Antibody-drug conjugate and CDK9 inhibitor combination

Abstract

Pharmaceutical products are provided for the administration of anti-HER2 antibody-drug conjugates in combination with CDK9 inhibitors. The anti-HER2 antibody-drug conjugates are antibody-drug conjugates in which a drug-linker represented by the following formula (wherein A represents the attachment position to the antibody) is conjugated to the anti-HER2 antibody via a thioether bond. Therapeutic uses and methods are also provided in which the antibody-drug conjugate and CDK9 inhibitor are administered in combination to a subject. [Formula 1] JPEG2023542065000060.jpg74170

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical products for the administration of specific antibody-drug conjugates having an anti-tumor drug conjugated via a linker structure to an anti-HER2 antibody in combination with a CDK9 inhibitor, and to therapeutic uses and methods in which the specific antigen-drug conjugate and the CDK9 inhibitor are administered in combination to a subject. [Background technology]

[0002] Cyclin-dependent protein kinases (CDKs) represent a family of serine / threonine protein kinases that become active upon binding to cyclin regulatory partners. CDK / cyclin complexes were first identified as regulators of cell cycle progression. CDK / cyclin complexes are also involved in transcription and mRNA processing. CDK9 / PTEFb (positive transcription elongation factor b) phosphorylates the carboxyl-terminal domain (CTD), primarily at Ser-2, of the large subunit of RNA polymerase II (RNAPII), regulating transcription elongation. Inhibition of CDK9 and transcriptional repression results in the rapid depletion of short-lived mRNA transcripts and associated proteins, including Mcl1 and c-myc, leading to the induction of apoptosis in tumor cells overdependent on these survival proteins. Thus, targeting transcriptional CDKs, including CDK9, has been shown to be effective in treating hematological malignancies such as acute myeloid leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter's syndrome, B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, and solid tumors such as breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, This represents a therapeutic strategy for treating tumor types that are highly dependent on these unstable pro-survival proteins, including, but not limited to, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, neuroblastoma, and colon cancer. CDK9 inhibitors may also have therapeutic utility in other disease indications, including cardiac disease, viral diseases, inflammation, and pain. CDK9 inhibitors are disclosed, for example, in International Publication No. WO 2017 / 001354.

[0003] Antibody-drug conjugates (ADCs), which consist of a cytotoxic drug conjugated to an antibody, can selectively deliver drugs to cancer cells, thus leading to their accumulation and death in cancer cells (Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13; Alley, SC, et al., Current Opinion in Chemical Biology (2010) 14, 529-537; Damle N.K. Expert Opinion. Biol. Ther. (2004) 4, 1445-1452; Senter PD, et al., Nature Biotechnology (2012) 30, 631-637; Burris HA., et al., J. Clin. Oncol. (2011) 29(4):398-405).

[0004] One such antibody-drug conjugate is trastuzumab-deruxtecan, which consists of an antibody targeting HER2 and a derivative of exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22 (20), 5097-5108; Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0005] Despite the therapeutic potential of antibody-drug conjugates and CDK9 inhibitors, there are no published studies demonstrating superior efficacy of the combined use of antibody-drug conjugates and CDK9 inhibitors or any scientific basis for suggesting such efficacy. Furthermore, in the absence of such studies, the possibility exists that administering an antibody-drug conjugate in combination with another cancer therapeutic agent, such as a CDK9 inhibitor, could lead to negative interactions and / or inferior therapeutic outcomes, and therefore, the superior or superior efficacy obtained by such combined treatment could not be predicted.

[0006] Thus, there remains a need for improved therapeutic compositions and methods that can enhance the efficacy, extend the duration of therapeutic response, and / or reduce dose-dependent toxicity of existing cancer treatments. Summary of the Invention [Means for solving the problem]

[0007] The antibody-drug conjugate used in the present disclosure (an anti-HER2 antibody-drug conjugate comprising a derivative of the topoisomerase I inhibitor exatecan) has been shown to exhibit excellent anti-tumor effects in the treatment of certain cancers, such as breast cancer and gastric cancer, when administered alone. Furthermore, CDK9 inhibitors have been shown to exhibit anti-tumor effects in the treatment of certain cancers. However, it is desirable to provide drugs and treatments that can achieve excellent anti-tumor effects in the treatment of cancer, such as enhanced efficacy, prolonged duration of therapeutic response, and / or reduced dose-dependent toxicity.

[0008] The present disclosure provides a pharmaceutical product that can exhibit excellent anti-tumor effects in the treatment of cancer through the administration of an anti-HER2 antibody-drug conjugate in combination with a CDK9 inhibitor. The present disclosure also provides therapeutic uses and methods in which the anti-HER2 antibody-drug conjugate and a CDK9 inhibitor are administered in combination to a subject.

[0009] Specifically, the present disclosure relates to the following [1] to

[61] : [1] A pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for combined administration, wherein the anti-HER2 antibody-drug conjugate is linked to a drug-linker represented by the following formula: [ka] wherein A represents a linkage site to the antibody, is conjugated to an anti-HER2 antibody via a thioether bond; [2] The pharmaceutical product according to [1], wherein the CDK9 inhibitor is a compound of the following formula (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 is H, C 1~3 alkyl, CN or halogen; R 2 is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl; R 10 , OR 10 , S.R. 10 , S(O)R 10 , S(O)2R 10 , C(O)R 10 , C(O)OR 10 ,OC(O)R 10 ,OC(O)OR 10 , NH2, NHR 10 , N(R 10 )2, NHC(O)H, NHC(O)R 10 , N.R. 10 C(O)H, NR 10 C(O)R 10 , NHS(O)2R 10 , N.R. 10 S(O)2R 10 , NHC(O)OR 10 , N.R. 10 C(O)OR 10 , NHC(O)NH2, NHC(O)NHR 10 , NHC(O)N(R 10 )2, NR 10 C(O)NH2, NR 10 C(O)NHR 10 , N.R. 10 C(O)N(R 10 )2, C(O)NH2, C(O)NHR 10 , C(O)N(R 10 )2, C(O)NHOH, C(O)NHOR 10 , C(O)NHS(O)2R 10 , C(O)NR 10 S(O)2R 10 , S(O)2NH2, S(O)2NHR 10 , S(O)2N(R 10 )2, S(O)2NHC(O)OR 10 , S(O)NR10 C(O)OR 10 , C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; one or more ring CH groups can be optionally replaced by a corresponding number of —C(O) groups, and one or more ring sulfur or nitrogen atoms can be optionally oxidized to form an S-oxide or N-oxide; R 10 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 independently selected from the group consisting of alkyl, NH, C(O)NH, C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; two R 10 groups, together with the atom to which they are attached, can form a 3- to 6-membered cycloalkyl or heterocycloalkyl group; each of the above R 10 Alkyl, cycloalkyl and heterocycloalkyl groups include CN, OH, halogen, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 Alkyl and NHC(O)-C 1~3 may be further substituted by 1 or 2 substituents independently selected from alkyl; R 4 teeth, [ka] and In this formula, X and Y, together with the atoms to which they are attached, represent one or two atoms selected from N, O, and S in addition to the bridging nitrogen. the ring may be saturated or partially saturated; one or two ring CH groups may be optionally replaced by a corresponding number of —C(O) groups, one or more ring sulfur or nitrogen atoms may be optionally oxidized to form S-oxides or N-oxides, and the ring may have one or two R10 R by substituents or on the ring nitrogen 12 may be substituted by a substituent; J is N or CR 11 and; R 11 is H, C 1~3 is alkyl; R 12 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 independently selected from the group consisting of alkyl, C(O)NH, and C(O)H; each R 12 Alkyl, cycloalkyl and heterocycloalkyl groups include CN, OH and halogens, C 1~3 Alkyl, NH2 and NH-C 1~3 Alkyl, NHC(O)-C 1~3 and (b) a substituted or unsubstituted alkyl group, which may be further substituted by one or two substituents independently selected from alkyl, or a pharmaceutically acceptable salt thereof; [3] In formula (I), A is C(R 5 ) the pharmaceutical product according to [2]; [4]R 5 The pharmaceutical product according to [3], wherein [5]R 5 The pharmaceutical product according to [3], wherein [6] In formula (I), R 2 is a 3- to 7-membered cycloalkyl; [7] In formula (I), R 2 NHCOR 10 or R 10 The pharmaceutical product according to [2], wherein the cycloalkyl is 3 to 7-membered; [8]R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; [9]R 2 is selected from cyclopentyl and cyclohexyl;

[10] R 2 However, NHCOR 10 the pharmaceutical product according to [7], wherein cyclohexyl is substituted with

[11] In formula (I), R 2 is a 3- to 7-membered heterocycloalkyl;

[12] In formula (I), R 2 However, NHCOR 10 The pharmaceutical product according to [2], wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl substituted with

[13] In the formula (I), R4 is [ka] The pharmaceutical product according to [2],

[14] J is C(R 11 ) the pharmaceutical product according to

[13] ;

[15] R 11 The pharmaceutical product according to

[14] , wherein

[16] The pharmaceutical product according to [2], wherein, in formula (I), X and Y together with the atom to which they are attached form a 5-membered heterocycloalkyl ring;

[17] The pharmaceutical product according to [2], wherein, in formula (I), X and Y together with the atoms to which they are connected form a 5-membered heterocycloalkyl ring in which one CH2 is substituted with two methyl groups;

[18] A CDK9 inhibitor having the following formula: [ka] or a pharmaceutically acceptable salt thereof;

[19] The pharmaceutical product according to any one of [1] to

[18] , wherein the anti-HER2 antibody comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3 [= amino acid residues 26 to 33 of SEQ ID NO: 1], CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4 [= amino acid residues 51 to 58 of SEQ ID NO: 1], and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5 [= amino acid residues 97 to 109 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 27 to 32 of SEQ ID NO: 2], CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 7 [= amino acid residues 50 to 52 of SEQ ID NO: 2], and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8 [= amino acid residues 89 to 97 of SEQ ID NO: 2];

[20] The pharmaceutical product according to any one of [1] to

[18] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 [= amino acid residues 1 to 120 of SEQ ID NO: 1], and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 1 to 107 of SEQ ID NO: 2];

[21] The pharmaceutical product according to any one of [1] to

[18] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2;

[22] The pharmaceutical product according to any one of [1] to

[18] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 1 to 449 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2;

[23] The anti-HER2 antibody-drug conjugate has the formula: [ka] (wherein "antibody" refers to an anti-HER2 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug-linker units conjugated per antibody molecule in the antibody-drug conjugate, and n is in the range of 7 to 8);

[24] The pharmaceutical product according to any one of [1] to

[23] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201);

[25] The pharmaceutical product according to any one of [1] to

[24] , which is a composition comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for simultaneous administration;

[26] The pharmaceutical product according to any one of [1] to

[24] , which is a combined preparation comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for sequential or simultaneous administration;

[27] The pharmaceutical product according to any one of [1] to

[26] , which is for treating cancer;

[28] Cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanocytic leukemia. the pharmaceutical product according to

[27] , wherein the patient is at least one selected from the group consisting of myeloma, acute myeloid leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter's syndrome, B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, and follicular lymphoma;

[29] The pharmaceutical product according to

[27] , wherein the cancer is breast cancer;

[30] The pharmaceutical product according to

[29] , wherein the breast cancer has a HER2 status score of IHC3+;

[31] The pharmaceutical product according to

[29] , wherein the breast cancer is HER2-low-expressing breast cancer;

[32] The pharmaceutical product of

[29] , wherein the breast cancer has a HER2 status score of IHC2+;

[33] The pharmaceutical product according to

[29] , wherein the breast cancer has a HER2 status score of IHC1+;

[34] The pharmaceutical product of

[29] , wherein the breast cancer has an IHC>0 and HER2 status score<1+;

[35] The pharmaceutical product according to

[29] , wherein the breast cancer is triple-negative breast cancer;

[36] The pharmaceutical product according to

[27] , wherein the cancer is gastric cancer;

[37] The pharmaceutical product according to

[27] , wherein the cancer is colon cancer;

[38] The pharmaceutical product according to

[27] , wherein the cancer is lung cancer;

[39] The pharmaceutical product according to

[38] , wherein the lung cancer is non-small cell lung cancer;

[40] The pharmaceutical product according to

[27] , wherein the cancer is pancreatic cancer;

[41] The pharmaceutical product according to

[27] , wherein the cancer is ovarian cancer;

[42] The pharmaceutical product according to

[27] , wherein the cancer is prostate cancer;

[43] The pharmaceutical product according to

[27] , wherein the cancer is kidney cancer;

[44] A pharmaceutical product as defined in any one of [1] to

[26] for use in the treatment of cancer;

[45] The pharmaceutical product for use according to

[44] , wherein the cancer is as defined in any one of

[28] to

[43] ;

[46] Use of an anti-HER2 antibody-drug conjugate or a CDK9 inhibitor in the manufacture of a medicament for administering an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor in combination for treating cancer, wherein the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor are as defined in any one of [1] to

[24] ;

[47] The method according to

[46] , wherein the cancer is as defined in any one of

[28] to

[43] ;

[48] ​​The use according to

[46] or

[47] , wherein the medicament is a composition comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for simultaneous administration;

[49] The use according to

[46] or

[47] , wherein the medicament is a combined preparation comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for sequential or simultaneous administration;

[50] An anti-HER2 antibody-drug conjugate for use in combination with a CDK9 inhibitor in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor are as defined in any one of [1] to

[24] ;

[51] The anti-HER2 antibody-drug conjugate for use according to

[50] , wherein the cancer is as defined in any one of

[28] to

[43] ;

[52] The anti-HER2 antibody-drug conjugate for use according to

[50] or

[51] , wherein the use comprises sequential administration of the anti-HER2 antibody-drug conjugate and a CDK9 inhibitor;

[53] The anti-HER2 antibody-drug conjugate for use according to

[50] or

[51] , wherein the use comprises concurrent administration of the anti-HER2 antibody-drug conjugate and a CDK9 inhibitor;

[54] A CDK9 inhibitor for use in combination with an anti-HER2 antibody-drug conjugate in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor are as defined in any one of [1] to

[24] ;

[55]

[54] A CDK9 inhibitor for use according to the method of the present invention, wherein the cancer is as defined in any one of

[28] to

[43] .

[56] A CDK9 inhibitor for use according to

[54] or

[55] , wherein the use comprises sequential administration of the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor;

[57] A CDK9 inhibitor for use according to

[54] or

[55] , wherein the use comprises simultaneous administration of an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor;

[58] A method for treating cancer, comprising administering to a subject in need thereof an anti-HER2 antibody-drug conjugate as defined in any one of [1] to

[24] and a CDK9 inhibitor in combination;

[59] The method according to

[58] , wherein the cancer is as defined in any one of

[28] to

[43] ;

[60] The method according to

[58] or

[59] , comprising sequentially administering an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor; and

[61] The method of

[58] or

[59] , comprising administering an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor simultaneously.

[0010] [Effects of the invention] The present disclosure provides pharmaceutical products in which an anti-HER2 antibody-drug conjugate having an anti-tumor drug conjugated to the anti-HER2 antibody via a linker structure and a CDK9 inhibitor are administered in combination, as well as therapeutic uses and methods in which a specific antibody-drug conjugate and a CDK9 inhibitor are administered in combination to a subject. Thus, the present disclosure may provide drugs and treatments that can achieve excellent anti-tumor effects in the treatment of cancer. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a diagram showing the amino acid sequence of the heavy chain of an anti-HER2 antibody (SEQ ID NO: 1). [Figure 2] FIG. 2 is a diagram showing the amino acid sequence of the light chain of an anti-HER2 antibody (SEQ ID NO: 2). [Figure 3] FIG. 3 is a diagram showing the amino acid sequence of heavy chain CDRH1 (SEQ ID NO: 3 [=amino acid residues 26 to 33 of SEQ ID NO: 1]). [Figure 4] FIG. 4 is a diagram showing the amino acid sequence of heavy chain CDRH2 (SEQ ID NO: 4 [=amino acid residues 51 to 58 of SEQ ID NO: 1]). [Figure 5] FIG. 5 is a diagram showing the amino acid sequence of heavy chain CDRH3 (SEQ ID NO: 5 [=amino acid residues 97 to 109 of SEQ ID NO: 1]). [Figure 6] FIG. 6 is a diagram showing the amino acid sequence of light chain CDRL1 (SEQ ID NO: 6 [=amino acid residues 27-32 of SEQ ID NO: 2]). [Figure 7]FIG. 7 is a diagram showing amino acid sequences including the amino acid sequence (SAS) of light chain CDRL2 (SEQ ID NO: 7 [=amino acid residues 50 to 56 of SEQ ID NO: 2]). [Figure 8] FIG. 8 is a diagram showing the amino acid sequence of light chain CDRL3 (SEQ ID NO: 8 [=amino acid residues 89-97 of SEQ ID NO: 2]). [Figure 9] FIG. 9 is a diagram showing the amino acid sequence of the heavy chain variable region (SEQ ID NO: 9 [=amino acid residues 1 to 120 of SEQ ID NO: 1]). [Figure 10] FIG. 10 is a diagram showing the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [=amino acid residues 1 to 107 of SEQ ID NO: 2]). [Figure 11] FIG. 11 is a diagram showing the amino acid sequence of the heavy chain (SEQ ID NO: 11 [=amino acid residues 1-449 of SEQ ID NO: 1]). [Figure 12] FIG. 12 is a chart showing dose-response curves for the selective CDK9 inhibitor AZD4573 in combination with increasing doses of the anti-HER2 antibody-drug conjugate DS-8201 in breast and gastric cancer cell lines. [Figure 13] FIG. 13 is a graph showing the change in tumor volume over time for treatment groups in CB17-SCID mice implanted subcutaneously with HCC12945 breast cancer cells treated with DS-8201 at 3 mg / kg or 10 mg / kg alone and in combination with AZD4573 at 10 mg / kg BID or 5 mg / kg TID. DETAILED DESCRIPTION OF THE INVENTION

[0012] In order that this disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0013] Before describing the present disclosure in detail, it is to be understood that the present disclosure is not limited to particular compositions or method steps, as such may vary. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), and "one or more" and "at least one" may be used interchangeably herein.

[0014] Furthermore, "and / or" as used herein should be considered a specific disclosure of each of the two particular features or components, regardless of the presence or absence of other features or components. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" when used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B, or C; A and C; A and B; B, and C; A (alone); B (alone); and C (alone).

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0016] Units, prefixes, and symbols are written in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0017] Whenever an embodiment is described herein with the word "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0018] The terms "inhibit," "block," and "suppress" are used interchangeably herein and refer to any statistically significant decrease in biological activity, including complete blocking of activity. For example, "inhibition" can refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in biological activity.

[0019] Cell proliferation may be assayed using art-recognized techniques that measure the rate of cell division and / or the proportion of cells within a cell population undergoing cell division and / or the rate of cell loss from the cell population due to terminal differentiation or cell death (e.g., thymidine incorporation).

[0020] The term "subject" refers to any animal (e.g., mammal) that will be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0021] The term "pharmaceutical product" refers to a preparation that is in a form that allows for the biological activity of the active ingredients, either as a composition containing all of the active ingredients (for simultaneous administration) or as a combination of individual compositions (combined preparations) each containing at least one but not all of the active ingredients (sequential or simultaneous administration), and that does not contain additional components that are unacceptably toxic to the subject to whom the product is administered. Such a product may be sterile. "Simultaneous administration" means that the active ingredients are administered at the same time. "Sequential administration" means that the active ingredients are administered one after the other, in either order, with a time interval between each administration. The time interval may be, for example, less than 24 hours, preferably less than 6 hours, and more preferably less than 2 hours.

[0022] Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow, reduce symptoms, and / or halt the progression of a diagnosed condition or disease, and (2) prophylactic or preventative measures that prevent and / or slow the onset of the targeted condition or disease. Thus, those in need of treatment include those already with the disorder, those prone to having the disorder, and those in whom the disorder is to be prevented. In some embodiments, a subject's cancer is successfully "treated" according to the methods of the present disclosure when the patient, for example, experiences a complete, partial, or temporary remission of a particular type of cancer.

[0023] The terms "cancer," "tumor," "cancerous," and "malignant" refer to or describe a physical condition in a mammal that is typically characterized by unregulated cell growth. Examples of cancer include breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, and the like. Cancers include, but are not limited to, hematologic malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, and follicular lymphoma. Cancers include hematologic malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, and follicular lymphoma, and solid tumors such as breast cancer, lung cancer, neuroblastoma, and colon cancer.

[0024] As used herein, the term "cytotoxic agent" is broadly defined and refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells (cell death) and / or exhibits antineoplastic / antiproliferative effects. For example, a cytotoxic agent directly or indirectly prevents the development, maturation, or spread of neoplastic tumor cells. The term also includes agents that cause only cytostatic, not merely cytotoxic, effects. The term includes chemotherapeutic agents, as defined below, as well as other HER2 antagonists, antiangiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, members of the cytokine family, radioisotopes, and toxins, e.g., enzymatically active toxins of bacterial, fungal, plant, or animal origin. The term "chemotherapeutic agent" is a subset of the term "cytotoxic agent," which includes natural or synthetic compounds.

[0025] According to the method or use of the present disclosure, a compound of the present disclosure can be administered to a patient to promote a positive therapeutic response for cancer. The term "positive therapeutic response" in the context of cancer treatment refers to an improvement in symptoms associated with the disease. For example, an improvement in the disease can be characterized as a complete response. The term "complete response" refers to the absence of clinically detectable disease accompanied by normalization of any prior test results. Alternatively, an improvement in the disease can be classified as being a partial response. A "positive therapeutic response" encompasses a reduction or inhibition of the progression and / or duration of cancer, a reduction or improvement in the severity of cancer, and / or the amelioration of one or more of its symptoms resulting from the administration of a compound of the present disclosure. In specific embodiments, such terms refer to one, two, or three or more results following administration of a compound of the present disclosure: (1) stabilization, reduction, or elimination of cancer cell populations; (2) stabilization or reduction of cancer growth; (3) reduced cancer formation; (4) eradication, removal, or control of primary, regional, and / or metastatic cancer; (5) reduced mortality; (6) increased disease-free, recurrence-free, progression-free, and / or overall survival, duration, or rate; (7) Increase in response rate, durability of response, or number of patients responding or remitting; (8) reduced hospitalization rates; (9) reduced length of hospital stay; (10) The size of the cancer remains the same and does not expand, or expands by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; and (11) Increase in the number of patients with remission; (12) A reduction in the number of other adjuvant therapeutic agents (e.g., chemotherapy or hormonal therapy agents) required to treat the cancer.

[0026] Clinical response may be assessed using screening techniques, such as changes detectable by PET, magnetic resonance imaging (MRI) scan, X-ray imaging, computed tomography (CT) scan, flow cytometry or fluorescence activated cell sorter (FACS) analysis, histology, macroscopic findings, and blood chemistry tests, including, but not limited to, ELISA, RIA, chromatography, etc. In addition to these positive therapeutic responses, subjects receiving treatment may experience beneficial effects of improvement in symptoms associated with the disease.

[0027] In this specification, C x~y When used in terms such as alkyl, where X and Y are integers, the prefix C x~y indicates the numerical range of carbon atoms present in the group; for example, C 1~4 Alkyl includes C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl (propyl and isopropyl), and C4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-butyl).

[0028] Unless specifically stated, the bonding atom of a group can be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.

[0029] As used herein, the phrase "optionally substituted" indicates that substitution is optional, and thus the specified group may be considered to be either substituted or unsubstituted. In the event that substitution is desired, any number of hydrogens on the specified group may be replaced with a selection from the indicated substituents, provided that the normal valence of the atom on the particular substituent is not exceeded and that the substitution results in a stable compound. In one aspect, when a particular group is specified as being optionally substituted with "one or more" substituents, the particular group may be unsubstituted. In another aspect, the particular group may have one substituent. In another aspect, the particular substituent may have two substituents. In yet another aspect, the particular group may have three substituents. In yet another aspect, the particular group may have four substituents. In a further aspect, the particular group may have one or two substituents. In yet a further aspect, the particular group may be unsubstituted or may have one or two substituents.

[0030] As used herein, the term "alkyl" refers to both straight- and branched-chain saturated hydrocarbon groups having the specified number of carbon atoms. References to individual alkyl groups, such as "propyl," are specific only to the straight-chain version, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific only to the branched-chain version. In one aspect, "alkyl" refers to "C 1~4 In another embodiment, "alkyl" and "C 1~4 Alkyl" is "C 1~3 In another embodiment, "alkyl" can be "C 1~4 Alkyl" and "C 1~3 "Alkyl" can be methyl. Similar variations apply to other general terms, such as "alkenyl" and "alkynyl."

[0031] "Cycloalkyl" is a monocyclic, saturated or partially unsaturated alkyl ring containing from 3 to 7 carbon atoms. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0032] "Heterocycloalkyl" refers to a saturated or partially saturated monocyclic ring containing 3 to 7 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from nitrogen, sulfur, or oxygen, the ring may be carbon- or nitrogen-bonded, and the -CH2- group may be optionally replaced by -C(O)-; the ring nitrogen or sulfur atom is optionally oxidized to form an N-oxide or S-oxide (i.e., sulfoxide and sulfone); the ring -NH is optionally substituted by acetyl, formyl, methyl, or mesyl; and the ring is optionally substituted by one or more halo. Specific examples of "5- or 6-membered heterocycloalkyl" include imidazolinyl, pyrazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, and thiomorpholinyl.

[0033] Any R group (R 1 ~R 12 Suitable values ​​for ) or any moiety or substituent on such a group include: C 1~4 For alkyl: methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl and tert-butyl; C 1~6 For alkyl: C 1~4 Alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; C 3~7 For cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and cycloheptyl; For halo or halogen: fluoro, chloro, bromo and iodo; For heterocycloalkyl: pyrrolidinyl, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioxiimidazolidinyl and 2,2-dimethyl-1,3-dioxolanyl. It should be noted that the examples given for the terms used in this description are not limiting.

[0034] As used herein, the phrase "effective amount" refers to an amount of a compound or composition sufficient to significantly and positively alter the condition and / or pathology being treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical product will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the particular active ingredient being used, the particular pharmaceutically acceptable excipients / carriers utilized, and similar factors within the knowledge and expertise of the attending physician. In particular, an effective amount of a compound of Formula (I) for use in the treatment of cancer in combination with an antibody-drug conjugate is an amount such that the combination is sufficient to symptomatically alleviate the symptoms of cancer in a warm-blooded animal such as a human, slow the progression of cancer, or reduce the risk of progression in a patient with a cancer condition.

[0035] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals, consistent with a reasonable benefit / risk ratio and without excessive toxicity, irritation, allergic response or other problem or complication.

[0036] For purposes of illustration, when referring to the substituent "R," the following substituent definitions apply to the structures shown: [ka] Refers to...

[0037] Within the scope of this disclosure, it should be understood that compounds of formula (I) or salts thereof may exhibit the phenomenon of tautomerism, and that the formula drawings within this specification may represent only one of the possible tautomeric forms. It should be understood that the present disclosure encompasses any tautomeric form that has CDK9 inhibitory activity and should not be limited solely to any one tautomeric form utilized in the formula drawings.

[0038] It will be understood that compounds of formula (I) may include compounds with one or more isotopic substitutions. For example, H may be: 1 H, 2 H(D) and 3 H(T) can be in any isotopic form; C can be in any isotopic form, including 12 C. 13 C and 14 C can be in any isotopic form; O can be 16 O and 18 It can be any isotopic form containing O; and so forth.

[0039] It should also be understood that certain compounds of formula (I) and salts thereof can exist in solvated and unsolvated forms, such as, for example, hydrated forms, and it is to be understood that the present disclosure encompasses all such solvated forms.

[0040] The compound of formula (I) can also be provided as an in vivo hydrolyzable ester. An in vivo hydrolyzable ester of a compound of formula (I) containing a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce the parent acid or alcohol. Such an ester can be identified, for example, by intravenously administering the compound to a test animal under test, followed by examining the body fluids of the test animal. Suitable pharmaceutically acceptable esters for carboxy include C 1~6 Alkoxymethyl esters, e.g., methoxymethyl, C 1~6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl, phthalidyl esters, C 3~8 Cycloalkcarbonyloxy C 1~6 Alkyl esters such as 1-cyclohexylcarbonyloxyethyl, (1,3-dioxolen-2-one)ylmethyl esters such as (5-methyl-1,3-dioxolen-2-one)ylmethyl and C 1~6Alkoxycarbonyloxyethyl esters include, for example, 1-methoxycarbonyloxyethyl; they can be formed at any carboxy group in the compounds of the present disclosure. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters, such as phosphate esters (including phosphoramidite ring esters) and α-acyloxyalkyl ethers and related compounds that generate the parent hydroxy group as a result of in vivo hydrolysis of the ester decomposition. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Selection of in vivo hydrolyzable ester-forming groups for hydroxy include C 1~10 Alkanoyl, for example, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; C 1~10 Alkoxycarbonyl (to give alkyl carbonate esters), e.g., ethoxycarbonyl; diC 1~4 Alkylcarbamoyl and N-(di-C 1~4 Alkylaminoethyl)-NC 1~4 Alkylcarbamoyl (to give carbamates); DiC 1~4 Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C 1~4 Alkylaminomethyl and di-(C 1~4 (alkyl)aminomethyl, and morpholino or piperazino linked from the ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring. Other interesting in vivo hydrolyzable esters include, for example, R A C(O)OC 1~6 alkyl-CO- (wherein R A For example, benzyloxy-C 1~4 Suitable substituents on the phenyl group in such esters include, for example, 4-C 1~4 Alkylpiperazino-C 1~4 Alkyl, piperazino-C 1~4 Alkyl and Morpholino-C 1~4 Examples of alkyl include:

[0041] The compounds of formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases, administration of the compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxybenzoate ... Examples of basic salts include maleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of basic salts include ammonium salts; alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as aluminum, calcium, and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-d-glucamine; and salts with amino acids such as arginine, lysine, and ornithine. Basic nitrogen-containing groups may also be quaternized with agents such as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates, such as dimethyl, diethyl, and dibutyl sulfates; diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl, and stearyl halides; aryl alkyl halides, such as benzyl bromide, and the like. Non-toxic, physiologically acceptable salts are preferred, although other salts may be useful, for example, in isolating or purifying the product.

[0042] These salts may be formed by conventional means, for example, by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, and the solvent removed in vacuo or by lyophilization, or by exchanging the anion of the existing salt for another anion on a suitable ion exchange resin.

[0043] The compounds of formula (I) have chiral centers and therefore exist as stereoisomers. It should be understood that the present disclosure encompasses all such stereoisomers, including enantiomers and diastereoisomers. Thus, to the extent that the compounds of formula (I) can exist in optically active or racemic forms, the present disclosure includes, by definition, any such optically active or racemic forms that have the above-mentioned activity. The present disclosure encompasses all such stereoisomers that have the activity as defined herein.

[0044] The synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic forms. Racemates can be separated into individual enantiomers using known procedures (see, for example, Advanced Organic Chemistry: 3rd Edition: author J March, pp. 104-107). A suitable procedure involves the formation of diastereomeric derivatives by reaction of the racemic material with a chiral auxiliary, followed by separation of the diastereomers, for example, by chromatography, and then cleavage of the auxiliary species. Similarly, the above-mentioned activity can be assessed using standard laboratory techniques.

[0045] Thus, throughout this specification, when referring to compounds of formula (I), it should be understood that the term compound includes stereoisomers, mixtures of stereoisomers and polymorphs that inhibit CDK9 activity in humans or animals.

[0046] Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Enantiomers can be isolated by separation of racemates, for example, by fractional crystallization, resolution, or HPLC. Diastereoisomers can be isolated by separation due to the different physical properties of the diastereoisomers, for example, by fractional crystallization, HPLC, or flash chromatography. Alternatively, specific stereoisomers can be prepared by chiral synthesis from chiral starting materials under conditions which will not cause racemization or epimerization, or by derivatization with a chiral reagent.

[0047] When a specified stereoisomer is provided (whether by separation, chiral synthesis, or other means), it is preferably provided substantially isolated from other stereoisomers of the same compound. In one embodiment, a mixture containing a specific stereoisomer of a compound of Formula (I) may contain less than 30% by weight, particularly less than 20% by weight, and more particularly less than 10% by weight, of other stereoisomers of the same compound. In another embodiment, a mixture containing a specific stereoisomer of a compound of Formula (I) may contain less than 6% by weight, particularly less than 3% by weight, and more particularly less than 2% by weight, of other stereoisomers of the compound. In another embodiment, a mixture containing a specific stereoisomer of a compound of Formula (I) may contain less than 1% by weight, particularly less than 0.5% by weight, more particularly less than 0.3% by weight, and even more particularly less than 0.1% by weight, of other stereoisomers of the compound. When the absolute configuration of isolated stereoisomers has not been determined, the stereoisomers may be distinguished by methods of preparation or separation. For example, isolated stereoisomers may be distinguished by their elution times and designated, for example, as Isomer 1, Isomer 2, etc.

[0048] Some structural forms of the present disclosure may offer advantages. For example, some forms of the compounds of the present disclosure may be easier to handle and store. Other forms of the compounds of the present disclosure may be easier to characterize because they exist in well-defined states. Furthermore, the compounds of the present disclosure may be more easily synthesized in a reproducible manner, thereby making them easier to handle in full-scale production.

[0049] When a specific polymorphic form is provided, it is preferably provided substantially isolated from other polymorphic forms of the same compound. In one embodiment, a mixture containing a specific polymorphic form of the compound of formula (I) may contain less than 30% by weight, particularly less than 20% by weight, and more particularly less than 10% by weight of other polymorphic forms of the same compound. In another embodiment, a mixture containing a specific polymorphic form of the compound of formula (I) may contain less than 6% by weight, particularly less than 3% by weight, and more particularly less than 2% by weight of other polymorphic forms of this compound. In another embodiment, a mixture containing a specific polymorphic form of the compound of formula (I) may contain less than 1% by weight, particularly less than 0.5% by weight, more particularly less than 0.3% by weight, and even more particularly less than 0.1% by weight of other polymorphic forms of this compound.

[0050] The CDK9 inhibitors disclosed herein can be characterized by the position and intensity of the main peaks in the X-ray powder diffraction pattern, but can also be characterized by conventional FT-IR spectroscopy. These can be used to distinguish one crystalline form of the compound from another. The CDK9 inhibitors disclosed herein can be characterized as being highly crystalline, i.e., having a higher degree of crystallinity than other forms. The phrase "any other form" refers to its anhydrate, hydrate, solvate, and polymorphic or amorphous forms disclosed in the prior art. Examples of any other form of the compound include, but are not limited to, anhydrate, monohydrate, dihydrate, sesquihydrate, trihydrate, alcoholates, such as methanolate and ethanolate, and their polymorphic or amorphous forms.

[0051] The compounds of formula (I) may also be characterized by their unit cell: The compounds of formula (I) may be analysed by XRPD, a technique known per se.

[0052] The amount of water in the compound can be determined by thermogravimetric analysis, a technique known per se.

[0053] Description of the embodiment Hereinafter, preferred modes for carrying out the present disclosure are described. The following embodiments are provided only to illustrate one example of a typical embodiment of the present disclosure, and are not intended to limit the scope of the present disclosure.

[0054] 1. Antibody-drug conjugates Antibody-drug conjugates used in this disclosure have the following formula: [ka] (wherein A represents the linking position to the antibody) is conjugated to the anti-HER2 antibody via a thioether bond.

[0055] In the present disclosure, the partial structure consisting of a linker and a drug in an antibody-drug conjugate is referred to as a "drug-linker." The drug-linker is linked to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) formed at an interchain disulfide bond site (two sites between heavy chains and two sites between a heavy chain and a light chain) in the antibody.

[0056] The drug linker of the present disclosure includes exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, also represented by chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)) as a component, which is a topoisomerase I inhibitor. Exatecan has the following formula: [ka] It is a camptothecin derivative having an antitumor effect represented by the formula:

[0057] Anti-HER2 antibody-drug conjugates used in this disclosure have the following formula: [ka] It can also be expressed by:

[0058] Here, the drug-linker is conjugated to the anti-HER2 antibody ("antibody-") via a thioether bond. The meaning of n is the same as the average number of drug molecules conjugated (DAR; drug-to-antibody ratio), which indicates the average number of drug-linker units conjugated per antibody molecule.

[0059] After translocation into the cancer cell, the anti-HER2 antibody-drug conjugates used in the present disclosure are cleaved at the linker moiety to form the following formula: [ka] The compound is then released.

[0060] This compound is suspected to be the source of the antitumor activity of the antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15; 22(20):5097-5108, Epub 2016 Mar 29).

[0061] The anti-HER2 antibody-drug conjugate used in the present disclosure is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). The bystander effect is exerted through the process in which the antibody-drug conjugate used in the present disclosure is internalized in cancer cells that express the target, and the compound that is then released exists in the surrounding area and exerts an anti-tumor effect even in cancer cells that do not express the target. This bystander effect is exerted as a superior anti-tumor effect even when the anti-HER2 antibody-drug conjugate is used in combination with a CDK9 inhibitor according to the present disclosure.

[0062] 2. Antibodies in antibody-drug conjugates The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be derived from any species, preferably human, rat, mouse, or rabbit. If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The anti-HER2 antibody can be a polyclonal or monoclonal antibody, preferably a monoclonal antibody.

[0063] The antibody in the antibody-drug conjugate used in the present disclosure is preferably an anti-HER2 antibody having characteristics that enable it to target cancer cells, and preferably an antibody that retains, for example, the properties of recognizing cancer cells, binding to cancer cells, being internalized in cancer cells, and / or cytocidal activity against cancer cells.

[0064] The binding activity of anti-HER2 antibodies to cancer cells can be confirmed using flow cytometry. Internalization of antibodies into cancer cells can be confirmed using (1) an assay that visualizes the antibody incorporated into cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) bound to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay that measures the light intensity incorporated into cells using a secondary antibody (fluorescently labeled) bound to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay that uses an immunotoxin bound to the therapeutic antibody, which releases the toxin upon cellular incorporation and inhibits cell growth (BioTechniques 28:162-165, January 2000). A recombinant complex protein of diphtheria toxin catalytic domain and protein G can be used as the immunotoxin.

[0065] The anti-tumor activity of an anti-HER2 antibody can be confirmed in vitro by determining its inhibitory activity against cell growth. For example, a cancer cell line that overexpresses HER2 as the target protein for the antibody is cultured, and the antibody is added to the culture system at various concentrations to determine its inhibitory activity against foci formation, colony formation, and spheroid growth. The anti-tumor activity can be confirmed in vivo, for example, by administering the antibody to nude mice implanted with a cancer cell line that highly expresses the target protein, and determining changes in the cancer cells.

[0066] Since the compound conjugated in the anti-HER2 antibody-drug conjugate exerts an anti-tumor effect, it is preferable, but not essential, that the anti-HER2 antibody itself should have an anti-tumor effect. For the purpose of exerting the cytotoxic activity of the anti-tumor compound specifically and selectively against cancer cells, it is important and preferable that the anti-HER2 antibody have internalizing properties in order to be transported to cancer cells.

[0067] The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by procedures known in the art. For example, the antibody of the present disclosure can be obtained using a method commonly used in the art, which includes immunizing an animal with an antigenic polypeptide and recovering and purifying the antibody produced in vivo. The source of the antigen is not limited to humans; animals can be immunized with antigens from non-human animals such as mice and rats. In this case, the cross-reactivity of the antibody binding to the obtained heterologous antigen with human antigens can be tested to screen for antibodies applicable to human diseases.

[0068] Alternatively, antibody-producing cells that produce antibodies against an antigen can be fused with myeloma cells according to methods known in the art (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; and Kennet, R. ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)) to establish hybridomas, from which monoclonal antibodies can then be obtained.

[0069] Antigens can be obtained by genetically modifying host cells to produce genes encoding antigenic proteins. Specifically, vectors capable of expressing antigen genes are prepared and transferred into host cells, allowing the genes to be expressed. The antigens thus expressed can be purified. Antibodies can also be obtained by immunizing animals with the above-mentioned genetically modified antigen-expressing cells or cell lines expressing the antigen.

[0070] The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or preferably an antibody of human origin, i.e., an antibody having only the gene sequence of a human antibody. These antibodies can be produced using known methods.

[0071] A typical example of a chimeric antibody is an antibody whose variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse or rat antibody variable region is linked to a human-derived antibody constant region (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0072] Typical examples of humanized antibodies include antibodies obtained by incorporating only the complementarity-determining regions (CDRs) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies obtained by grafting the framework of a heterologous antibody and some of the amino acid residues of the CDR sequences of the heterologous antibody into a human antibody by CDR grafting (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0073] Typical examples of human antibodies include antibodies produced by using human antibody-producing mice carrying human chromosomal fragments containing the heavy and light chain genes of human antibodies (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727). Alternatively, antibodies obtained by phage display or antibodies selected from human antibody libraries (see Wormstone, I. et. al., Investigative Ophthalmology & Visual Science. (2002) 43(7), pp. 2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), pp. 189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), pp. 427-431, etc.) are typical examples.

[0074] The present disclosure also encompasses modified variants of the anti-HER2 antibodies in the antibody-drug conjugates used herein. Modified variants refer to variants obtained by chemically or biologically modifying an antibody according to the present disclosure. Examples of chemically modified variants include variants containing a chemical moiety linked to the amino acid backbone, variants containing a chemical moiety linked to an N-linked or O-linked carbohydrate chain, etc. Examples of biologically modified variants include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, aspartic acid isomerization, or methionine oxidation), and variants in which a methionine residue has been added to the N-terminus upon expression in a prokaryotic host cell. Furthermore, antibodies labeled to enable detection or isolation of the antibody or antigen according to the present disclosure, such as enzyme-labeled antibodies, fluorescently labeled antibodies, and affinity-labeled antibodies, are also included within the meaning of modified variants. Such modified variants of antibodies according to the present disclosure are useful for improving antibody stability and blood retention, reducing their antigenicity, detecting or identifying antibodies or antigens, etc.

[0075] Furthermore, antibody-dependent cellular cytotoxicity can be enhanced by adjusting the modification (glycosylation, defucosylation, etc.) of glycans linked to the antibodies of the present disclosure. Techniques for adjusting antibody glycan modification are known, including those disclosed in International Publication Nos. 99 / 54342, 00 / 61739, 02 / 31140, 2007 / 133855, and 2013 / 120066. However, the techniques are not limited thereto. Anti-HER2 antibodies of the present disclosure also include antibodies in which glycan modification is adjusted.

[0076] It is known that antibodies produced in cultured mammalian cells have a deletion of the lysine residue at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705:129-134 (1995)). It is also known that antibodies produced in cultured mammalian cells have a deletion of two amino acid residues (glycine and lysine) at the carboxyl terminus of their heavy chains, and that the newly added proline residue at the carboxyl terminus is amidated (Analytical Biochemistry, 360:75-83 (2007)). However, such deletions and modifications of the heavy chain sequence do not affect the antigen-binding affinity and effector functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the anti-HER2 antibodies disclosed herein also include antibodies and functional fragments of antibodies that have undergone such modifications, including deletion mutants in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain and mutants obtained by amidation of deletion mutants (e.g., heavy chains in which the carboxyl-terminal proline residue is amidated). The type of deletion mutant having a deletion at the carboxyl terminus of the heavy chain of an anti-HER2 antibody according to the present disclosure is not limited to the above mutants, as long as the antigen-binding affinity and effector function are preserved. The two heavy chains constituting an antibody according to the present disclosure may be one type selected from the group consisting of a full-length heavy chain and the above-mentioned deletion mutants, or two types in combination selected therefrom. The ratio of the amounts of each deletion mutant may be affected by the type of cultured mammalian cells producing the anti-HER2 antibody according to the present disclosure and the culture conditions; however, an antibody according to the present disclosure in which one amino acid residue is deleted at the carboxyl terminus of both of its two heavy chains may be a preferred example.

[0077] Typical examples of the isotype of the anti-HER2 antibody according to the present disclosure include IgG (IgG1, IgG2, IgG3, and IgG4), with IgG1 or IgG2 being preferred.

[0078] In the present disclosure, the term "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 (human epidermal growth factor receptor type 2; ErbB-2), and preferably has internalization activity in HER2-expressing cells upon binding to HER2.

[0079] Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (WO 01 / 00245), with trastuzumab being a preferred example.

[0080] 3. Production of antibody-drug conjugates Drug-linker intermediates for use in making anti-HER2 antibody-drug conjugates according to the present disclosure have the following formula: [ka] It is expressed by:

[0081] The drug-linker intermediate has the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino [1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced by reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2019 / 044947, and the like.

[0082] The anti-HER2 antibody-drug conjugates used in the present disclosure can be prepared by reacting the drug-linker intermediates described above and an anti-HER2 antibody bearing a thiol group (also called a sulfhydryl group).

[0083] Anti-HER2 antibodies having sulfhydryl groups can be obtained by methods well known in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, an anti-HER2 antibody having sulfhydryl groups with partially or completely reduced interchain disulfides in the antibody can be obtained by reacting the antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA) using 0.3 to 3 molar equivalents per interchain disulfide in the antibody.

[0084] Furthermore, by using 2 to 20 molar equivalents of drug-linker intermediate per anti-HER2 antibody bearing a sulfhydryl group, anti-HER2 antibody-drug conjugates can be made in which 2 to 8 drug molecules are conjugated per antibody molecule.

[0085] The average number of drug molecules conjugated per anti-HER2 antibody molecule in the antibody-drug conjugate produced can be determined, for example, by a calculation method based on measurement of UV absorption for the antibody-drug conjugate and its conjugation reaction precursor at two wavelengths, 280 nm and 370 nm (UV method), or by a calculation method based on quantification through HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0086] The conjugation reaction between an anti-HER2 antibody and a drug-linker intermediate and the calculation of the average number of drug molecules conjugated per antibody molecule of the antibody-drug conjugate can be performed with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2017 / 002776, WO 2018 / 212136, etc.

[0087] In the present disclosure, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present disclosure, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0088] The anti-HER2 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence of amino acid residues 89 to 97 of SEQ ID NO: 2. and more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 2, and even more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2.

[0089] The average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0090] The anti-HER2 antibody-drug conjugate used in the present disclosure can be prepared by referring to the descriptions in WO 2015 / 115091 and the like.

[0091] In a preferred embodiment, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201).

[0092] 4. CDK9 inhibitors In the present disclosure, the term "CDK9 inhibitor" refers to a drug that inhibits cyclin-dependent kinase 9 (CDK9). In the present disclosure, a CDK9 inhibitor may selectively inhibit the kinase CDK9, or may non-selectively inhibit CDK9 and also inhibit kinases other than CDK9. The CDK9 inhibitor is not particularly limited as long as it is a drug having the characteristics described in the present disclosure, and preferred examples thereof may include those disclosed in WO 2017 / 001354.

[0093] Examples of CDK9 inhibitors that may be used in accordance with the present disclosure are selective inhibitors of CDK9 including AZD4573, BAY-1251152 and BAY-1143572, and non-selective inhibitors of CDK9 include CYC065, alvocidib, AT7519, voruciclib, roniciclib and dinaciclib.

[0094] Preferably, the CDK9 inhibitors of the present disclosure selectively inhibit CDK9.

[0095] According to a preferred embodiment of the CDK9 inhibitor used in the present disclosure, the CDK9 inhibitor has the following formula (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 is H, C 1~3 alkyl, CN or halogen; R 2 is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl; R 10 , OR 10 , S.R. 10 , S(O)R 10 , S(O)2R 10 , C(O)R 10 , C(O)OR 10 ,OC(O)R 10 ,OC(O)OR 10, NH2, NHR 10 , N(R 10 )2, NHC(O)H, NHC(O)R 10 , N.R. 10 C(O)H, NR 10 C(O)R 10 , NHS(O)2R 10 , N.R. 10 S(O)2R 10 , NHC(O)OR 10 , N.R. 10 C(O)OR 10 , NHC(O)NH2, NHC(O)NHR 10 , NHC(O)N(R 10 )2, NR 10 C(O)NH2, NR 10 C(O)NHR 10 , N.R. 10 C(O)N(R 10 )2, C(O)NH2, C(O)NHR 10 , C(O)N(R 10 )2, C(O)NHOH, C(O)NHOR 10 , C(O)NHS(O)2R 10 , C(O)NR 10 S(O)2R 10 , S(O)2NH2, S(O)2NHR 10 , S(O)2N(R 10 )2, S(O)2NHC(O)OR 10 , S(O)NR 10 C(O)OR 10 , C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; one or more ring CH groups can be optionally replaced by a corresponding number of —C(O) groups, and one or more ring sulfur or nitrogen atoms can be optionally oxidized to form an S-oxide or N-oxide; R 10 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6independently selected from the group consisting of alkyl, NH, C(O)NH, C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; two R 10 groups, together with the atom to which they are attached, can form a 3- to 6-membered cycloalkyl or heterocycloalkyl group; each of the above R 10 Alkyl, cycloalkyl and heterocycloalkyl groups include CN, OH, halogen, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 Alkyl and NHC(O)-C 1~3 may be further substituted by 1 or 2 substituents independently selected from alkyl; R 4 teeth, [ka] and In this formula, X and Y, together with the atoms to which they are attached, represent one or two atoms selected from N, O, and S in addition to the bridging nitrogen. The ring may contain heteroatoms, forming a 5- to 7-membered heterocycloalkyl ring, which may be saturated or partially saturated; one or two ring CH groups may be optionally replaced by a corresponding number of —C(O) groups, one or more ring sulfur or nitrogen atoms may be optionally oxidized to form an S-oxide or N-oxide, and the ring may contain one or two R 10 R by substituents or on the ring nitrogen 12 may be substituted by a substituent; J is N or CR 11 and; R 11 is H, C 1~3 is alkyl; R 12 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 independently selected from the group consisting of alkyl, C(O)NH, and C(O)H; each R 12Alkyl, cycloalkyl and heterocycloalkyl groups include CN, OH and halogens, C 1~3 Alkyl, NH2 and NH-C 1~3 Alkyl, NHC(O)-C 1~3 and (b) a substituted or unsubstituted alkyl group, which may be further substituted by one or two substituents independently selected from alkyl, or a pharmaceutically acceptable salt thereof.

[0096] Further embodiments of CDK9 inhibitors are compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the substituents are defined as follows: Such specific substituents may be used, where appropriate, in any of the definitions, claims, or embodiments defined herein.

[0097] A In one embodiment, A is C(R 5 )

[0098] R 5 In one embodiment, R 5 is a halogen. In another embodiment, R 5 is chloro. In another embodiment, R 5 is fluoro. In another embodiment, R 5 is cyano.

[0099] R 2 In one embodiment, R 2 is a 3- to 7-membered cycloalkyl. In another embodiment, R 2 NHCOR 10 or R 10 is a 3- to 7-membered cycloalkyl substituted with In another embodiment, R 2 NHCOR 10 is cyclohexyl substituted with In another embodiment, R 2 is R 10is cyclopropyl substituted with In another embodiment, R 2 is a 3- to 7-membered heterocycloalkyl. In another embodiment, R 2 NHCOR 10 is a 3- to 7-membered heterocycloalkyl substituted with In another embodiment, R 2 is piperidinyl. In another embodiment, R 2 is cyclobutyl. In another embodiment, R 2 is R 10 is cyclobutyl substituted with

[0100] R 4 In one embodiment, R 4 teeth, [ka] is. In another embodiment, R 4 teeth, [ka] is.

[0101] J In one embodiment, J is C(R 11 ) and R 11 is H.

[0102] X and Y In one embodiment, X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring. In another embodiment, X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring containing an additional heteroatom which is oxygen. In another embodiment, X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring containing an additional heteroatom which is nitrogen. In another embodiment, X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring in which one CH2 is replaced with two methyl groups. In another embodiment, X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring. In another embodiment, X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring in which one CH2 is replaced with two methyl groups. In another embodiment, X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring. In another embodiment, X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring in which one CH2 is replaced with two methyl groups.

[0103] In one embodiment, A is C(R 5 ) and; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0104] In another embodiment, A is C(R 5 ) and; R 5 is a halogen; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0105] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0106] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is cyclohexyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0107] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0108] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring.

[0109] In another embodiment, A is C(R 5 ) and; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0110] In another embodiment, A is C(R 5 ) and; R 5 is a halogen; R 2 is cyclohexyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0111] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is cyclohexyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0112] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0113] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0114] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a piperidinyl ring.

[0115] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y, together with the atoms to which they are attached, form a ring carbon bonded to one or two R 10 It forms a piperidinyl ring which may be substituted by substituents.

[0116] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a piperazinyl ring.

[0117] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a morpholinyl ring.

[0118] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a pyrrolidinyl in which one CH2 is replaced by two methyl groups.

[0119] In another embodiment, A is C(R 5 ) and; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0120] In one embodiment, A is C(R 5 ) and; R 5 is a halogen; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0121] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is a 3- to 7-membered cycloalkyl; R 4 teeth, [ka] and: X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0122] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is cyclohexyl; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0123] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 4 teeth, [ka] and; X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0124] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 is NHC(O)R 10 is cyclohexyl substituted with; R 10 is C 1~6 is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 is H; X and Y together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring.

[0125] In other embodiments, the CDK9 inhibitor used in the present disclosure is a compound selected from: (R)—N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; cis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide; (R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide; cis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamide)cyclohexanecarboxamide; N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide; N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamide)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide; (S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide; cis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide; cis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide; (1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide; trans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide; (1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexanecarboxamide; tert-butyl ((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate; (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamide)cyclohexanecarboxamide; (R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide; N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-3-methyloxetane-3-carboxamide; (S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide; (R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide; (1S,3R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide; (S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide; (1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 1 of (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide; (R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-hydroxypropanamido)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(cis-3-hydroxycyclobutanecarboxamide)cyclohexanecarboxamide (1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamide)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamide)cyclohexanecarboxamide; N-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide; cis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide; trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 1; trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 2; trans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 1; trans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 2; (1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 1 of (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 1; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 1; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide isomer 1; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexanecarboxamide; N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide; (1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 1 of (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; Isomer 2 of (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; (1R,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide; (1R,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide; and (1S,3S)-3-Acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide and pharmaceutically acceptable salts thereof.

[0126] In a preferred embodiment, the CDK9 inhibitor used in the present disclosure has the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0127] In a further preferred embodiment, the CDK9 inhibitor used in the present disclosure has the following formula: [ka] The compound AZD4573 is in free base form, represented by:

[0128] CDK9 inhibitors such as compounds of formula (I), including AZD4573, may be prepared by methods known in the art, such as those disclosed in WO 2017 / 001354.

[0129] 5. Combination of antibody-drug conjugates and CDK9 inhibitors In a first combination embodiment of the present disclosure, the anti-HER2 antibody-drug conjugate that is combined with the CDK9 inhibitor is one in which the drug-linker has the following formula: [ka] where A represents the linking site to the antibody and is conjugated to the anti-HER2 antibody via a thioether bond.

[0130] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above for the first combination embodiment has the following formula (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 is H, C 1~3 alkyl, CN or halogen; R 2 is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl; R 10 , OR 10 , S.R. 10 , S(O)R 10 , S(O)2R 10 , C(O)R 10 , C(O)OR 10 ,OC(O)R 10 ,OC(O)OR 10 , NH2, NHR 10 , N(R 10 )2, NHC(O)H, NHC(O)R 10 , N.R. 10 C(O)H, NR 10 C(O)R 10 , NHS(O)2R 10 , N.R. 10 S(O)2R 10 , NHC(O)OR 10 , N.R. 10 C(O)OR 10 , NHC(O)NH2, NHC(O)NHR 10 , NHC(O)N(R 10 )2, NR 10 C(O)NH2, NR 10 C(O)NHR 10 , N.R. 10 C(O)N(R 10 )2, C(O)NH2, C(O)NHR 10, C(O)N(R 10 )2, C(O)NHOH, C(O)NHOR 10 , C(O)NHS(O)2R 10 , C(O)NR 10 S(O)2R 10 , S(O)2NH2, S(O)2NHR 10 , S(O)2N(R 10 )2, S(O)2NHC(O)OR 10 , S(O)NR 10 C(O)OR 10 , C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; one or more ring CH groups can be optionally replaced by a corresponding number of —C(O) groups, and one or more ring sulfur or nitrogen atoms can be optionally oxidized to form an S-oxide or N-oxide; R 10 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 independently selected from the group consisting of alkyl, NH, C(O)NH, C(O)H, C(O)OH, OH, CN, NO, F, Cl, Br, and I; two R 10 The groups, together with the atom to which they are attached, can form a 3- to 6-membered cycloalkyl or heterocycloalkyl group; each of the above R 10 Alkyl, cycloalkyl and heterocycloalkyl groups include: CN, OH, halogens, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 Alkyl and NHC(O)-C 1~3 may be further substituted by 1 or 2 substituents independently selected from alkyl; R 4 teeth, [ka] and; In this formula, X and Y, together with the atoms to which they are attached, represent one or two atoms selected from N, O, and S in addition to the bridging nitrogen. heteroatoms, forming a 5- to 7-membered heterocycloalkyl ring, which may be saturated or partially saturated; one or two ring CH groups may be optionally replaced by a corresponding number of —C(O) groups, one or more ring sulfur or nitrogen atoms may be optionally oxidized to form S-oxides or N-oxides, and the ring may contain one or two R 10 R by substituents or on the ring nitrogen 12 may be substituted by a substituent; J is N or CR 11 and; R 11 is H, C 1~3 is alkyl; R 12 represents, in each occurrence, a 3- to 6-membered cycloalkyl or heterocycloalkyl group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 independently selected from the group consisting of alkyl, C(O)NH, and C(O)H; each R 12 Alkyl, cycloalkyl and heterocycloalkyl groups include CN, OH and halogens, C 1~3 Alkyl, NH2 and NH-C 1~3 Alkyl, NHC(O)-C 1~3 and (b) a substituted or unsubstituted alkyl group, which may be further substituted with 1 or 2 substituents independently selected from alkyl, or a pharmaceutically acceptable salt thereof.

[0131] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is a compound of formula (I) where A is C(R 5 ) in combination with a CDK9 inhibitor which is a compound represented by formula (I) as defined above.

[0132] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is a compound of formula (I) where A is C(R 5 ) and R5 is in combination with a CDK9 inhibitor as defined above, wherein

[0133] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is a compound of formula (I) where A is C(R 5 ) and R 5 is in combination with a CDK9 inhibitor as defined above, wherein

[0134] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 is in combination with a CDK9 inhibitor as defined above, wherein is 3-7 membered cycloalkyl.

[0135] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 However, NHCOR 10 or R 10 in combination with a CDK9 inhibitor as defined above, wherein the 3- to 7-membered cycloalkyl substituted with

[0136] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 is combined with a CDK9 inhibitor as defined above selected from the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0137] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 is combined with a CDK9 inhibitor as defined above, wherein is selected from cyclopentyl and cyclohexyl.

[0138] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 NHCOR 10is in combination with a CDK9 inhibitor as defined above, wherein the compound is cyclohexyl substituted with

[0139] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 is in combination with a CDK9 inhibitor as defined above, wherein is a 3- to 7-membered heterocycloalkyl.

[0140] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is represented by the formula (I) 2 NHCOR 10 is in combination with a CDK9 inhibitor as defined above, which is a 3-7 membered heterocycloalkyl substituted with

[0141] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above has the formula (I) where R4 is [ka] in combination with a CDK9 inhibitor as defined above, wherein

[0142] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is [ka] and J is C(R 11 ) in combination with a CDK9 inhibitor as defined above.

[0143] In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is [ka] and J is C(R 11 ) and R 11is in combination with a CDK9 inhibitor as defined above, wherein

[0144] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined above is combined with a CDK9 inhibitor as defined above in formula (I), wherein X and Y, together with the atoms to which they are attached, form a 5-membered heterocyclylalkyl ring.

[0145] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined in Formula (I) wherein X and Y, together with the atoms to which they are attached, form a 5-membered heterocycloalkyl ring in which one CH2 is substituted with two methyl groups.

[0146] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined above may be combined with a CDK9 inhibitor as defined above, wherein the CDK9 inhibitor has the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0147] In each of the above combination embodiments, the anti-HER2 antibody comprises a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, a CDRL2 consisting of amino acid residues 1 to 3 of SEQ ID NO: 7, and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8. In another embodiment of each of the above combination embodiments, the anti-HER2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10. In another embodiment of each of the above combination embodiments, the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2. In another embodiment of each of the above combination embodiments, the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0148] In a particularly preferred combination embodiment of the present disclosure, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the CDK9 inhibitor is a compound of the following formula: [ka] and is also identified as AZD4573.

[0149] 6. Combined Uses and Methods of Treatment Pharmaceutical products and therapeutic uses and methods are described below in which an anti-HER2 antibody-drug conjugate according to the present disclosure and a CDK9 inhibitor are administered in combination.

[0150] The pharmaceutical products and therapeutic uses and methods of the disclosure may be characterized in that the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor are contained as active ingredients separately in different formulations and administered simultaneously or at different times, or in that the antibody-drug conjugate and the CDK9 inhibitor are contained as active ingredients in a single formulation and administered.

[0151] In the pharmaceutical products and methods of treatment of the present disclosure, a single CDK9 inhibitor used in the present disclosure may be administered in combination with an anti-HER2 antibody-drug conjugate, or two or more different CDK9 inhibitors may be administered in combination with an antibody-drug conjugate.

[0152] The pharmaceutical products and therapeutic methods of the present disclosure may be used to treat cancer, including breast cancer (including triple-negative breast cancer and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colon and rectal cancer, including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, The present invention can be preferably used to treat at least one cancer selected from the group consisting of myeloma, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter's syndrome, B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, and follicular lymphoma, and more preferably used to treat at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer (preferably non-small cell lung cancer), pancreatic cancer, ovarian cancer, prostate cancer, and kidney cancer.

[0153] For example, the presence or absence of the HER2 tumor marker can be determined by collecting tumor tissue from a cancer patient and preparing a formalin-fixed, paraffin-embedded (FFPE) specimen, and subjecting the specimen to testing for the gene product (protein) using, for example, immunohistochemistry (IHC), flow cytometry, or Western blotting, or for gene transcription by, for example, in-situ hybridization (ISH), quantitative PCR (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to testing by methods such as next-generation sequencing (NGS).

[0154] The pharmaceutical products and treatments of the present disclosure may be used for HER2-expressing cancers, which may be HER2-overexpressing cancers (high or moderate) or HER2-low expressing cancers.

[0155] In the present disclosure, the term "HER2-overexpressing cancer" is not particularly limited, as long as it is recognized as a HER2-overexpressing cancer by those skilled in the art. Preferred examples of HER2-overexpressing cancers may include cancers that are assigned a score of 3+ for HER2 expression in IHC and cancers that are assigned a score of 2+ for HER2 expression in IHC and are determined to be positive for HER2 expression in in situ hybridization (ISH). In situ hybridization methods of the present disclosure include fluorescent in situ hybridization (FISH) and dual color in situ hybridization (DISH).

[0156] In the present disclosure, the term "HER2-low-expressing cancer" is not particularly limited, as long as it is recognized as a HER2-low-expressing cancer by those skilled in the art. Preferred examples of HER2-low-expressing cancers may include cancers that are assigned a score of 2+ for HER2 expression by the IHC method and are determined to be negative for HER2 expression by in situ hybridization, and cancers that are assigned a score of 1+ for HER2 expression by the IHC method.

[0157] The method for scoring the HER2 expression level by the IHC method or the method for determining whether HER2 expression is positive or negative by the in situ hybridization method is not particularly limited, as long as it is recognized by those skilled in the art. Examples of the method may include the method described in the 4th edition of the HER2 Testing Guidelines for Breast Cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).

[0158] The cancer may be a HER2 overexpressing (high or moderate) or low expressing breast cancer or triple negative breast cancer, particularly with respect to the treatment of breast cancer, and / or may have a HER2 status score of IHC3+, IHC2+, IHC1+ or IHC>0 and <1+.

[0159] The pharmaceutical products and treatments of the present disclosure may be used preferably in mammals, and more preferably in humans.

[0160] The anti-tumor effects of the pharmaceutical products and treatment methods of the present disclosure can be confirmed by transplanting cancer cells into test animals to prepare a model and measuring the reduction in tumor volume or survival effect of the pharmaceutical products and treatment methods of the present disclosure. The effect of the combined use of the antibody-drug conjugate and CDK9 inhibitor used in the present disclosure can then be confirmed by comparing the anti-tumor effects of the antibody-drug conjugate and CDK9 inhibitor used in the present disclosure with those of the antibody-drug conjugate and CDK9 inhibitor administered alone.

[0161] The antitumor effects of the pharmaceutical products and treatment methods disclosed herein may be confirmed in clinical trials using any of the Response Evaluation Criteria in Solid Tumors (RECIST), WHO evaluation, Macdonald evaluation, body weight measurement, and other approaches, and may be determined based on indicators such as complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0162] By using the above method, the superiority of the anti-tumor effects of the pharmaceutical products and therapeutic methods of the present disclosure over existing pharmaceutical products and therapeutic methods for cancer treatment can be confirmed.

[0163] The pharmaceutical products and treatment methods disclosed herein can delay the development of cancer cells, inhibit their growth, and even kill cancer cells. These effects can eliminate symptoms caused by cancer in cancer patients, or improve the quality of life (QOL) of cancer patients, and achieve therapeutic effects by preserving the lives of cancer patients. Even if the pharmaceutical products and treatment methods disclosed herein do not completely kill cancer cells, they can inhibit or regulate the growth of cancer cells, thereby achieving longer survival and higher QOL for cancer patients.

[0164] The pharmaceutical products of the present disclosure may be expected to exert therapeutic effects by application as a systemic therapy to patients and also by local application to cancerous tissue.

[0165] The pharmaceutical product of the present disclosure may be administered containing at least one pharmaceutically suitable ingredient. The pharmaceutically suitable ingredient may be suitably selected and applied from formulation additives commonly used in the art according to the dosage, administration concentration, etc. of the antibody-drug conjugate and CDK9 inhibitor used in the present disclosure. The anti-HER2 antibody-drug conjugate used in the present disclosure may be administered as a pharmaceutical product containing, for example, a histidine buffer, a vehicle such as sucrose and trehalose, and a surfactant such as polysorbate 80 and 20. The pharmaceutical product containing the antibody-drug conjugate used in the present disclosure may be preferably administered as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[0166] When the pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in the present disclosure is an aqueous injection, the aqueous injection is preferably diluted with a suitable diluent and then administered as an intravenous infusion. Examples of diluents include dextrose solution, preferably saline, dextrose solution, and more preferably 5% dextrose solution.

[0167] When the pharmaceutical product of the present disclosure is a freeze-dried injection, the required amount of the freeze-dried injection, which is pre-dissolved in water for injection, is preferably diluted with a suitable diluent and then administered as an intravenous infusion. Examples of diluents include dextrose solution and saline, preferably dextrose solution, more preferably 5% dextrose solution.

[0168] Examples of administration routes applicable for administering the pharmaceutical products of the present disclosure may include intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes, with the intravenous route being preferred.

[0169] The anti-HER2 antibody-drug conjugates used in the present disclosure may be administered to humans at intervals of 1 to 180 days, preferably at 1-week, 2-week, 3-week, or 4-week intervals, and more preferably at 3-week intervals. The anti-HER2 antibody-drug conjugates used in the present disclosure may be administered at a dose of approximately 0.001 to 100 mg / kg per administration, preferably at a dose of 0.8 to 12.4 mg / kg per administration. For example, the anti-HER2 antibody-drug conjugates may be administered once every three weeks at a dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, preferably at a dose of 5.4 mg / kg or 6.4 mg / kg.

[0170] The CDK9 inhibitors used in the present disclosure may be administered to humans as an intravenous infusion at intervals of 1 to 180 days, preferably at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks. The CDK9 inhibitors used in the present disclosure may be administered as an intravenous infusion at a dose of 0.1 mg to 3000 mg per administration, preferably at a dose of 10 mg to 100 mg per administration or 1 mg to 20 mg per administration.

[0171] The size of the dose required for therapeutic treatment of a particular condition will necessarily vary depending on the subject being treated, the route of administration, and the severity of the disease being treated. Weekly doses of the CDK9 inhibitor ranging from 0.1 to 50 mg / kg may be used. For example, when the CDK9 inhibitor used in the present disclosure is the compound AZD4573 or a pharmaceutically acceptable salt thereof, the CDK9 inhibitor may be administered intravenously, preferably once weekly, at a dose of 1 mg to 50 mg per dose, e.g., 3 mg, 6 mg, 9 mg, 12 mg, 15 mg, or 18 mg per dose.

[0172] The pharmaceutical products and treatment methods of the present disclosure can be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical products of the present disclosure can be administered before surgery to reduce tumor size (called neoadjuvant chemotherapy or neoadjuvant therapy), or can be administered after surgery to prevent tumor recurrence (called adjuvant chemotherapy or adjuvant therapy). [Example]

[0173] The present disclosure will be specifically described in view of the following examples, but the present disclosure is not limited thereto, and should not be construed as limiting in any way.

[0174] Example 1: Preparation of antibody-drug conjugates According to the production method described in WO 2015 / 115091, and using an anti-HER2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 (amino acid residues 1 to 449 of SEQ ID NO: 1) and a light chain consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2), a compound represented by the following formula: [ka] (wherein A represents the linking position to the antibody) We prepared an anti-HER2 antibody-drug conjugate (DS-8201: trastuzumab deruxtecan) in which the drug-linker represented by the formula (I) was conjugated to the anti-HER2 antibody via a thioether bond. The DAR of the antibody-drug conjugate was 7.7 or 7.8.

[0175] Example 2: Preparation of CDK9 inhibitors The CDK9 inhibitor of formula (I) is prepared according to the method described in WO 2017 / 001354, specifically, (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide; [ka] can be prepared according to Example 14 of WO 2017 / 001354.

[0176] Example 3: Antitumor test Combination of the antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) with the CDK9 inhibitor AZD4573 ((1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide) method: Four HER2 cell lines—three breast cancers (SKBR3, MDA-MB-468, and KPL4) and one gastric cancer (NCI-N87) as shown in Table 1—were treated with either vehicle (DMSO) or three log-fold increasing concentrations of DS-8201 (3, 30, and 300 ng / mL) for 66 hours, at which point either vehicle or 10-point, half-log serial dilutions of AZD4573 were added for an additional 6 hours.

[0177] [Table 1]

[0178] After 6 hours of incubation with AZD4573, both drugs were washed out by removing the medium and adding fresh phosphate-buffered saline (PBS) twice, removing it, and replacing the final wash with fresh medium. Cells were then incubated for an additional 18 hours before assessing cell viability using CellTiter-Glo reagent. GraphPad Prism was used to generate dose-response curves, as shown in Figure 12.

[0179] Preclinical breast and gastric cancer cell lines exhibit differential activity to DS-8201 across a range of doses, but complete loss of viability is not observed even in the most sensitive of the four cell lines selected for this screen.

[0180] In two of the four cell lines tested (Figure 12: top row), a 6-hour treatment with AZD4573 followed by a 66-hour lead-in period of DS-8201 resulted in a dose-dependent enhanced loss of cell viability, thus demonstrating a benefit of the combination.

[0181] Thus, the combination of DS-8201 with acute CDK9 inhibition using AZD4573 revealed enhanced loss of viability in preclinical HER2 cancer cell lines.

[0182] Example 4: Antitumor test Combination of the antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) with the CDK9 inhibitor AZD4573 ((1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide) method: To evaluate the combined effect of AZD4573 (a CDK9 inhibitor) and DS-8201, 69 CB17-SCID mice were subcutaneously implanted with HCC1954 breast cancer cells (a HER2+ cell line). Tumor volume was monitored via caliper measurement, and mice were randomized based on average tumor size. At randomization, DS-8201 treatment was administered intravenously. AZD4573 was given 24 hours after DS-8201 treatment. All AZD4573 doses were administered IP, 2 hours apart. A BID regimen was used for the 10 mg / kg dose, and TID for the 5 mg / kg dose. AZD4573 administration was administered weekly thereafter for a total of three cycles. Thus, as indicated by the vertical dotted lines in Figure 13, DS-8201 was administered via IV on day 0, and AZD4573 treatment occurred on days 1, 8, and 15.

[0183] result: Tumor volumes in response to treatment with DS-8201 and / or AZD4573 are shown in Figure 13. Data represent the change in tumor volume over time for treatment groups. Tumor growth inhibition (TGI) was calculated for tumor measurements relative to vehicle controls as shown in Table 2.

[0184] [Table 2]

[0185] Tumor kinetic growth curves (Figure 13) and TGI analysis (Table 2) show that AZD4573 exhibits minimal tumor growth control as monotherapy in the HCC1954 model.

[0186] Treatment with DS-8201 at 3 mg / kg alone resulted in 91.867% TGI and at 10 mg / kg resulted in 96.441% TGI. The most robust response was observed in the DS-8201 10 mg / kg treatment groups combined with AZD4573 10 mg / kg and 5 mg / kg (99.829% TGI and 99.776% TGI, respectively), with maximal activity observed with 10 mg / kg DS-8201 plus 10 mg / kg BID AZD4573 (99.829% TGI).

[0187] The foregoing specification documents are believed to be sufficient to enable one skilled in the art to practice the embodiments. The above description and examples detail certain particular embodiments and set forth the best mode contemplated by the inventors. However, no matter how detailed the above appears in text, it should be understood that the embodiments may be practiced in many ways, and that the claims include any equivalents thereof.

[0188] Free text in sequence listing SEQ ID NO: 1 - Amino acid sequence of the heavy chain of the anti-HER2 antibody SEQ ID NO: 2 - Amino acid sequence of the light chain of the anti-HER2 antibody SEQ ID NO:3—amino acid sequence of heavy chain CDRH1 [=amino acid residues 26-33 of SEQ ID NO:1] SEQ ID NO: 4—amino acid sequence of heavy chain CDRH2 [=amino acid residues 51-58 of SEQ ID NO: 1] SEQ ID NO:5—amino acid sequence of heavy chain CDRH3 [=amino acid residues 97-109 of SEQ ID NO:1] SEQ ID NO:6 - Amino acid sequence of light chain CDRL1 [= amino acid residues 27-32 of SEQ ID NO:2] SEQ ID NO:7 - Amino acid sequence containing the amino acid sequence (SAS) of light chain CDRL2 [= amino acid residues 50 to 56 of SEQ ID NO:2] SEQ ID NO:8 - Amino acid sequence of light chain CDRL3 [= amino acid residues 89-97 of SEQ ID NO:2] SEQ ID NO:9 - Amino acid sequence of heavy chain variable region [= amino acid residues 1-120 of SEQ ID NO:1] SEQ ID NO: 10 - Amino acid sequence of light chain variable region [= amino acid residues 1-107 of SEQ ID NO: 2] SEQ ID NO:11 - Amino acid sequence of heavy chain [= amino acid residues 1-449 of SEQ ID NO:1]

Claims

1. 1. A pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for use in the treatment of breast cancer by administration in combination, wherein said anti-HER2 antibody-drug conjugate has the following formula: 【Chemistry 1】 wherein A represents a linking position to the antibody, is conjugated to an anti-HER2 antibody via a thioether bond; The CDK9 inhibitor has the following formula: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof; A pharmaceutical product, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:

8.

2. 2. The pharmaceutical product of claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO:

10.

3. The pharmaceutical product of claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

2.

4. The pharmaceutical product of claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

2.

5. 5. The pharmaceutical product of any one of claims 1 to 4, wherein the anti-HER2 antibody-drug conjugate has the following formula: 【Transformation 3】 is represented by wherein "antibody" refers to an anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n refers to the average number of drug-linker units conjugated per antibody molecule in the antibody-drug conjugate, and n is in the range of 7 to 8.

6. The pharmaceutical product of any one of claims 1 to 5, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

7. The pharmaceutical product of any one of claims 1 to 6, which is a composition comprising the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor for simultaneous administration.

8. The pharmaceutical product of any one of claims 1 to 6, which is a combined preparation comprising the anti-HER2 antibody-drug conjugate and the CDK9 inhibitor for sequential or simultaneous administration.

9. The pharmaceutical product of any one of claims 1 to 8, wherein the breast cancer has a HER2 status score of IHC3+.

10. The pharmaceutical product according to any one of claims 1 to 8, wherein the breast cancer is HER2 low-expressing breast cancer.

11. The pharmaceutical product of any one of claims 1 to 8, wherein the breast cancer has a HER2 status score of IHC2+.

12. The pharmaceutical product of any one of claims 1 to 8, wherein the breast cancer has a HER2 status score of IHC1+.

13. The pharmaceutical product of any one of claims 1 to 8, wherein the breast cancer has an IHC>0 and a HER2 status score<1+.

14. The pharmaceutical product according to any one of claims 1 to 8, wherein the breast cancer is triple-negative breast cancer.

Images