 0, 1, 2, or 3. In some embodiments, m may be 0. In some embodiments, m may be 1. In some embodiments, m may be 2. In some embodiments, m may be 3. When m is 2 or 3, R 3 groups may be the same as or different from each other.

[0131] In some embodiments, X may be selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted 4- to 6-member monocyclic heterocyclyl, substituted or unsubstituted amine (C1-C6 alkyl), substituted or unsubstituted -NH-(CH2) 1-6 -amine, mono-substituted amine, di-substituted amine, amino, substituted or unsubstituted C1-C6 alkyl (such as those described herein), substituted or unsubstituted C1-C6 alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy (linear or branched), or hexoxy (linear or branched), etc.), substituted or unsubstituted C3-C6 cycloalkoxy (cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy, etc.), substituted or unsubstituted (C1-C6 alkyl) acyl, substituted or unsubstituted C-amide, substituted or unsubstituted N-amide, 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 may be hydrogen. In other embodiments, X may be halogen. In some embodiments, X may be fluoro. In some embodiments, X may be chloro. In still other embodiments, X may be hydroxy. In yet still other embodiments, X may be cyano. In some embodiments, X may be amino.

[0133] In some embodiments, X may be unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, X may be unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In some embodiments, X may be substituted C1-C6 alkyl (such as those described herein). In some embodiments, X may be unsubstituted C1-C6 haloalkyl (such as C1-C6 fluoroalkyl, C1-C6 chloroalkyl, or C1-C6 chlorofluoroalkyl). In some embodiments, X may be selected from -CHF2, -CF3, -CF2CH3, and -CH2CF3. In some embodiments, X may be unsubstituted C1-C6 hydroxyalkyl (such as C1-C6 monohydroxyalkyl or C1-C6 dihydroxyalkyl). In some embodiments, X may be selected from -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -C(OH)(CH3)2. In some embodiments, X may be unsubstituted C1-C6 cyanoalkyl (such as C1-C6 monocyanoalkyl or C1-C6 dicyanoalkyl). In some embodiments, X may be

[0134]

Chemical formula

[0135]

Chemical formula

[0136]

Chemical formula

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

[0138] In some embodiments, X is

[0139] [ka] You may choose from the following.

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

[0141] In some embodiments, X may be a substituted (C1-C6 alkyl) acyl, for example, a substituted-(CO)-CH3. In some embodiments, X may be an unsubstituted (C1-C6 alkyl) acyl, for example, an unsubstituted-(CO)-CH3.

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

[0143]

Chemical formula

[0144] In some embodiments, X may be a 4- to 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), mono-substituted amine (such as those described herein), di-substituted 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 may be a 4- to 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 is

[0145]

Chemical formula

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

[0147] [ka] The following may be selected, and each of the above groups may contain any -NH group, either substituted or unsubstituted. That is the case.

[0148] In some embodiments, X is a substitution -NH-(CH2) 1-6 It may be an amine. In some embodiments, X is an unsubstituted-NH-(CH2) 1-6 It may be an amine. In some embodiments, X is

[0149] [ka] The following may be selected, and each of the above groups may be substituted or unsubstituted, containing any -NH group.

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

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

[0152] In some embodiments, X is

[0153] [Chemical] may be selected from.

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

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

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

[0157] In some embodiments, Y 1 and Y 2 may each be N (nitrogen). In some embodiments, Y 1 may be CR 4A and Y 2 may be CR 4B . In some embodiments, Y 1 may be CR 4A and Y 2may be N (nitrogen). In some embodiments, Y 1 can be N (nitrogen), and Y 2 CR 4B That's fine.

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

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

[0160] In some embodiments, R 4A and R 4B Each of these may be hydrogen. In some embodiments, R 4A and R 4B Each of these may be a halogen (where the halogens may be the same or different from each other). In some embodiments, R 4A and R 4B These are unsubstituted C 1~4 Alkyl (as described herein, where C 1~4 The alkyls may be the same or different from each other. In some embodiments, R 4A and R 4B One of them may be hydrogen, R 4A and R 4B The other of the two may be a halogen. In some embodiments, R 4A and R 4B One of them may be hydrogen, R 4A and R 4B The other of these is non-substituted C 1~4It may be an alkyl group (such as those described herein). In some embodiments, R 4A and R 4B One of them may be a halogen, R 4A and R 4B The other of these is non-substituted C 1~4 It may be an alkyl group (such as those described herein).

[0161] In some embodiments, R 2 teeth,

[0162] [ka] That's fine. For example, R 2 teeth,

[0163] [ka] That's fine. 2 but

[0164] [ka] In some embodiments, R 5 R may be a substituted 5-7 member monocyclic heterocycline. In other embodiments, R 5 R may be an unsubstituted 5-7 member monocyclic heterocycline. 5 Examples of groups include substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, and substituted or unsubstituted azepanyl. When substituted, R 5 Substituents that can be introduced include unsubstituted C 1~4 Alkyl, halogen, hydroxy, and unsubstituted C 1~4 Haloalkyl groups are examples.

[0165] In some embodiments, ring C is substituted or unsubstituted C6-C 10The following may be selected: aryl compounds, substituted or unsubstituted monocyclic 5-10 member heteroaryl compounds, substituted or unsubstituted monocyclic 5-7 member carbocyclil compounds, substituted or unsubstituted 5-7 member monocyclic heterocyclil compounds, and substituted or unsubstituted 7-10 member bicyclic heterocyclil compounds.

[0166] In some embodiments, ring C is substituted with C6~C 10 It may be an aryl ring. In some embodiments, the ring C is an unsubstituted C6-C 10 It may be an aryl compound. In some embodiments, ring C may be a substituted C6 aryl compound. In some embodiments, ring C may be an unsubstituted C6 aryl compound.

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

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

[0169] In some embodiments, ring C may be a substituted or unsubstituted five-membered monocyclic heterocycline. In some embodiments, ring C may be a substituted or unsubstituted six-membered monocyclic heterocycline. In some embodiments, ring C may be a substituted or unsubstituted seven-membered monocyclic heterocycline. In some embodiments, ring C may be selected from imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, tetrahydropyran, azepine, oxepine, and diazepine, each of the above groups being substituted or unsubstituted and containing any -NH group.

[0170] In some embodiments, ring C is a substituted or unsubstituted 7-membered bicyclic heterocycline (e.g.) Ring C may be a condensed, cross-linked, or spiroheterocyclyl. In some embodiments, ring C may be a substituted or unsubstituted 8-membered bicyclic heterocyclyl, e.g., a condensed, cross-linked, or spiroheterocyclyl. In some embodiments, ring C may be a substituted or unsubstituted 9-membered bicyclic heterocyclyl (e.g., a condensed, cross-linked, or spiroheterocyclyl). In some embodiments, ring C may be a substituted or unsubstituted 10-membered bicyclic heterocyclyl (e.g., a condensed, cross-linked, or spiroheterocyclyl). In some embodiments, ring C may be selected from pyrrolizidine, indoline, 1,2,3,4-tetrahydroquinoline, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane, each of the above groups being substituted or unsubstituted and containing any -NH group.

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

[0172] In some embodiments, R 2 teeth,

[0173] [ka] The selection may be made from the above, and each of the above bases may be substituted or unsubstituted.

[0174] A non-exclusive list of chemotherapeutic agents is provided herein, including those provided in Figure 1. Examples of PARP inhibitors are provided herein, including those provided in Figure 2. Examples of PD-1 inhibitors are provided herein, including those provided in Figure 3. Exemplary PD-L1s are provided herein, including those provided in Figure 4.

[0175] Examples of compound (A) include:

[0176] [ka]

[0177] [ka]

[0178] [ka]

[0179] [ka]

[0180] [ka] Alternatively, any of the pharmaceutically acceptable salts mentioned above may be used.

[0181] Compound (A), along with its pharmaceutically acceptable salt, can be prepared as described herein and in International Publication No. 2019 / 173082, which is incorporated herein by reference in its entirety. As described in International Publication No. 2019 / 173082, compound (A) is a WEE1 inhibitor.

[0182] Table 1 provides embodiments of combinations of compound (A) and compound (B) (including the pharmaceutically acceptable salts mentioned above). For example, in Table 1, the combination represented by 3:5A is paclitaxel and

[0183] [ka] This corresponds to the combination (including the pharmaceutically acceptable salts mentioned above). An example of compound (A) is provided in Figure 5.

[0184] [Table 1-1]

[0185] [Table 1-2]

[0186] [Table 1-3]

[0187] [Table 1-4]

[0188] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A), which contains its pharmaceutically acceptable salt, is used in combination with all compounds (B) or It can be administered before its pharmaceutically acceptable salt. In other embodiments, compound (A) containing its pharmaceutically acceptable salt can be administered before at least one compound (B) or its pharmaceutically acceptable salt. In yet another embodiment, compound (A) containing its pharmaceutically acceptable salt can be administered simultaneously with compound (B) or its pharmaceutically acceptable salt. In yet another embodiment, compound (A) containing its pharmaceutically acceptable salt can be administered following the administration of at least one compound (B) or its pharmaceutically acceptable salt. In some embodiments, compound (A) containing its pharmaceutically acceptable salt can be administered following the administration of all compounds (B) or their pharmaceutically acceptable salts.

[0189] Several advantages may exist in using the combination of compounds described herein. For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers such as those described herein compared to when the combination of compounds is used as monotherapy.

[0190] In some embodiments, a combination of compound (A), including a pharmaceutically acceptable salt thereof as described herein, and one or more compounds (B), or a pharmaceutically acceptable salt thereof, can reduce the number and / or severity of adverse events that may occur due to compounds such as compound (B), or a pharmaceutically acceptable salt thereof, as described herein.

[0191] The combinations of compounds described herein may produce additive, synergistic, or strongly synergistic effects. The combinations of compounds described herein may also produce non-antagonistic effects.

[0192] In some embodiments, a combination of compound (A), including its pharmaceutically acceptable salt as described herein, and one or more compounds (B), or its pharmaceutically acceptable salt, may produce an additive effect. In some embodiments, a combination of compound (A), including its pharmaceutically acceptable salt as described herein, and one or more compounds (B), or its pharmaceutically acceptable salt, may produce a synergistic effect. In some embodiments, a combination of compound (A), including its pharmaceutically acceptable salt as described herein, and one or more compounds (B), or its pharmaceutically acceptable salt, may produce a strong synergistic effect. In some embodiments, a combination of compound (A), including its pharmaceutically acceptable salt as described herein, and one or more compounds (B), or its pharmaceutically acceptable salt, may not produce an antagonistic effect.

[0193] As used herein, the term “antagonistic” means that the combined activity of a compound is lower than the sum of the individual activities of each compound in the combination when their activities are determined individually (i.e., as single compounds). As used herein, the term “synergistic” means that the combined activity of a compound is higher than the sum of the individual activities of each compound in the combination when their activities are determined individually. As used herein, the term “additive” means that the combined activity of a compound is approximately equal to the sum of the individual activities of each compound in the combination when their activities are determined individually.

[0194] A potential advantage of using the combinations described herein is that the amount of compound required to treat the disease pathophysiology disclosed herein may be reduced 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 disease markers (e.g., tumor size) when administered as a monotherapy. Another potential advantage of using these combinations is that the use of two or more compounds with different mechanisms of action can be a greater impediment to the development of resistance compared to when the compounds are administered as monotherapy. Further advantages of using the combinations described herein include the fact that there is little to no cross-resistance between the compounds in the combinations described herein, that the elimination pathways of the compounds in the combinations described herein are different, and Furthermore, and / or the combinations described herein, there is little to no overlapping toxicity between the compounds.

[0195] Pharmaceutical composition Compound (A) containing the pharmaceutically acceptable salt may be provided in a pharmaceutical composition. Similarly, compound (B) containing the pharmaceutically acceptable salt may be provided in a pharmaceutical composition.

[0196] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Pharmaceutical compositions may also be obtained by reacting compounds with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally prepared to suit the specific intended route of administration.

[0197] As used herein, “carrier” refers to a compound that facilitates the uptake of a compound into a cell or tissue. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of interest.

[0198] As used herein, “diluent” refers to a component in a pharmaceutical composition that does not have apparent pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the volume of a potent drug that is too small in mass for manufacture and / or administration. It may also be a liquid for dissolving a drug administered by injection, ingestion, or inhalation. Common forms of diluents in the art, though not limited to, are buffered aqueous solutions, such as phosphate-buffered saline that mimics the pH and isotonicity of human blood.

[0199] As used herein, “excipient” refers to an intrinsically inert substance added to a pharmaceutical composition to provide the composition with properties such as bulk, consistency, stability, binding ability, lubrication, or disintegration ability, but is not limited to these properties. For example, antioxidants and stabilizers such as metal chelators are excipients. In some embodiments, the pharmaceutical composition includes an antioxidant and / or a metal chelator. “Diluent” is a certain type of excipient.

[0200] In some embodiments, compound (B) may be provided together with a pharmaceutically acceptable salt thereof in a pharmaceutical composition comprising compound (A) containing the pharmaceutically acceptable salt thereof. In other embodiments, compound (B) may be administered together with a pharmaceutically acceptable salt thereof in a pharmaceutical composition separate from the pharmaceutical composition comprising compound (A) containing the pharmaceutically acceptable salt thereof.

[0201] The pharmaceutical compositions described herein can be administered to human patients either on their own or in combination with other active ingredients, carriers, diluents, excipients, or combinations thereof, as in combination therapy. The appropriate formulation depends on the selected route of administration. The formulations and administration techniques of the compounds described herein are known to those skilled in the art.

[0202] The pharmaceutical compositions disclosed herein are, for example, known by conventional mixing, dissolution, granulation, dragée production, elutriation, emulsification, encapsulation, capture, or tableting processes. It can be manufactured by [method]. In addition, the active ingredient is contained in an effective amount to achieve its intended purpose. Many of the compounds used in the drug combinations disclosed herein may be provided as salts having pharmaceutically compatible counterions.

[0203] Multiple techniques exist in the art for administering compounds, salts, and / or compositions, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intrathecal, subarachnoid, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In some embodiments, compound (A), comprising its pharmaceutically acceptable salt, can be administered orally. In some embodiments, compound (A), comprising its pharmaceutically acceptable salt, may be provided to a subject by the same route of administration as compound (B) and its pharmaceutically acceptable salt. In other embodiments, compound (A), comprising its pharmaceutically acceptable salt, may be provided to a subject by a different route of administration than compound (B) and its pharmaceutically acceptable salt.

[0204] Furthermore, compounds, salts, and / or compositions may be administered locally rather than systemically, for example, by direct injection or implantation of the compound at the affected site, often as a depot or sustained-release formulation. Additionally, compounds can be administered using targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. These liposomes are targeted to and selectively taken up by organs. For example, intranasal or intrapulmonary delivery may be desirable to target respiratory diseases or conditions.

[0205] The composition may be provided in a pack or dispenser device, which may, if desired, contain one or more unit dosage forms containing the active ingredient. The pack may include, for example, metal or plastic foil such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a container-associated cautionary note in the format prescribed by the administrative agency that regulates the manufacture, use, or sale of the drug, which reflects the agency's approval of the drug in a form for human or animal administration. Such cautionary notes may be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions containing the compounds and / or salts described herein, formulated in a suitable pharmaceutical carrier, may also be prepared for the treatment of indicated medical conditions, placed in a suitable container, and labeled.

[0206] Method of Use and Treatment As provided herein, in some embodiments, a disease or condition can be treated using a combination of compound (A) comprising an effective amount of a pharmaceutically acceptable salt thereof and a compound comprising an effective amount of one or more of compound (B) or any of the pharmaceutically acceptable salts thereof.

[0207] In some embodiments, the disease or condition is brain cancer, cervicocerebral cancer Hmm, esophageal cancer, thyroid cancer, lung cancer, breast cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer Cancer, pancreatic cancer, gastric cancer, colon cancer, rectal cancer, ovarian cancer, endometrial cancer, You can choose from choriocarcinoma, endometrial cancer, cervical cancer, renal pelvis / ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, uterine cancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, squamous cell carcinoma of the head and neck, glioblastoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0208] In some embodiments, the disease or condition is lung cancer (small cell lung cancer, SCLC) and / or non-small cell lung cancer (NSCL). C) etc., breast cancer (including triple-negative breast cancer), gastric cancer, colon cancer The cancer may be rectal cancer, ovarian cancer (e.g., TP53 mutation ovarian cancer), uterine cancer, endometrial cancer, head and neck squamous cell carcinoma, and / or glioblastoma. In some embodiments, endometrial cancer may be serous uterine cancer. In some embodiments, the disease or condition may be osteosarcoma.

[0209] DNA damage repair (DDR) genes maintain the stability of the human genome. It can play an important role in this process. Conversely, loss of DDR function is a significant determinant of cancer risk, progression, and / or treatment response. DDR genes can be grouped into functional pathways defined by genetic, biochemical, and mechanistic criteria. Proteins in the same pathway often work together to repair specific types of DNA damage. Base excision repair (BER), nucleotide excision repair (NER), and damage reversal / repair (DR) pathways repair DNA base damage. Mismatch repair (MMR) is, Base mispairs and small loops often found in repetitive DNA sequences can be corrected. Homology-dependent recombination (HR), non-homologous end joining (NHEJ), Fanconi anemia (FA) pathway, and translesion DNA synthesis (TLS) are all related to interstrand crosslinking. These can act alone or in combination to repair DNA strand breaks and complex events such as those described herein. With the exception of the FA pathway, all major DDR pathways have been identified in virtually all organisms. This reflects a universal need to counteract the chemical instability of DNA and repair additional damage, such as those described herein.

[0210] Research has shown that homologous recombination deficiency (HRD) It has been shown that A can predict defects in the BRCA1 and / or BRCA2 genes. Several studies have been conducted to determine the potential correlation between a subject's HRD score and their sensitivity to the subject's anticancer drug. See Sharma et al., Annals of Oncology (2018) 29(3):645-660, Frey et al., Gynecologic Oncology Research and Practice (2017) 4:4, Hoppes et al., J Natl Cancer Inst (2018) 110(7):704-713 and Ledermann et al., Eur J Cancer (2016) 60:49-58. If a subject is determined to have an HRD-positive state, the subject's DNA may not be repairable. In some embodiments, subjects utilizing the methods and / or uses described herein may be determined to have a homologous recombination deficiency (HRD)-positive state. In other embodiments, subjects utilizing the methods and / or uses described herein may be determined to have a homologous recombination deficiency (HRD)-negative state. In some embodiments, subjects are diagnosed with cancer selected from ovarian cancer (including recurrent ovarian cancer), breast cancer (such as triple-negative breast cancer and / or metastatic breast cancer), prostate cancer (e.g., metastatic castration-resistant prostate cancer), fallopian tube cancer, and primary peritoneal cancer. In some embodiments, subjects determined to have homologous recombination deficiency (HRD) positivity may be female. In some embodiments, subjects determined to have homologous recombination deficiency (HRD) positivity may be male.

[0211] In some embodiments, a combination of compound (1A) and a PARP inhibitor (including compound (1A) and / or a pharmaceutically acceptable salt of the PARP inhibitor) can be used to treat subjects with a homologous recombination deficiency (HRD) positive condition. In other embodiments, a combination of compound (1A) and a PARP inhibitor (including compound (1A) and / or a pharmaceutically acceptable salt of the PARP inhibitor) can be used to treat subjects with a homologous recombination deficiency (HRD) negative condition. In some embodiments, compound (1A) and nirapa The combination of rib can be used with any of the pharmaceutically acceptable salts described above to treat subjects with a homologous recombination deficiency (HRD) positive condition. In other embodiments, the combination of compound (1A) and niraparib can be used with any of the pharmaceutically acceptable salts described above to treat subjects with a homologous recombination deficiency (HRD) negative condition.

[0212] In some embodiments, a combination of compound (1A) and niraparib (including a pharmaceutically acceptable salt of compound (1A) and / or a PARP inhibitor) can be used to treat ovarian cancer in subjects with homologous recombination deficiency (HRD)-positive status. In other embodiments, a combination of compound (1A) and niraparib (including a pharmaceutically acceptable salt of compound (1A) and / or a PARP inhibitor) can be used to treat ovarian cancer in subjects with homologous recombination deficiency (HRD)-negative status. In some embodiments, a combination of compound (1A) and niraparib can be used with any of the aforementioned pharmaceutically acceptable salts to treat breast cancer in subjects with homologous recombination deficiency (HRD)-positive status. In other embodiments, a combination of compound (1A) and niraparib can be used with any of the aforementioned pharmaceutically acceptable salts to treat breast cancer in subjects with homologous recombination deficiency (HRD)-negative status. In some embodiments, the combination of compound (1A) and niraparib (with any of the pharmaceutically acceptable salts described above) can be used to treat prostate cancer in subjects with homologous recombination deficiency (HRD) positivity. In other embodiments, the combination of compound (1A) and niraparib (with any of the pharmaceutically acceptable salts described above) can be used to treat prostate cancer in subjects with homologous recombination deficiency (HRD) negative status. In some embodiments, the combination of compound (1A) and niraparib, including any of the pharmaceutically acceptable salts described above, can be used to treat metastatic breast cancer in subjects with homologous recombination deficiency (HRD) positivity. In other embodiments, the combination of compound (1A) and niraparib, including any of the pharmaceutically acceptable salts described above, can be used to treat metastatic breast cancer in subjects with homologous recombination deficiency (HRD) negative status. In some embodiments, a combination of compound (1A) and niraparib (with any of the pharmaceutically acceptable salts described above) can be used to treat fallopian tube cancer in subjects with homologous recombination deficiency (HRD)-positive conditions.In other embodiments, a combination of compound (1A) and niraparib (with any of the pharmaceutically acceptable salts described above) can be used to treat fallopian tube cancer in subjects with homologous recombination deficiency (HRD)-negative status. In some embodiments, a combination of compound (1A), or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof, can be used to treat primary peritoneal cancer in subjects with homologous recombination deficiency (HRD)-positive status. In other embodiments, a combination of compound (1A), or a pharmaceutically acceptable salt thereof, and niraparib, or a pharmaceutically acceptable salt thereof can be used to treat primary peritoneal cancer in subjects with homologous recombination deficiency (HRD)-negative status. In some embodiments, a combination of compound (1A) and niraparib, with any of the pharmaceutically acceptable salts described above, can be used to treat recurrent ovarian cancer in subjects with homologous recombination deficiency (HRD)-positive status. In other embodiments, the combination of compound (1A) and niraparib, along with any of the aforementioned pharmaceutically acceptable salts, can be used to treat recurrent ovarian cancer in subjects with homologous recombination deficiency (HRD)-negative status. In some embodiments, the combination of compound (1A) and niraparib (including any of the aforementioned pharmaceutically acceptable salts) can be used to treat metastatic castration-resistant prostate cancer in subjects with homologous recombination deficiency (HRD)-positive status. In other embodiments, the combination of compound (1A) and niraparib (including any of the aforementioned pharmaceutically acceptable salts) can be used to treat metastatic castration-resistant prostate cancer in subjects with homologous recombination deficiency (HRD)-negative status.

[0213] As used herein, “subject” means an animal that is the subject of treatment, observation, or experimentation. “Animals” include cold-blooded and warm-blooded vertebrates and invertebrates, e.g., fish, crustaceans, reptiles, and in particular mammals. “Mammals” include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates, e.g., monkeys, chimpanzees, and apes, and in particular humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, e.g., a child or infant with a fever. In other embodiments, the subject may be an adult.

[0214] As used herein, the terms “to treat,” “to treat,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean the complete cure or elimination of a disease or condition. Any relief of any degree of any undesirable sign or symptom of a disease or condition may be considered treatment and / or therapy. Furthermore, treatment may include any action that may worsen the overall perception of the subject’s health or appearance.

[0215] The term “effective dose” is used to indicate the amount of an active compound or drug that elicits an indicated biological or medical response. For example, an effective dose of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or improve 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 may include the alleviation of signs or symptoms of the disease or condition being treated. Determining an effective dose is within the capabilities of a person skilled in the art, given the disclosures provided herein. The effective dose of a compound disclosed herein required as a dose depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. Dosages may be adjusted to achieve the desired effect, but depend on factors such as body weight, diet, concomitant medications, and other factors that a person skilled in the art in the medical field would recognize.

[0216] For example, an effective dose of a compound or radiation is an amount that results in (a) reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) reduction of tumor size, (c) removal of the tumor, and / or (d) long-term disease stabilization (cessation of growth) of the tumor.

[0217] The amount of compound, salt, and / or composition required for therapeutic use varies not only with respect to the specific compound or salt selected, but also with respect to the route of administration, the nature and / or symptoms of the disease or condition being treated, and the patient's age and condition, and ultimately depends on the judgment of the attending physician or clinician. In the case of administration of pharmaceutically acceptable salts, the dose can be calculated as free base. As will be understood by those skilled in the art, in certain circumstances, particularly to effectively and aggressively treat progressive diseases or conditions, it may be necessary to administer the compounds disclosed herein in amounts exceeding, or even far exceeding, the dose ranges described herein.

[0218] As will be readily apparent to those skilled in the art, the useful in vivo doses and specific methods of administration vary depending on age, weight, severity of pain, species of mammal being treated, the specific compounds used, and the specific applications for which these compounds are used. Determining the effective dose level, i.e., the dose level required to achieve the desired result, can be achieved by those skilled in the art using routine methods, e.g., human clinical trials, in vivo studies, and in vitro studies. For example, useful doses of compounds of formula (A) and / or (B), or the pharmaceutically acceptable salts described above, can be determined by comparing their in vitro and in vivo activities in animal models. Such comparisons can be made by comparison with established drugs such as cisplatin and / or gemcitabine.

[0219] The dosage and interval are individually adjusted to provide plasma levels sufficient for the active portion to maintain regulatory effects or the minimum effective concentration (MEC). This may be done. MEC varies from compound to compound but can be estimated from in vivo and / or in vitro data. The dose required to achieve MEC depends on the individual characteristics and route of administration. However, HPLC assays or bioassays may be used to determine plasma concentrations. The dosing interval can also be determined using MEC values. Compositions should be administered using regimens that maintain plasma levels above MEC for periods of 10–90%, preferably 30–90%, and most preferably 50–90%. In the case of topical administration or selective uptake, the effective topical concentration of the drug may not depend on the plasma concentration.

[0220] It should be noted that the attending physician will be aware of the method and timing of discontinuing, interrupting, or adjusting administration due to toxicity or organ failure. Conversely, the attending physician will also be aware of adjusting treatment to a higher level if the clinical response is inadequate (excluding toxicity). The size of the dose administered in the management of the target disease will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of the disease or condition may be assessed to some extent by standard prognostic assessment methods. Furthermore, the dose and possibly the number of doses will also vary depending on the individual patient's age, weight, and response. Programs corresponding to those considered above may be used in veterinary medicine.

[0221] The compounds, salts, and compositions disclosed herein may be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or subset of compounds sharing a certain chemical part may be established by determining its in vitro toxicity to cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in mammals, or animals, particularly humans. Alternatively, the toxicity of a particular compound in animal models, such as mice, rats, rabbits, dogs, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several accepted methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, those skilled in the art can rely on state-of-the-art techniques to guide the selection of an appropriate model, dose, route of administration, and / or regimen. [Examples]

[0222] Further embodiments, which do not limit the scope of the claims, are disclosed in more detail in the following embodiments.

[0223] CTG assay TOV112D cells were cultured in a complete growth medium containing 15% fetal bovine serum and a basic medium consisting of a 1:1 mixture of MCDB105 medium containing a final concentration of 1.5 g / L sodium bicarbonate and 199 medium containing a final concentration of 2.2 g / L sodium bicarbonate. MDA-MB-436 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. When the cells were in the exponential growth phase, they were seeded into 96-cell plates and treated with the indicated compounds in single or combined concentrations. The antiproliferative effect of the test compounds was measured by the CellTiter-Glo luminescent cell viability assay (Promega). IC was measured using Graphpad Prism software. 50Values ​​were generated. In Figure 6, the top line is compound 1A + talazoparib, the middle line shown as a circle is compound 1A alone, and the bottom line shown as a square is talazoparib. Results for TOV112D and MDA-MB-436 cell lines are shown in Figure 6 (talazoparib-PARP inhibitor, TOV112D cell line) and Figure 7 (niraparib-PARP inhibitor, MDA-MB-436 cell line). Figures 6 and 7 show how combinations of compound (A) and compound 1A, with or without a PARP inhibitor, affect cell proliferation. Effective inhibition is demonstrated. To avoid any doubt, "Compound 1A" and "Compound (1A)" as used herein refer to the same compound, and no discrepancy between the two is implied or should be inferred.

[0224] Cell proliferation was measured using the CellTiter-Glo® luminescence cell viability assay. This assay involved the direct addition of a single reagent (CellTiter-Glo® reagent) to cells cultured in serum-supplemented medium. KMS-12-BM, OPM-2, and MOLP8 cells were cultured according to DSMZ recommendations, with 20,000 cells seeded per well. Each compound evaluated was prepared in DMSO stock solution (10 mM). Each compound was tested three times on each plate, and the single concentrations are shown in each table. Compound treatment (10.0 μL) was added to the cells from each compound at a 10-fold concentration. The plates were then incubated at 37°C in 5% CO2. After 72 hours, the cell plates were equilibrated at room temperature (rt) for approximately 30 minutes. Equal volumes of CellTiter-Glo® reagent (100 μL) were added to each well. The plates were mixed in an orbital shaker for 2 minutes to induce cell lysis, and then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence was recorded using a SpectraMax, M5e plate reader according to the CellTiter-Glo protocol. Table 2 (and Figure 24) shows that the combination of compound (1A) and gemcitabine in the KMS-12-BM cell line exhibited synergistic inhibition of cell proliferation compared to monotherapy.

[0225] [Table 2]

[0226] Table 3 (and Figure 25) shows that the combination of compound (1A) and gemcitabine in the OPM-2 cell line exhibited synergistic inhibition of cell proliferation compared to monotherapy.

[0227] [Table 3]

[0228] Table 4 (and Figure 26) shows that the combination of compound (1A) and gemcitabine in the MOLP-8 cell line exhibited synergistic inhibition of cell proliferation compared to monotherapy.

[0229] [Table 4]

[0230] Ovarian cell lines with moderate sensitivity to WEE1 inhibitors (UWB1.289 and OVCAR3) were treated with hydroxyurea (i.e., an inducer of replication stress) and compound (1A). 5,000 cells per well were seeded in 96-well plates. The compound was prepared in DMSO (compound (1A)) at an initial concentration of 10 μM, in a 1:3 dilution range. Hydroxyurea was added to the cells at 0, 10, 30, 100, 300, or 1000 μM (matrix). The cells were then incubated at 37°C in 5% CO2. CTG assays were performed at 3 days (UWB1.289 cells) or 5 days (OVCAR3 cells). Luciferase (relative luminescence unit, RLU) biocounts and normalized data are shown in Figures 20-23.

[0231] Figure 20 shows the inhibition of cell proliferation in UWB1.289 cells by compound (1A) in combination with hydroxyurea (HU). Data are expressed in relative luminescence units (RLU). The data show the synergistic effect of hydroxyurea in combination with compound (1A) in UWB1.289 cells. The HU0μm condition (upper line including the circle) shows monotherapy with compound (1A) as a reference. The HU100μm condition is the third line from the bottom including the circle, and the HU1000μm condition is the bottom line including the circle.

[0232] Figure 21 shows the inhibition of cell proliferation in UWB1.289 cells by compound (1A) in combination with hydroxyurea (HU). The data are expressed as normalized relative luminescence units (RLU) for all hydroxyurea concentrations, demonstrating the synergistic effect of the combination of compound (1A) and HU in UWB1.289 cells. The HU 0 μm condition (upper line including the circle) shows compound (1A) monotherapy for reference.

[0233] Figure 22 shows the inhibition of cell proliferation in OVCAR3 cells by compound (1A) in combination with hydroxyurea (HU). Data are expressed in relative luminescence units (RLU). The data shows the synergistic effect of hydroxyurea in combination with compound (1A) in OVCAR3 cells. The HU0μm condition (upper line including the circle) shows monotherapy with compound (1A) as a reference. The HU100μm condition is the third line from the bottom including the circle, and the HU1000μm condition is the bottom line including the circle.

[0234] Figure 23 shows the inhibition of cell proliferation in OVCAR3 cells by compound (1A) in combination with hydroxyurea (HU). The data are expressed as normalized relative luminescence units (RLU) for all hydroxyurea concentrations, demonstrating the synergistic effect of the combination of compound (1A) and HU in OVCAR3 cells. The HU 0 μm condition (upper line including the circle) represents monotherapy with compound (1A) for reference.

[0235] Experimental method: 3000 A427 cells were seeded in a 96-well plate and allowed to adhere overnight. Treatment with compound (1A) and / or triapin was added the following day. Cells were harvested on day 6 and assayed for DNA content using Hoechst33258. Fluorescence intensity was read using a plate reader at excitation 346 nM and emission 460 nM. The data shown in Figure 27 represent three independent experiments (raw fluorescence readings). As demonstrated, suboptimal doses of compound (1A) and triapine as monotherapies do not inhibit A427 cell proliferation. In contrast, the combination of compound (1A) and triapine synergistically inhibits cell proliferation in A427 cells.

[0236] Xenograft tumor model A TOV21G xenograft model was established by subcutaneously inoculating 200 μL of TOV-21G tumor cell suspension (5 × 10⁶ cells / mouse, containing 50% Matrigel) into the right axilla of BALB / c nude mice. The tumor size was approximately 100–150 mm. 3 When the target was reached, tumor-bearing animals were randomly assigned to treatment groups of 10 animals each. The animals were orally administered either the vehicle or 60 mg / kg of compound (1A) for 19 days, and 50 mg / kg of carboplatin was administered intraperitoneally once a week, resulting in compound (1A) therapy in combination with carboplatin. Tumor volume was assessed twice a week and calculated over time, and mice were weighed twice a week as a substitute for signs of toxicity. The results are shown in Figure 8. As shown in Figure 8, combination therapy of compound (1A) with carboplatin induced significant tumor regression with a TGI value of 117%, while compound (1A) and carboplatin alone yielded antitumor activity with TGI values ​​of 94.4% and 89.75%, respectively.

[0237] In the SJSA-1 sarcoma subcutaneous xenograft efficacy study, SJSA-1 tumor cells were subcutaneously inoculated into the right flank of mice. The average tumor size was approximately 150-200 mm. 3When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each and administered the vehicle and the compound at the indicated doses and frequencies. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The efficacy results in the SJSA-1 tumor model are shown in Figure 9. In Figure 9, the top line is the vehicle, the next top line, indicated by a diamond, is compound 1A alone, the next line, indicated by a circle, is gemcitabine alone, and the bottom line is compound 1A + gemcitabine.

[0238] In the OVCAR3 xenograft efficacy study, OVCAR3 tumor cells were subcutaneously transplanted into the right flank of mice. The tumor was approximately 106 mm in size. 3 When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each and administered the vehicle and the compound at the indicated doses and frequencies. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results of the OVCAR3 tumor model are shown in Figure 10. In Figure 10, the top line is the vehicle, the next top line, indicated by a circle, is talazoparib alone, the next line, indicated by a square, is compound 1A alone, and the bottom line, indicated by "x", is compound 1A + talazoparib.

[0239] In the MC-38 syngeneic xenotransplant efficacy study, MC38 tumor cells were subcutaneously transplanted into the central right flank of mice. The tumor was approximately 102 mm in size. 3When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each and administered the vehicle and the indicated compound or anti-PD-1 antibody (supplied by Pharmaron (BioXCell)) at the indicated doses and frequencies. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results of the MC38 syngeneic tumor model are shown in Figures 11 and 12. In Figure 11, the top line is the vehicle, the next top line, indicated by a triangle, is compound 1A alone, the next line, indicated by a white square, is anti-PD1 antibody alone, and the bottom line, indicated by an inverted triangle, is compound 1A + anti-PD1. In Figure 12, the leftmost solid line is the vehicle, the next leftmost line, indicated by a uniform dash, is compound 1A, the next solid line is anti-PD1 alone, and the next line, indicated by alternating dots and dashes, is compound 1A + anti-PD1.

[0240] As shown in Figures 8 to 11, compound (A) and compound 1A are compounds with a PARP inhibitor (talazoparib), or a chemotherapeutic agent containing carboplatin and gemcitabine, or an anti-PD1 antibody. The combination is effective in reducing tumor size. Furthermore, the combination of compound (A), compound 1A, and the anti-PD1 antibody shows superior survival benefits compared to the monotherapy alone, as shown in Figure 12. Compound (A) and compound 1A are also effective as monotherapies. For example, Figure 8 demonstrates that compound (A) and compound 1A significantly reduce tumor volume.

[0241] The A-427 tumor cell line was maintained in vitro as a monolayer culture in MEM medium supplemented with 10% fetal bovine serum and 400 ng / mL puromycin at 37°C under an atmosphere of 5% CO2 in air. Cells in the exponential growth phase were collected and counted for tumor inoculation. 95% viable tumor cells (1 × 10⁶) in 100 μL of serum-free MEM Matrigel mixture (1:1 ratio) were inoculated into the right flank of each NOD / SCID mouse for tumor development. 7 A single-cell suspension of ) was subcutaneously inoculated. The average tumor size was approximately 224 mm. 3Treatment was initiated when the TGI value was reached. Mice were then randomized into groups and orally administered either the vehicle or 80 mg / kg of compound (1A) for 28 days. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 13, where the upper line represents the vehicle and the lower line represents 80 mg / kg of compound (1A). As shown by the data in Figure 13, compound (1A) treatment achieved significant antitumor activity with a TGI value of 132.7%.

[0242] NCI-H1755 NSCLC cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C under an atmosphere of 5% CO2 in air. Cells in the exponential growth phase were collected and counted for tumor inoculation. 95% viable tumor cells (1 × 10⁶) in 100 μL of serum-free RPMI1640 Matrigel mixture (1:1 ratio) were inoculated into the right flank of each NOD SCID mouse for tumor development. 7 A single-cell suspension of ) was subcutaneously inoculated. The average tumor size was 176 mm. 3 Treatment was initiated when the TGI value was reached. Mice were randomized into treatment groups (10 mice per group). Tumor-bearing mice were orally administered either the vehicle or 80 mg / kg of compound (1A) for 28 days. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 14, where the upper line represents the vehicle and the lower line represents 80 mg / kg of compound (1A). The results demonstrate that treatment with compound (1A) as a monotherapy achieved significant antitumor activity with a TGI value of 89.6%.

[0243] The SK-UT-1 tumor cell line was maintained in vitro as a monolayer culture in EMEM supplemented with 10% fetal bovine serum at 37°C under an atmosphere of 5% CO2 in air. Cells growing in the exponential growth phase were collected and counted for tumor inoculation. 95% viable tumor cells (1 × 10⁶) in 100 μL of serum-free EMEM-Matrigel mixture (1:1 ratio) were inoculated into the right flank of each BALB / c nude mouse for tumor development. 7 A single-cell suspension of ) was subcutaneously inoculated. The average tumor size was 193 mm.3 Treatment was initiated when the TGI value reached a certain level. Mice were randomized to a treatment group (10 mice per group). Tumor-bearing mice were administered either the vehicle or 80 mg / kg of compound (1A) for 4 cycles on a 1-day on, 6-day off schedule. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 15, where the upper line represents the vehicle and the lower line represents 80 mg / kg of compound (1A). As shown in Figure 15, compound (1A) monotherapy achieved significant antitumor activity with a TGI value of 98%.

[0244] OVCAR-3 tumor cell lines were maintained in vitro as monolayer cultures in RPMI1640 supplemented with 20% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. Cells in the exponential growth phase were collected and counted for tumor inoculation. 95% viable tumor cells (2 × 10⁶) in 200 μL of serum-free RPMI1640 Matrigel mixture (1:1 ratio) were inoculated into the right flank of each NOD / SCID mouse for tumor development. 7 A single-cell suspension of ) was subcutaneously inoculated. The average tumor size was 111 mm. 3 Treatment was started on the 15th day, when the mice reached this stage. Mice were randomized to a treatment group (10 mice per group) and orally administered either the vehicle or 80 mg / kg of compound (1A) for 28 days. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 16, where the upper line represents the vehicle and the lower line represents 80 mg / kg of compound (1A). As shown in Figure 16, compound (1A) demonstrated robust antitumor activity with a TGI value of 91.3%.

[0245] x2-MDA-MB-468 cells (ATCC-Chempartner) were maintained in vitro as a monolayer culture in DMEM medium supplemented with 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C under an atmosphere of 5% CO2 in air. 1 x 10¹⁶ cells were placed in the right flank of each CB-17SCID mouse in a 0.2 mL mixture of RPMI1640 medium and BD Matrigel (basic medium: Matrigel = 100 µl: 100 µl) to induce tumor formation. 7 x2-MDA-MD-468 cells were subcutaneously transplanted. The average tumor size was approximately 196 mm. 3 When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each and orally administered the vehicle and compound (1A) at 80 mg / kg for 56 days. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 17. As shown in Figure 17, treatment with compound (1A) resulted in significant antitumor activity with a TGI value of 87.1%.

[0246] x2-MDA-MB-468 cells (ATCC-Chempartner) were maintained in vitro as a monolayer culture in DMEM medium supplemented with 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C under an atmosphere of 5% CO2 in air. In the right flank of each mouse, 1 x 10⁶ cells were placed in a 0.2 mL mixture of RPMI1640 medium and BD Matrigel (basic medium:Matrigel = 100 μL:100 μL) to induce tumor development. 7 x2-MDA-MD-468 cells were subcutaneously transplanted. The average tumor size was approximately 196 mm. 3When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each and orally administered the vehicle, 60 mg / kg of compound (1A), 45 mg / kg of niraparib, and compound (1A) in combination with niraparib. Compound (1A) or niraparib was administered as monotherapy in a 7-day on-7-day off regimen for 4 cycles. In the combination group, the animals were administered niraparib and compound (1A) in an alternating dosing schedule, with niraparib administered in weeks 1, 3, 5, and 7, and compound (1A) administered in weeks 2, 4, 6, and 8. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 18. As shown in Figure 18, combination therapy with compound (1A) and niraparib induced significantly greater antitumor activity compared to compound (1A) and niraparib as monotherapy. Compound (1A) monotherapy, niraparib monotherapy, and compound (1A) in combination with niraparib resulted in antitumor activity of TGI values ​​of 52.6%, 47.7%, and 70.7%, respectively.

[0247] Fadu cells were grown in EMEM medium supplemented with 20% fetal bovine serum at 37°C under a 5% CO2 atmosphere. 95% viable tumor cells (5 × 10) in 100 μL of EMEM containing 10% FBS were placed in the right flank of BALB / c nude mice. 6 A single-cell suspension of ) was subcutaneously transplanted. The tumor was approximately 138 mm. 3When the target was reached, the animals were randomly assigned to treatment groups of 10 animals each, administered a vehicle for 25 days, orally administered compound (1A) once daily at 40 mg / kg for 30 days, and received X-ray therapy at 2 Gy / mouse in three cycles of a fractionated radiation schedule of 5 days on, 7 days off, followed by 5 days on, 2 days off, and compound (1A) in combination with X-ray. Tumor volume was assessed twice weekly and calculated over time, and mice were weighed twice weekly as a substitute for signs of toxicity. The results are shown in Figure 19. As shown in Figure 19, the combination of compound (1A) and X-ray was more effective in reducing tumor size compared to compound (1A) and X-ray as monotherapy. Compound (1A) monotherapy, X-ray monotherapy, and compound (1A) in combination with X-ray each had a TGI value of 58. It yielded antitumor activity of 7%, 70.7%, and 82.6%.

[0248] An OVCAR3 xenograft model was prepared using a 200 μL OVCAR3 tumor cell suspension (1 × 10⁶). 7 The method was established by subcutaneous inoculation of cells / mouse (containing 50% Matrigel) into the right axilla of BABL / c nude mice. The tumor was approximately 180.8 mm. 3When the target was reached, tumor-bearing animals were randomly assigned to treatment groups of 10 animals each. The animals were orally administered either a vehicle or compound (1A) at 40 mg / kg or 60 mg / kg for 28 days, and intraperitoneally injected with 2.5 mg / kg of doxorubicin once a week for 4 weeks, and treated with compound (1A) in combination with doxorubicin. Tumor volume was assessed twice a week and calculated over time, and mice were weighed twice a week as a substitute for signs of toxicity. The results are shown in Figure 28. Combination therapy with compound (1A) at 40 mg / kg or 60 mg / kg and 2.5 mg / kg of doxorubicin induced improved antitumor activity, with TGI values ​​of 63.47% and 82.57%, respectively. In comparison, compound (1A) at 40 mg / kg or 60 mg / kg and doxorubicin at 2.5 mg / kg, as monotherapy, yielded antitumor activity with TGI values ​​of 51.66%, 73.48%, and 43.11%, respectively. Since the active pharmaceutical component in pegylated liposomal doxorubicin is doxorubicin, it is reasonable to assume that pegylated liposomal doxorubicin combined with compound (1A) will yield similar results.

[0249] Furthermore, although the above text is described in some detail with figures and examples for clarity and understanding, it will be understood by those skilled in the art that numerous and varied modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of this disclosure, but rather encompass all modifications and alternative forms that are in line with the true scope and spirit of the invention.

Claims

1. A pharmaceutical product comprising a combination of compounds for treating a disease or condition, wherein the disease or condition is selected from the group consisting of breast cancer, ovarian cancer, uterine cancer, fallopian tube cancer, primary peritoneal cancer, and osteosarcoma, and the combination comprises one or more of the following: 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】 A pharmaceutical product wherein one or more of the compounds (B) are chemotherapeutic agents selected from the group consisting of carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacitidine, capecitabine, AraC-FdUMP[10](CF-10), cladribine, decitabine, hydroxyurea, and oxaliplatin, and any pharmaceutically acceptable salt of any of the above.

2. The pharmaceutical product according to claim 1, wherein compound (A), or a pharmaceutically acceptable salt thereof, is administered before compound (B), or a pharmaceutically acceptable salt thereof.

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

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

5. The pharmaceutical product according to any one of claims 1 to 4, wherein compound (B) is carboplatin or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical product according to any one of claims 1 to 4, wherein compound (B) is paclitaxel or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical product according to any one of claims 1 to 4, wherein compound (B) is gemcitabine or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical product according to any one of claims 1 to 4, wherein compound (B) is a triapine or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical product according to any one of claims 1 to 4, wherein compound (B) is a hydroxyurea or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein the disease or condition is breast cancer.

11. The pharmaceutical product according to claim 10, wherein the breast cancer is triple-negative breast cancer.

12. The pharmaceutical product according to any one of claims 1 to 9, wherein the disease or condition is ovarian cancer.

13. The pharmaceutical product according to claim 12, wherein the ovarian cancer is TP53-mutated ovarian cancer.

14. The pharmaceutical product according to any one of claims 1 to 9, wherein the disease or condition is uterine cancer.

15. The pharmaceutical product according to claim 14, wherein the uterine cancer is endometrial cancer.

16. The pharmaceutical product according to claim 15, wherein the endometrial cancer is serous uterine cancer.

17. The pharmaceutical product according to claim 14, wherein the uterine cancer is cervical cancer.

18. The pharmaceutical product according to any one of claims 1 to 9, wherein the disease or condition is osteosarcoma.

19. A use of a pharmaceutical product according to claims 1-4, wherein compound (B) is paclitaxel or a pharmaceutically acceptable salt thereof, and the disease or condition is selected from the group consisting of breast cancer, ovarian cancer, and uterine cancer.

20. Use of a pharmaceutical product according to claims 1-4, wherein compound (B) is doxorubicin or a pharmaceutically acceptable salt thereof, or pegylated liposomal doxorubicin or a pharmaceutically acceptable salt thereof, and the disease or condition is ovarian cancer.

21. Use of a pharmaceutical product according to claims 1-4, wherein compound (B) is gemcitabine or a pharmaceutically acceptable salt thereof, and the disease or condition is osteosarcoma.

22. Use of a pharmaceutical product according to claims 1-4, wherein compound (B) is paclitaxel or a pharmaceutically acceptable salt thereof, and the disease or condition is ovarian cancer.

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