Antibody-drug conjugates and CDK9 inhibitor combinations

Abstract

We provide pharmaceutical products for the administration of anti-HER2 antibody-drug conjugates combined with CDK9 inhibitors. [Solution] A pharmaceutical product containing the following anti-HER2 antibody-drug complex is provided. JPEG2026048890000059.jpg74170 (In the formula, A represents the binding site to the antibody.)

Description

[Technical Field]

[0001] This disclosure relates to the combination of a CDK9 inhibitor and an anti-HER2 antibody via a linker structure. Pharmaceutical products and special for the administration of specific antibody-drug complexes having combined antitumor drugs A therapeutic use in which heterogeneous antigen-drug complexes and CDK9 inhibitors are administered in combination to the target. Regarding use and method. [Background technology]

[0002] Cyclin-dependent protein kinases (CDKs) bind to cyclin regulatory partners. This corresponds to a family of serine / threonine protein kinases that become active. The CDK / cyclin complex was identified as a regulator of cell cycle progression. The ichrin complex is also involved in transcription and mRNA processing. CDK9 / PTE Fb (positive transcription elongation factor b) is a large subunit of RNA polymerase II (RNAPII). The carboxyl terminal domain (CTD) of the nitrate, mainly Ser-2, is phosphorylated, and the extension of the transcription is enhanced. Adjusts the length. CDK9 inhibition and transcriptional repression result in the lifetime of Mcl1 and c-myc. This leads to the rapid depletion of short mRNA transcripts and related proteins, and their survival proteins This leads to the induction of apoptosis in tumor cells that is overly dependent on quality. Therefore, CDK9 is involved. Targeted transcription CDKs are used in hematological malignancies, such as acute myeloid leukemia and acute lymphoblastic leukemia. High-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-Hodgkin's disease Lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic lymphoma Pachycytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma And solid tumors, such as breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, and esophagogastric junction cancer. Cancer, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer Bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatic cell carcinoma Cellular carcinoma, endometrial carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, phenotype Cell tumors, myelomas, glioblastomas multiforme, osteosarcomas, sarcomas, melanomas, neuroblastomas, and colon cancers Tumors that are heavily dependent on these unstable pro-survival proteins, including but not limited to them. This corresponds to a treatment strategy for treating the disease. CDK9 inhibitors are used for heart disease and viral infections. It may also have therapeutic utility in other disease indications, including diseases, inflammation, and pain. CDK9 inhibitor The harmful agents are disclosed, for example, in the brochure International Publication No. 2017 / 001354.

[0003] Antibody-drug conjugates (ADCs), which consist of a cytotoxic drug combined with an antibody, are effective against cancer cells. It can selectively deliver the drug to cancer cells, thus causing drug accumulation within cancer cells and killing the cancer cells. It is expected that this will occur (Ducry, L., et al., Bioconjugate Chem.(2010)21,5-13;Alley,SC,et al.,Cur rent Opinion in Chemical Biology(2010)14 ,529-537;DamleN.K.Expert Opin.Biol.Ther. (2004)4,1445-1452;Senter PD,et al.,Nat ure 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, and this It consists of an antibody that targets HER2 and a derivative of exatecan (Ogitan i Y. et al.,Clinical Cancer Research(2016 )22(20),5097-5108;Ogitani Y.et al.,Cance r Science (2016) 107, 1039-1046).

[0005] Despite the therapeutic potential of antibody-drug conjugates and CDK9 inhibitors, antibody-drug conjugates and test results that demonstrate the outstanding efficacy of the combination use of CDK9 inhibitors or No literature has been published that describes any scientific basis suggesting the results of the eel test. In the absence of test results, antibody-drug conjugates together with other cancer treatments such as CDK9 inhibitors Combining these therapies may lead to negative interactions and / or inferior therapeutic outcomes. The possibility exists, and therefore, the outstanding or superior results obtained by such combination treatments. The effect was unpredictable.

[0006] Therefore, to enhance the effectiveness of existing cancer treatments, extend the duration of the therapeutic response, and / or Improvements to therapeutic compositions and methods that can reduce dose-dependent toxicity are still needed. Yes, they are. [Overview of the project] [Means for solving the problem]

[0007] Antibody-drug complex used in this disclosure (inducing the topoisomerase I inhibitor exatecan) Anti-HER2 antibody-drug complexes (including those containing the body) are effective against certain cancers when administered alone, for example. It has been confirmed to exhibit outstanding antitumor effects in the treatment of breast cancer and gastric cancer. Furthermore, CDK9 inhibitors have been shown to exhibit antitumor effects in the treatment of certain cancers. However, enhanced efficacy, prolonged duration of therapeutic response, and / or dose-dependent reduction of toxicity. To provide drugs and treatments that can achieve excellent antitumor effects in cancer treatment, such as those mentioned above. This is desirable.

[0008] This disclosure relates to the administration of anti-HER2 antibody-drug conjugates combined with CDK9 inhibitors. This disclosure provides a pharmaceutical product that can demonstrate outstanding antitumor effects in the treatment of cancer. Therapeutic use of ER2 antibody-drug conjugates and CDK9 inhibitors administered in combination to the target. We also provide usage instructions and methods.

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

[61] : [1] Includes anti-HER2 antibody-drug conjugates and CDK9 inhibitors for combined administration. A pharmaceutical product in which an anti-HER2 antibody-drug complex is represented by the following formula: drug-linker -: [ka] (In the formula, A represents the linkage site to the antibody) is linked to the anti-HER2 antibody via thioether binding. A pharmaceutical product that is a compound antibody-drug complex; [2][1] The pharmaceutical product described above, wherein the CDK9 inhibitor is of the following formula (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 H, C 1~3is alkyl, CN or halogen; R 2 is 3- to 7-membered heterocycloalkyl or 3- to 7-membered cycloalkyl; R 10 、 OR 10 、SR 10 、S(O)R 10 、S(O)2R 10 、C(O)R 10 、C(O)O R 10 、OC(O)R 10 、OC(O)OR 10 、NH2、NHR 10 、N(R 10 )2 、NHC(O)H、NHC(O)R 10 、NR 10 C(O)H、NR 10 C(O)R 10 、NHS(O)2R 10 、NR 10 S(O)2R 10 、NHC(O)OR 10 s、NR 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 、NR 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)2NR 10 C(O)OR 10 , C(O) Independently from the group consisting of H, C(O)OH, OH, CN, NO2, F, Cl, Br, and I Optionally substituted with 1 to 3 selected substituents; one or more ring CH2 groups, It can be optionally replaced by a corresponding number of -C(O) groups, and one or more ring sulfur or nitrogen atoms. Atoms can be selectively oxidized to form S-oxides or N-oxides; R 10 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 a Lucil, NH2, C(O)NH2, C(O)H, C(O)OH, OH, CN, NO2, F Independently selected from the group consisting of Cl, Br, and I; two R 10 The base is that they are connected Together with the atoms involved, they form a 3-6 membered cycloalkyl or heterocycloalkyl group. can; each of the above R 10 Alkyl, cycloalkyl, and heterocycloalkyl groups are CN, O H, halogen, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 a Lukil and NHC(O)-C 1~3 One or two substituents independently selected from alkyl groups It may be further replaced by; R 4 teeth, [ka] And, In this formula, X and Y, together with the atoms to which they are linked, in addition to bridging nitrogen, N, One or two selected from O and S 5-7 member heterocycloads that may contain heteroatoms It forms a lukyl ring; the ring may be saturated or partially saturated; one or two ring CH2 groups, It can be optionally substituted with a corresponding number of -C(O) groups, and one or more ring sulfur or nitrogen atoms The child can be selectively oxidized to form an S-oxide or an N-oxide, and the ring is a ring carbon. One or two R's above 10 By substituents, or on the cyclic nitrogen, R 12 Substituted by substituents Gain, J is N or CR 11 and; R 11 H, C 1~3 It is alkyl; R 12 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 Alkyl, C(O)NH2, Independently selected from the group consisting of C(O)H; each R 12 Alkyl, cycloalkyl and he Terocycloalkyl groups include CN, OH, and halogens, C 1~3 Alkyl, NH2 and NH -C 1~3 Alkyl, NHC(O)-C 1~3 1 or 2 independently selected from alkyl (May be further substituted by a plurality of substituents) A pharmaceutical product which is a compound represented by or a pharmaceutically acceptable salt thereof; [3] In equation (I), A is C(R 5 ) the pharmaceutical products described in [2]; [4]R 5 The pharmaceutical product described in [3] is chloro; [5]R 5 The pharmaceutical product described in [3] is fluoro; [6] In equation (I), R2 The pharmaceutical product described in [2], wherein the member is a 3- to 7-membered cycloalkyl group. ; [7] In equation (I), R 2 NHCOR 10 or R 10 It is a 3- to 7-membered cycloalkyl group. The pharmaceutical products listed in [2]; [8]R 2 However, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopropyl A pharmaceutical product selected from the group of chlorheptils, as described in [6]; [9]R 2 However, the pharmaceutically acceptable drug described in [8] is selected from cyclopentyl and cyclohexyl. product;

[10] R 2 However, NHCOR 10 The cyclohexyl substituted with the drug described in [7] Pharmaceutical products;

[11] In equation (I), R 2 The is a 3- to 7-membered heterocycloalkyl group, as described in [2]. Pharmaceutical products;

[12] In equation (I), R 2 However, NHCOR 10 3-7 member heterocyclo The pharmaceutical product described in [2] is alkyl;

[13] In equation (I), R4 is [ka] The pharmaceutical products described in [2];

[14] J is C(R 11 ) the pharmaceutical products described in

[13] ;

[15] R 11 The pharmaceutical product described in

[14] , wherein H is;

[16] In formula (I), X and Y, together with the atom to which they are linked, form a 5-membered atom. A pharmaceutical product according to [2] that forms a heterocycloalkyl ring;

[17] In formula (I), X and Y together with the atom to which they are linked form one atom The CH2 of the compound forms a five-membered heterocycloalkyl ring substituted with two methyl groups, [2] The pharmaceutical products listed below;

[18] CDK9 inhibitors are expressed by the following formula: [ka] AZD4573 represented by [2] or a pharmaceutically acceptable salt thereof, as described in [2] Pharmaceutical products;

[19] Anti-HER2 is represented by the amino acid sequence of SEQ ID NO: 3 [= amino acid sequence of SEQ ID NO: 1] The amino acid sequence represented by CDRH1, SEQ ID NO: 4, consists of acid residues 26-33. Represented by CDRH2, consisting of amino acid residues 51-58 of sequence number 1, and sequence number 5. A heavy CDRH3 containing the amino acid sequence [= amino acid residues 97-109 of SEQ ID NO: 1] The chain and the amino acid sequence represented by Sequence ID No. 6 [= amino acid residues 27-32 of Sequence ID No. 2] CDRL1 consists of ], and the amino acid sequence consisting of amino acid residues 1-3 of sequence number 7 [=sequence] CDRL2, consisting of amino acid residues 50-52 of number 2, and represented by Sequence ID No. 8 A light chain containing CDRL3 consisting of a amino acid sequence [=amino acid residues 89-97 of SEQ ID NO: 2] A pharmaceutical product described in any one of [1] to

[18] , which is an antibody containing ,;

[20] Anti-HER2 antibody, the amino acid sequence represented by SEQ ID NO: 9 [=SEQ ID NO: 1 A heavy chain containing a heavy chain variable region consisting of [mino acid residues 1-120], and represented by SEQ ID NO: 10 It includes a light chain variable region consisting of the amino acid sequence [=amino acid residues 1-107 of SEQ ID NO: 2]. A pharmaceutical product described in any one of [1] to

[18] , which is an antibody containing a light chain;

[21] Anti-HER2 antibody consists of a heavy chain made up of the amino acid sequence represented by Sequence ID No. 1, and A pharmaceutical product according to any one of [1] to

[0018] , comprising a light chain consisting of the amino acid sequence represented by column number 2, and an antibody;

[22] Anti-HER2 antibody, the amino acid sequence represented by SEQ ID NO: 11 [=SEQ ID NO: 1 A heavy chain consisting of amino acid residues 1-449 and the amino acid sequence represented by Sequence ID No. 2 A pharmaceutical product described in any one of [1] to

[18] , which is an antibody containing a light chain;

[23] The anti-HER2 antibody-drug conjugate has the following formula: [ka] (In the formula, "antibody" is an anti-HER complex that is conjugated to the drug-linker via a thioether bond.) 2 refers to antibodies, where n is the number of drug-linkers that are complexed per antibody molecule in the antibody-drug complex. This represents the average number of units, where n is in the range of 7 to 8, as expressed by [1] to

[22] . A pharmaceutical product listed in any one of the following;

[24] Anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (DS-820) 1) A pharmaceutical product listed in any one of [1] to

[23] ;

[25] Compositions for co-administration including an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor A physical product, a pharmaceutical product listed in any one of [1] to

[24] ;

[26] Anti-HER2 antibody-drug complexes and CDK9 inhibitors for continuous or simultaneous administration A combination preparation containing the agent, as described in any one of [1] to

[24] . Product;

[27] A pharmaceutical product described in any one of [1] to

[26] , which is for the treatment of cancer;

[28] Cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, bile duct cancer Urothelial cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, Gastrointestinal stromal tumors, digestive tract stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, Endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, Myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblast Myelodysplastic syndrome, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B cell Non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma , chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma and leukemia At least one selected from the group consisting of cystic lymphomas, as described in

[27] . Product;

[29] The drug product described in

[27] , wherein the cancer is breast cancer;

[30] Breast cancer with an IHC3+ HER2 status score, as described in

[29] Pharmaceutical products;

[31] Breast cancer is HER2-low expressing breast cancer, as described in

[29] ;

[32] Breast cancer with an IHC2+ HER2 status score, as described in

[29] Pharmaceutical products;

[33] Breast cancer with an IHC1+ HER2 status score, as described in

[29] Pharmaceutical products;

[34] Breast cancer patients with IHC > 0 and < 1+ HER2 status scores,

[29] The pharmaceutical products listed below;

[35] The drug product described in

[29] , in which breast cancer is triple-negative breast cancer;

[36] The drug product described in

[27] , wherein the cancer is gastric cancer;

[37] The pharmaceutical product described in

[27] , wherein the cancer is colon cancer;

[38] The drug product described in

[27] , wherein the cancer is lung cancer;

[39] The pharmaceutical product described in

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

[40] The drug product described in

[27] , wherein the cancer is pancreatic cancer;

[41] The drug product described in

[27] , wherein the cancer is ovarian cancer;

[42] The pharmaceutical product described in

[27] , wherein the cancer is prostate cancer;

[43] The drug product described in

[27] , wherein the cancer is kidney cancer;

[44] For use in the treatment of cancer, as specified in one of [1] to

[26] . Unagi pharmaceutical products;

[45] Cancer is defined by any one of

[28] to

[43] ,

[44] Pharmaceutical products for the use described;

[46] A combination of anti-HER2 antibody-drug conjugates and CDK9 inhibitors for treating cancer. Anti-HER2 antibody-drug complexes or CDK9 inhibitors in the manufacture of drugs for administering harmful agents. The use of agents, in which anti-HER2 antibody-drug conjugates and CDK9 inhibitors are used [1]~

[24] Use as defined by one of the following;

[47] Cancer is defined by one of

[28] to

[43] ,

[46] Method of description;

[48] ​​The drugs include an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor for co-administration. Uses of compositions including

[46] or

[47] as described above;

[49] The drug is an anti-HER2 antibody-drug complex and CDK9 for sequential or simultaneous administration. Use as described in

[46] or

[47] , which is a combined preparation containing an inhibitor;

[50] Anti-HER2 antibody for use in combination with CDK9 inhibitors in cancer treatment A drug conjugate comprising an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor as defined in any one of [1] to

[0024] , for use;

[51] Cancer is defined by one of

[28] to

[43] , as noted in

[50] . Anti-HER2 antibody-drug conjugate for use; An anti-HER2 antibody-drug conjugate for use as described in

[52]

[50] or

[51] Therefore, the use involves continuous administration of an anti-HER2 antibody-drug complex and a CDK9 inhibitor, HER2 antibody-drug conjugate; An anti-HER2 antibody-drug complex for use as described in

[53]

[50] or

[51] Therefore, the use involves the simultaneous administration of an anti-HER2 antibody-drug complex and a CDK9 inhibitor, HER2 antibody-drug conjugate;

[54] CDK for use in combination with anti-HER2 antibody-drug conjugates in the treatment of cancer 9 Inhibitors, which include anti-HER2 antibody-drug conjugates and CDK9 inhibitors [1]~

[24] CDK9 inhibitors as defined in any one of the following: CDK9 inhibitors for use as described in

[55]

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

[28] to

[0043] ; A CDK9 inhibitor for use as described in

[56]

[54] or

[55] , wherein the use is A CDK9 inhibitor is administered sequentially, including an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor. ; A CDK9 inhibitor for use as described in

[57]

[54] or

[55] , wherein the use is The CDK9 inhibitor is administered simultaneously with an anti-HER2 antibody-drug conjugate. ;

[58] In combination with the required object, determine in one of [1] to

[24] This includes administering an anti-HER2 antibody-drug complex and a CDK9 inhibitor as described above. Methods of treating cancer;

[59] The method of

[0058] wherein cancer is as defined in any one of

[28] to

[43] ;

[60] This includes administering an anti-HER2 antibody-drug complex and a CDK9 inhibitor in succession. The method described in

[58] or

[59] ; and

[61] The administration of an anti-HER2 antibody-drug complex and a CDK9 inhibitor simultaneously is one of the following: The method described in

[58] or

[59] .

[0010] [Effects of the invention] This disclosure relates to an anti-H2 antibody having an antitumor agent that is conjugated to an anti-HER2 antibody via a linker structure. Pharmaceutical products in which an ER2 antibody-drug complex and a CDK9 inhibitor are administered in combination, Therapeutic treatment involves administering a specific antibody-drug conjugate and a CDK9 inhibitor in combination to the target. The disclosure provides a method for use in treating cancer. Accordingly, this disclosure provides an excellent antitumor effect in the treatment of cancer. We can provide drugs and treatments that can be used. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 is a diagram showing the amino acid sequence (SEQ ID NO: 1) of the heavy chain of the anti-HER2 antibody. [Figure 2] Figure 2 is a diagram showing the amino acid sequence of the light chain of the anti-HER2 antibody (SEQ ID NO: 2). [Figure 3] Figure 3 is a diagram showing the amino acid sequence of heavy chain CDRH1 (SEQ ID NO: 3 [= amino acid residues 26-33 of SEQ ID NO: 1]). [Figure 4] Figure 4 is a diagram showing the amino acid sequence of the heavy chain CDRH2 (Sequence ID 4 [= amino acid residues 51-58 of Sequence ID 1]). [Figure 5] Figure 5 is a diagram showing the amino acid sequence of heavy chain CDRH3 (SEQ ID NO: 5 [= amino acid residues 97-109 of SEQ ID NO: 1]). [Figure 6] Figure 6 is a diagram showing the amino acid sequence of the light chain CDRL1 (SEQ ID NO: 6 [= amino acid residues 27-32 of SEQ ID NO: 2]). [Figure 7]Figure 7 is a diagram showing the amino acid sequence (SAS) of the light chain CDRL2 (SEQ ID NO: 7 [= amino acid residues 50-56 of SEQ ID NO: 2]). [Figure 8] Figure 8 is a diagram showing the amino acid sequence of the light chain CDRL3 (SEQ ID NO: 8 [= amino acid residues 89-97 of SEQ ID NO: 2]). [Figure 9] Figure 9 is a diagram showing the amino acid sequence of the heavy chain variable region (SEQ ID NO: 9 [= amino acid residues 1-120 of SEQ ID NO: 1]). [Figure 10] Figure 10 is a diagram showing the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [= amino acid residues 1-107 of SEQ ID NO: 2]). [Figure 11] Figure 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] Figure 12 shows dose-response curves for selective CDK9 inhibitor AZD4573 in combination with escalating doses of the anti-HER2 antibody-drug conjugate DS-8201 in breast cancer and gastric cancer cell lines. [Figure 13] Figure 13 shows the changes in tumor volume over time in CB17-SCID mice treated with DS-8201 alone at 3 mg / kg or 10 mg / kg, and in combination with AZD4573 at 10 mg / kg BID or 5 mg / kg TID, with subcutaneously transplanted HCC12945 breast cancer cells. [Modes for carrying out the invention]

[0012] Certain terms are defined first in order to make this disclosure easier to understand. Additional definitions are provided throughout the detailed explanation.

[0013] Before detailing this disclosure, it should be noted that this disclosure is not limited to any particular composition or method step, and therefore may vary. It should be understood that it is movable. In cases where the context explicitly indicates otherwise, the singular forms "a," "an," and "the" are used. Includes the number of references. The term "a" (or "an"), as well as "one or more" and "few". The term "at least one" may be used interchangeably in this specification.

[0014] Furthermore, as used herein, "and / or" does not imply the presence or absence of other features or components. Nevertheless, each of the two specific features or components shall be considered a specific disclosure. Therefore, the terms used in this specification such as "A and / or B" are... The terms "and / or" are used in phrases such as "A and B," "A or B," "A" (alone), and "B" (alone). (German) shall include. Similarly, the term "and / or" shall include "A, B and / or C". When used in phrases such as the following, it shall encompass each of the following forms: 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 (Solo); B (Solo); and C (Solo).

[0015] Unless otherwise defined, all technical and scientific terms used herein refer to the terms relating to this disclosure. It has the same meaning as commonly understood by those skilled in the art in that field. For example, Conci se Dictionary of Biomedicine and Molecule ar Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press;The Dictionary of Cell and Molecule lar Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology,Revised,2000,Oxford Un International Press has provided a general dictionary of terms used in this disclosure to those skilled in the art. provide.

[0016] Units, prefixes, and symbols are expressed in the form recognized by their respective International System of Units (SI). The numerical range includes the number that defines that range.

[0017] When an aspect is described in this specification together with the word “including,” it is always “consisting of and / or similar embodiments are also provided, which are described in terms of "essentially being from" Please understand this.

[0018] The terms “inhibit,” “block,” and “suppress” are interchangeable herein. Used to indicate any statistically significant decrease in biological activity (including complete blockade of activity). For example, "inhibition" refers to approximately 10%, 20%, 30%, 40%, 50% of biological activity. This can refer to a decrease of 60%, 70%, 80%, 90%, or 100%.

[0019] Cell proliferation is the rate of cell division and / or the percentage of cells undergoing cell division within a cell population. and / or the rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine removal) The assay can be performed using techniques recognized in the art to measure (including).

[0020] The term "subject" can include, but is not limited to, humans, non-human primates, rodents, etc. i. This refers to any animal (e.g., a mammal) that is the recipient of a specific treatment. Typically, The terms “subject” and “patient” are interchangeable herein in relation to human subjects. It will be used.

[0021] The term "pharmaceutical product" refers to a composition containing all active ingredients (for simultaneous administration). ), or each containing at least one active ingredient but not all of the active ingredients. Any combination of individual compositions (combined preparations) (sequential or simultaneous administration) In a form that enables the biological activity of the active ingredient, the product is administered to the target population. This refers to a preparation that does not contain any further components that are unacceptably toxic to the subject. Such products may be sterile. "Simultaneous administration" means that the active ingredients are administered at the same time. "Continuous administration" means that the active ingredients are administered sequentially in any order, with time intervals between each dose. This means that it is administered. The time interval is, for example, less than 24 hours, preferably less than 6 hours. It may be less than two hours, or more preferably less than two hours.

[0022] "treating" or "treatment" Ku means "to treat" or "to alleviate". Terms such as "to alleviate" or "(1) diagnosed" To cure, slow down, reduce, and / or halt the progression of a pathological condition or disease. Therapeutic measures and (2) measures to prevent and / or slow the onset of the target condition or disease. Prophylactic or preventative measures, It refers to both. Therefore, those who require treatment include those who already have a disability, and those who have a disability. This includes individuals who tend to develop certain conditions and those who should be protected from developing disabilities. In some aspects, the patient may, for example, For example, in cases of complete, partial, or transient remission of a particular type of cancer, according to the method of this disclosure The target cancer is successfully "treated".

[0023] The terms "cancer," "tumor," "cancerous," and "malignant" typically refer to disordered cellular formation. This refers to or describes physical pathological conditions in mammals characterized by their length. An example of cancer is... For example, breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, pa Jett's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal interstitial cancer Tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer , kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, Glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic leukemia High-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-Hodgkin syndrome Lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic lymphoma Lymphocyte leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, and follicular lymphoma While peritoneum is one example, it is not limited to peritoneum. Cancers include hematological malignancies, such as acute myeloid leukemia. Diseases, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt Trimphoma, follicular lymphoma, and solid tumors, such as breast cancer, lung cancer, neuroblastoma, and colon cancer. Cancer is one example.

[0024] As used herein, the term “cytotoxic drug” is broadly defined as “cell-mediated drug.” It inhibits or prevents the function of, and / or causes cell destruction (cell death), and / or This refers to substances that exhibit antineoplastic / antiproliferative effects. For example, cytotoxic drugs are effective against neoplastic tumor cells. To directly or indirectly prevent the occurrence, maturation, or spread of [unclear]. This term refers only to the cell proliferation inhibitory effect. including agents that cause this but do not cause mere cytotoxic effects. This term includes the chemotherapeutic agents defined below, as well as other HER2 antagonists, anti-angiogenic agents, tyrosine kinases inhibitors, protein kinase A inhibitors, members of the cytokine family, radioisotopes, and toxins, such as enzymatically active toxins of bacterial, fungal, plant or animal origin. The term "chemotherapeutic agent" is a subset of the term "cytotoxic drug" which includes natural or synthetic compounds.

[0025] According to the methods or uses of the present disclosure, the compounds of the present disclosure can be administered to a patient to promote a positive therapeutic response regarding cancer. The term "positive therapeutic response" regarding the treatment of cancer refers to the improvement of the symptoms associated with the disease. For example, the improvement of the disease can be characterized as a complete response. The term "complete remission" refers to the absence of a clinically detectable disease, accompanied by the normalization of any prior test results. Alternatively, the improvement in the disease can be classified as a partial response. The "positive therapeutic response" includes the reduction or inhibition of cancer progression and / or duration, the reduction or improvement of cancer severity, and / or the remission of one or more of its symptoms resulting from the administration of the compounds of the present disclosure. In a specific embodiment, such terms refer to one, two or three or more of the following results after the administration of the compounds of the present disclosure: (1) stabilization, reduction or elimination of the cancer cell population; (2) stabilization or reduction of cancer growth; (3) reduction of cancer formation; (7) Increase in response rate, duration of response, or number of patients who respond or improve; (8) Reduction in hospitalization rates; (9) Shortening of hospital stay; (10) The size of the tumor is maintained and does not enlarge, or enlarges by less than 10%, preferably less than 5%. It is full, preferably less than 4%, preferably less than 2%; and (11) Increase in the number of patients whose condition has improved; (12) Other adjuvant therapies necessary for the treatment of cancer (e.g., chemotherapy drugs or hormone therapy drugs) A decrease in the number.

[0026] Clinical response is measured by screening techniques, such as PET and magnetic resonance imaging (MRI). Scanning, X-ray imaging, computed tomography (CT) scan, flow scanning Tometry or fluorescence-activated cell sorting (FACS) analysis, histological examination, macroscopic findings And blood chemistry tests, for example, but not limited to, ELISA, RIA, chromatography These positive therapeutic responses can be evaluated using changes detectable by methods such as tography. In addition, those receiving treatment may experience beneficial effects such as improvement in symptoms associated with the disease.

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

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

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

[0030] As used herein, the term "alkyl" refers to both straight-chain and branched-chain saturated hydrocarbon groups having a 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 embodiment, "alkyl" may be "C 1~4 alkyl". In another embodiment, "alkyl" and "C 1~4 alkyl" are "C 1~3 ​​​​​​​​​​​​​​​​​​​​​​​​can be "alkyl". In another aspect, "alkyl", "C 1~4 alki l", and "C 1~3 alkyl" can be methyl. Similar conversions apply to other general terms, such as "alkenyl" and "alkynyl".

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

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

[0033] For any of the R groups (R 1 ~R 12 ), suitable values or any parts or substituents of such groups include the following: 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-acetylpiperidi nyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, pyrani l, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioxyimidazoli nyl 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" means an amount of a compound or composition sufficient to cause a significant and positive change (e.g., provide a positive clinical response) in the symptoms and / or condition being treated. The effective amount of an active ingredient for use in a pharmaceutical product will vary depending on the specific condition being treated, the severity of the condition, the duration of treatment, the nature of any combination therapy, the specific active ingredient being used, the specific pharmaceutically acceptable additive(s) / carrier(s) being utilized, and like factors within the knowledge and skill of the attending physician. In particular, in combination with an antibody-drug conjugate ​​​The effective amount of the compound of formula (I) for use in the treatment of combined cancers is such that this combination is human In warm-blooded animals such as the following, in order to symptomatically alleviate cancer symptoms and slow the progression of cancer, or an amount sufficient to reduce the risk of worsening in patients with cancer symptoms. That is the case.

[0035] Where used herein, the term “pharmaceutically acceptable” means reasonable benefits / rewards. It is consistent with the saturation ratio and shows no excessive toxicity, irritation, allergic reactions, or other problems or complications in humans. and compounds that are suitable for use in contact with animal tissues and within the bounds of reasonable medical judgment. This refers to materials, compositions, and / or dosage forms.

[0036] For illustrative purposes, the substituent "R" is used as a reference to the following substituent definition in the shown structure: [ka] It refers to.

[0037] Within the scope of this disclosure, compounds of formula (I) or salts thereof may exhibit the phenomenon of interchangeability. Furthermore, please understand that the diagrams of formulas in this specification may represent only one of the possible tautomerized forms. This disclosure encompasses any tautomer form having CDK9 inhibitory activity and the diagram of the formula. It should be understood that it should not be simply limited to any one tautomer form used within the system. That is the case.

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

[0039] A compound of formula (I) and its salts exist in solvated and non-solvated forms, for example, in a hydrated form. It should also be understood that they can exist in this form. This disclosure encompasses all such solvation forms. Please understand this.

[0040] The compound of formula (I) may also be provided as an in vivo hydrolyzable ester. Alternatively, an in vivo hydrolyzable ester of a compound of formula (I) containing a hydroxyl group is, for example, , pharmaceutically acceptable es that are cleaved in the human or animal body to produce hydrophilic acids or alcohols It is a ester. Such esters are obtained, for example, by intravenously administering the compound to test animals under test conditions. Subsequently, it can be identified by testing the body fluids of the test animal. Suitable pharmaceutically for carboxy As for acceptable esters, C 1~6 Alkoxymethyl esters, for example, methoxymethyl esters Chill, C 1~6 Alkanoyloxymethyl esters, for example, pivaloyloxymethyl, f Taridyl ester, C 3~8 Cycloalkcarbonyloxy onyloxy)C 1~6 Alkyl esters, for example, 1-cyclohexylcarbonyl oxy 5-methyl ethyl, (1,3-dioxolenn-2-one)ylmethyl ester, e.g., (5-methyl Lu-1,3-dioxolenn-2-one)ylmethyl and C 1~6 Alkoxycarbonyl Examples of oxyethyl esters include 1-methoxycarbonyloxyethyl; this disclosure It can be formed at any carboxyl group in the compound. hydroxy is pharmaceutically acceptable. Acceptable esters include inorganic esters, such as phosphate esters (phosphoramidites). (including ring esters) and α-acyloxyalkyl ethers and esterification in vivo Related compounds that produce a hydroxyl group as a result of hydrolysis include α-acyl compounds. Examples of oxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropyl Onyloxymethoxy is an example. In vivo hydrolyzable esters of hydroxyl groups. As for the choice of the forming group, C 1~10 Alkanoyl, for example, acetyl, benzoyl, f Phenylacetyl, substituted benzoyl and phenylacetyl; C 1~10 Alkoxycarbon (to produce alkyl carbonate esters), for example, ethoxycarbonyl; Ji C 1~4 Alkylcarbamoyl and N-(di-C) 1~4 Alkylaminoethyl)-N- C 1~4 Alkylcarbamoyl (to produce carbamates); diC 1~4 Alkyl Examples include aminoacetyl and carboxyacetyl. Phenyleacetyl and benzoyl Examples of the above ring substituents include aminomethyl and C 1~4 Alkylaminomethyl and di-(C 1~4 via an alkyl)aminomethyl group and a methylene bond to the 3rd or 4th position of the benzoyl ring. Examples include morpholinos or piperazines linked from a ring nitrogen atom. Other interesting Examples of ionic hydrolyzable esters include R A C(O)OC 1~6 Alkyl-CO- (In the formula, R A For example, benzyl oxy-C 1~4Examples include alkyl or phenyl compounds. 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 mo Ruhorino-C 1~4 Alkyl compounds are examples.

[0041] The compound of formula (I) may form a stable, pharmaceutically acceptable acidic or basic salt, and so In such cases, administration of the compound as a salt may be appropriate. Examples of acid addition salts include acetates. Adipine salts, ascorbic acid salts, benzoates, benzenesulfonates, bicarbonates, sodium bicarbonates Salts, butyrates, camphor salts, camphor sulfonates, choline, citrates, cyclo Hexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, Lutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, hep Tanates, hexanoates, hydrochlorides, hydrobroms, hydroiodides, hydroxymalein Salts, lactates, malates, maleates, methanesulfons, meglumine, 2-naphtheria Talenesulfonates, nitrates, oxalates, pamoates, persulfates, phenylacetates, phosphorus Salic acid salts, diphosphates, picrates, pivalates, propionates, quinates, salicylic acid Salt, stearate, succinate, sulfamate, sulfanilate, sulfate, tartaric acid Salts, tosylates (p-toluenesulfonates), trifluoroacetates, and undecanoic acid Examples of salts include ammonium salts; sodium, lithium, and ammonium salts. Alkali metal salts such as aluminum salts; aluminium, calcium, and magnesium salts. Lucal earth metal salts; dicyclohexylamine salts and N-methyl-d-glucamine, etc. Examples include salts with a specific base, and salts with amino acids such as arginine, lysine, and ornithine. Furthermore, basic nitrogen-containing groups can be quaternized with the following chemicals: lower halogenated compounds. Lukil, for example, methyl halogen, ethyl halogen, propyl halogen and halogen Butyl sulfate; dialkyl sulfate, e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate; sulfur Diamyl acid; long-chain halides, e.g., decyl halides, lauryl halides, halo Myristyl genates and stearyl halides; aryl alkyl halides, e.g., bromides Benzyl and similar substances. Non-toxic, physiologically acceptable salts are preferred, for example, Other salts may be useful in the isolation or purification of the product.

[0042] These salts, by conventional means, for example, convert the free base form of the product to the insoluble form of the salt. React with 1 equivalent or more of a suitable acid in a solvent or medium, or in a solvent such as water. It can be formed by and, the solvent can be dried in a vacuum or freeze-dried, or a suitable ion The existing salt anions are removed by exchanging them with other anions using an exchange resin.

[0043] The compound of formula (I) has a chiral center and therefore exists as a stereoisomer. This disclosure is, This includes all such stereoisomers, including enantiomers and diastereoisomers. Please understand that, in this way, the compound of formula (I) may exist in an optically active or racemic form. To the extent that, this disclosure refers to any such optical activity having the above-described activity in its definition. or including racemic form. This disclosure includes all so-called active substances as defined herein. It includes stereoisomers such as the following.

[0044] The synthesis of the optically active form is carried out using standard techniques of organic chemistry well known in the art, for example, optical This can be carried out by synthesis from active starting materials or by the division of a racemic form. It can be separated into individual enantiomers using known procedures (e.g., Advance d Organic Chemistry:3rd Edition:author J (See March, pp. 104-107). A preferred procedure involves a racemic material and a chiral auxiliary agent. Formation of diastereomer derivatives by reaction, and subsequent, for example, chromatography This includes the separation of this diastereomer by - and then the cleavage of this auxiliary molecular species. The aforementioned activity can be evaluated using standard laboratory techniques.

[0045] Therefore, throughout this specification, when referring to the compound of formula (I), the term "compound" is used. This includes stereoisomers, mixtures of stereoisomers, and that inhibit CDK9 activity in humans or animals. It should be understood that this includes polymorphisms.

[0046] Stereoisomers are separated using conventional techniques, such as chromatography or fractional crystallization. Enantiomers can be separated from the racemic mixture by, for example, fractional crystallization, cleavage, or HP. It can be isolated by LC. Diastereoisomers have different physical properties. Separation by means of, for example, fractional crystallization, HPLC, or flash chromatography Therefore, it can be isolated. Alternatively, under conditions that do not cause racemization or epimerization, Through chiral synthesis from chiral starting materials, or through derivatization with chiral reagents, specific stereochemistry can be achieved. Isomers can be created.

[0047] If the specified stereoisomers are provided (provided by separation, chiral synthesis, or other means), Regardless of the method of provision, it is preferably derived from other stereoisomers of the same compound. It is provided in a substantially isolated state. In one embodiment, it includes specific stereoisomers of the compound of formula (I). The mixture contains less than 30% by weight, particularly less than 20% by weight, and more specifically less than 10% by weight. It may contain other stereoisomers of the same compound. In another embodiment, a specific compound of formula (I) A mixture containing stereoisomers is less than 6% by weight, particularly less than 3% by weight, and more specifically 2% by weight. This compound may contain other stereoisomers in less than 1% by weight. In another embodiment, the compound of formula (I) A mixture containing specific stereoisomers of a substance is less than 1% by weight, especially less than 0.5% by weight. In addition to this compound, which is found in amounts of less than 0.3% by weight and, more specifically, less than 0.1% by weight. It may contain stereoisomers. If the absolute configuration of the isolated stereoisomer has not been determined, Stereoisomers can be distinguished by methods of preparation or separation. For example, isolated stereoisomers are... They can be distinguished by their elution time and labeled, for example, as isomer 1, isomer 2, etc.

[0048] Some structural forms of the compounds disclosed may offer advantages. For example, some forms of the compounds disclosed It can be handled and stored more easily. Other forms of the compounds of this disclosure are well defined. Because they exist in a specified state, they can be more easily characterized. Furthermore, the compounds of this disclosure are It can be synthesized more easily in a reproducible manner, thereby making full-scale generation easier. It can be handled easily.

[0049] If a prescribed polymorph is provided, it is preferably another polymorph of the same compound. They are provided substantially isolated. In one embodiment, it includes specific polymorphic forms of the compound of formula (I). The mixture contains less than 30% by weight, particularly less than 20% by weight, and more specifically less than 10% by weight. It may contain other polymorphic forms of the same compound. In another embodiment, a specific compound of formula (I) Mixtures containing polymorphic forms are less than 6% by weight, particularly less than 3% by weight, and more specifically, double This compound may contain other polymorphic forms in amounts less than 1%. In another embodiment, the compound of formula (I) Mixtures containing specific polymorphic forms are less than 1% by weight, particularly less than 0.5% by weight, and more specifically... Other polymorphs of this compound: less than 0.3% by weight and, more specifically, less than 0.1% by weight. It may contain a form.

[0050] The CDK9 inhibitors disclosed herein affect the position of the main peak in the X-ray powder diffraction pattern. It can be characterized by its intensity, but it can also be characterized by conventional FT-IR spectroscopy. These can be used to distinguish one crystalline form of a compound from other crystalline forms. In this specification The disclosed CDK9 inhibitor is highly crystalline, i.e., it has a higher degree of crystallinity than other forms. It may be characterized by having a degree of transformation. The expression "some other form" is used in the prior art. This refers to the anhydrous, hydrate, solvate, and polymorphic or amorphous forms disclosed. Examples of any other forms of compound include anhydrous, monohydrate, dihydrate, sesquihydrate, and trihydrate. Alcoates, such as methanelates and ethanolates, and their polymorphs or non- Crystalline morphology is a possible but not limited form.

[0051] Compounds of formula (I) can also be characterized by their unit cell. It can be analyzed using XRPD, which is a publicly known technique.

[0052] The amount of water in this compound can be measured by thermogravimetric analysis, a technique that is itself well known.

[0053] Description of the Embodiment Hereafter in this specification, preferred methods for making this disclosure will be described. The embodiments described below are: This is provided solely to illustrate a typical embodiment of the present disclosure and does not limit the scope of the present disclosure. It is not something that can be done.

[0054] 1. Antibody-drug complex The antibody-drug complex used in this disclosure has the following formula: [ka] (In the formula, A represents the binding site to the antibody.) The drug linker represented by is conjugated to the anti-HER2 antibody via thioether linkage. It is an antibody-drug complex.

[0055] In this disclosure, a partial structure consisting of a linker and a drug in an antibody-drug complex is defined as "drug- It is called a "linker". A drug-linker is an interchain disulfide bond site in an antibody. Thiol groups formed at two sites between the heavy chains and two sites between the heavy chain and the light chain ( When replaced, it is linked to the sulfur atom of the cysteine ​​residue.

[0056] The drug linker in this disclosure is exatecan (IUPAC name: (1S,9S)-1-amino -9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydro Xy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indo Lisino[1,2-b]quinoline-10,13-dione, (Chemical name: (1S,9S)-1- Amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1H,12H-benzo[de]pirano[3',4':6,7]indridino[1,2-b] It is composed of quinoline (also represented as quinoline-10,13(9H,15H)-dione) It contains and is a topoisomerase I inhibitor. Exatecan has the following formula: [ka] It is a camptothecin derivative that has an antitumor effect as represented by [the formula shown].

[0057] The anti-HER2 antibody-drug conjugate used in this disclosure has the following formula: [ka] It can also be represented by...

[0058] Here, the drug-linker is linked to the anti-HER2 antibody ("antibody-") via a thioether bond. It is compounded. The meaning of n is called the average number of compounded drug molecules (DAR; drug-to-antibody ratio). This is the same as the one shown, and indicates the average number of complexed drug linkers per antibody molecule. .

[0059] After migrated to cancer cells, the anti-HER2 antibody-drug conjugate used in this disclosure is linked to the linker portion. Cut in minutes, the following equation: [ka] It releases the compound represented by [the formula shown].

[0060] This compound is the source of the antitumor activity of the antibody-drug complex used in this disclosure. It is speculated that it has 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 conjugates used in this disclosure are known to exhibit the bystander effect. (Ogitani Y. et al., Cancer Science (2016) )107,1039-1046). The bystander effect is the antibody-drug complex used in this disclosure. However, it is exerted through the process of internalization in cancer cells that express the target, and then released. The compound exerts antitumor effects even on cancer cells that are present in the surrounding area and do not express the target. This bystander effect occurs when an anti-HER2 antibody-drug conjugate is combined with a CDK9 inhibitor in accordance with this disclosure. Even when used in combination, it exhibits excellent antitumor effects.

[0062] 2. Antibodies in antibody-drug complexes The anti-HER2 antibody in the antibody-drug complex used in this disclosure may be derived from any species. Preferably, the antibody is an anti-HER2 antibody derived from human, rat, mouse, or rabbit. If derived from a species other than the specified one, it is preferably chimerized or humanized using well-known techniques. Anti-HER2 antibodies can be polyclonal or monoclonal antibodies, preferably mo It is a noclonal antibody.

[0063] The antibodies in the antibody-drug complexes used in this disclosure preferably target cancer cells. An anti-HER2 antibody having the characteristic of being able to recognize cancer cells, preferably for example. Characteristics of binding to cancer cells, characteristics of internal migration within cancer cells and / or characteristics of cancer cells It is an antibody that possesses cell-destroying activity.

[0064] The binding activity of anti-HER2 antibodies against cancer cells was confirmed using flow cytometry. It is possible. Internal transfer of antibodies to cancer cells is possible (1) secondary antibodies to therapeutic antibodies (fluorescently labeled) ) Assay to visualize antibodies incorporated into cells under fluorescence microscopy using binding ( Cell Death and Differentiation(2008)15,7 51-761), (2) Cells using secondary antibody (fluorescently labeled) conjugation to therapeutic antibody An assay for measuring light intensity incorporated in Molecular Biology of the Cell,Vol.15,5268-5282,December 2 004) or (3) A therapeutic agent that releases toxins upon integration into cells, thereby inhibiting cell growth. Mab-ZAP assay using immunotoxin binding to antibodies (Bio Technique) This can be confirmed using (s 28:162-165, January 2000). Immunology As a toxin, it is a recombinant complex protein of the diphtheria toxin catalytic domain and protein G. It can be used.

[0065] The antitumor activity of anti-HER2 antibodies is determined by their inhibitory activity against cell growth. This can be confirmed in vitro. For example, overexpression of HER2 as a target protein against an antibody. We cultured cancer cell lines and investigated inhibitory activities against lesion formation, colony formation, and spheroid growth. Antibodies are added to the culture system at various concentrations to determine sex. Antitumor activity is measured, for example, by targeting Nude mice transplanted with cancer cell lines highly expressing a protein were given antibodies, and the cancer cells... By determining the change in this state, it can be confirmed in vivo.

[0066] In anti-HER2 antibody-drug conjugates, the compound that is conjugated exerts an antitumor effect. It is desirable, but not essential, that the anti-HER2 antibody itself should have an antitumor effect. The objective is to exert cytotoxic activity of antitumor compounds specifically and selectively against cancer cells. Therefore, anti-HER2 antibodies should possess the property of internalizing into cancer cells in order to move to them. This is important and desirable.

[0067] The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is known in the art. It can be obtained by procedure. For example, the antibodies of this disclosure can be obtained by using methods commonly used in the art. This is obtained by using an antigenic polypeptide to immunize animals and produce in vivo This includes recovering and purifying the antibodies. The origin of the antigen is not limited to humans; animals such as mice are also included. Immunity can be conferred using antigens derived from non-human animals such as rats. In this case, the interaction with human antigens... The cross-reactivity of antibody binding to heterologous antigens obtained is used for antibodies applicable to human diseases. It may be tested to lean.

[0068] Alternatively, antibody-producing cells that produce antibodies against an antigen, according to methods known in the art. By fusing with myeloma cells (for example, Kohler and Milstein, Natur e(1975) 256, p. 495-497; and Kennet, R. ed., Mono clonal antibodies, p.365-367, Plenum Press NY (1980), established hybridoma, and then developed monoclonal antibody It is possible to obtain this.

[0069] Antigens are genetically modified organisms that produce genes encoding antigenic proteins. It can be obtained by chief cells. Specifically, a vector that enables the expression of the antigen gene is prepared. The antigen is then transferred to a host cell, where it begins to be expressed. The expressed antigen is then purified. Antibodies can be produced using the above-mentioned genetically modified antigen-expressing cells or cell lines that express the antigen. It can also be obtained by methods of conferring immunity to animals.

[0070] The anti-HER2 antibody in the antibody-drug complex used in this disclosure is preferably a chimeric anti-HER2 antibody. Obtained through artificial modification for the purpose of reducing heterogeneity against humans, such as the body or humanized antibodies. It is a recombinant antibody, or preferably a human-derived antibody, i.e., a human antibody gene These antibodies consist only of a sequence. These antibodies can be produced using known methods.

[0071] Chimeric antibodies are antibodies whose antibody variability and constant region originate from different species, for example, mouse antibodies. Alternatively, chimeric antibodies in which the variable region of a rat antibody is linked to the constant region of a human-derived antibody are a typical example. Possible (Proc.Natl.Acad.Sci.USA,81,6851-6855) (1984).

[0072] As a humanized antibody, only the complementarity-determining region (CDR) of a heterologous antibody is incorporated into a human-derived antibody. Antibodies obtained by [doing something] (Nature (1986) 321, pp. 522-525) And the CDR transplantation method (International Publication No. 90 / 07861 pamphlet) to convert to human antibodies Transplanting the antibody framework and a portion of the amino acid residues from the CDR sequence of a heterologous antibody. Antibodies obtained by this method and antibodies humanized using gene conversion mutagenesis strategies. U.S. Patent No. 5,821,337 may be a typical example.

[0073] As a human antibody, it is a human having a human chromosome fragment containing the genes for the heavy and light chains of the human antibody. Antibodies produced using antibody-producing mice (Tomizuka, K. et a l.,Nature Genetics(1997)16,p.133-143;Kur oiwa, Y. et.al., Nucl. Acids Res. (1998) 26, p. 3447-3448;Yoshida,H.et.al.,Animal Cell T echnology:Basic and Applied Aspects vol. 10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iij ima, S. eds.), Kluwer Academic Publishers, 1 999;Tomizuka,K.et.al.,Proc.Natl.Acad.Sci See .USA(2000)97, pp.722-727, etc., which can be a typical example. Alternatively, antibodies obtained by phage display or selected from human antibody libraries can be used. The antibody being tested (Wormstone, IMet.al, Investigative e Ophthalmology & Visual Science.(2002)4 3(7),p.2301-2308;Carmen,S.et.al.,Briefin gs in Functional Genomics and Proteomics (2002),1(2),p.189-203;Siriwardena,D.et.a i., Ophthalmology (2002) 109(3), pp. 427-431, etc. (See reference) could be a typical example.

[0074] In this disclosure, modifications of anti-HER2 antibodies in antibody-drug complexes used in this disclosure This also includes modified variants. Modified variants are chemically or biologically modified in accordance with this disclosure. This refers to mutants obtained by modification. Examples of chemically modified mutants include... Therefore, mutants, N-linked or O-linked carbohydrates, which include the linkage of chemical parts to the amino acid backbone. Examples include mutants that involve the linkage of chemical parts to the chain. Biologically modified mutants Examples include mutants obtained by post-translational modification (N-linked or O-linked glycosylation, N -or C-terminal processing, deamidation, aspartic acid isomerization, or methionine oxidation (and so on) and when expressed in prokaryotic host cells, methionine residues are attached to the N-terminus. Examples of added variants include: Furthermore, the detection or isolation of antibodies or antigens according to this disclosure Antibodies that are labeled to enable, for example, enzyme-labeled antibodies, fluorescently labeled antibodies and Affinity-labeled antibodies are also included in the meaning of modified variants. Modified mutants, such as those mentioned above, improve antibody stability and blood retention, while reducing their antigenicity. It is useful for detecting or identifying antibodies or antigens.

[0075] Furthermore, the modification of glycans linked to antibodies according to this disclosure (glycosylation, defucosylation) By regulating factors such as these, antibody-dependent cellular cytotoxic activity can be promoted. As a technique for regulating the modification of antibody glycans, see International Publication No. 99 / 54342, PAN Fret, International Publication No. 00 / 61739 pamphlet, International Publication No. 02 / 31140 Brochure, International Publication No. 2007 / 133855, Brochure, International Publication No. 2013 It is known that this is disclosed in pamphlet No. 120066, etc. However, the technology is The anti-HER2 antibodies described herein may have modified glycans. It also includes antibodies.

[0076] The lysine residue at the carboxyl terminus of the heavy chain of antibodies produced in cultured mammalian cells is missing. It is known that it is missing (Journal of Chromatography A,705:129-134(1995)), Anti- The two amino acid residues (glycine and lysine) at the carboxyl terminus of the body's heavy chain are missing. Furthermore, it is known that the newly placed proline residue at the carboxyl terminus is amidated. (Analytical Biochemistry,360:75-83(2007 However, such deletions and modifications of the heavy chain sequence affect the antigen-binding affinity and ephrastosis of the antibody. It does not affect receptor function (such as complement activation or antibody-dependent cellular cytotoxicity). In the anti-HER2 antibody described herein, the antibody and the mechanism of the antibody are modified in this manner. Potency fragments are also included, and deletion mutations are characterized by the deletion of one or two amino acids at the carboxyl terminus of the heavy chain. Mutants obtained by amidation of isomorphs and deletion mutants (e.g., carboxyl-terminal proline residues) This also includes heavy chains in which the group is amidated. The type of deletion variant with a deletion at the ruboxyl terminus is determined by antigen-binding affinity and effect. The antibody comprising the two antibodies described herein is not limited to the above variants, as long as the function is preserved. This heavy chain can be one type selected from the group consisting of the full-length heavy chain and the deletion variants described above. There may be two types, either one or one of the combinations selected from there. Each deletion variant The ratio of the amounts of the type of cultured mammalian cells that produce anti-HER2 antibodies according to this disclosure and may be affected by culture conditions; however, in the antibody according to this disclosure, two heavy chains An antibody in which one amino acid residue at the carboxyl terminus is deleted in both parts could be a preferred example. ru.

[0077] Examples of isotypes of anti-HER2 antibodies according to this disclosure include IgG(IgG1, IgG) 2. IgG3, IgG4) can be typical examples, while IgG1 or IgG2 can be preferred examples. could be.

[0078] In this disclosure, the term "anti-HER2 antibody" refers to HER2 (human epidermal growth factor receptor receptor). This refers to an antibody that specifically binds to HER2 type 2 (ErbB-2), preferably an antibody that specifically binds to HER2. Upon binding, it exhibits internal distribution activity in HER2-expressing cells.

[0079] An example of an anti-HER2 antibody is trastuzumab (U.S. Patent No. 5821337). And pertuzumab (International Publication No. 01 / 00245) is mentioned, and Trust Zumab could be a favorable example.

[0080] 3. Production of antibody-drug complexes Drug-linker intermediate for use in the preparation of anti-HER2 antibody-drug complexes as disclosed herein. The body is given by the following formula: [ka] It is represented by [this].

[0081] The drug-linker intermediate has the chemical name N-[6-(2,5-dioxo-2,5-dihydro- 1H-pyrrole-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl- N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl Tyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,1 2H-benzo[de]pyrano[3',4':6,7]indridino[1,2-b]quinoline It can be represented as -1-yl]amino}-2-oxoethoxy)methyl]glycinamide, International Publication No. 2014 / 057687, International Publication No. 2015 / 098099 Pamphlet No. 2015 / 115091, International Publication No. 201 Pamphlet No. 5 / 155998, International Publication No. 2019 / 044947 It can be prepared by referring to the description in [location].

[0082] The anti-HER2 antibody-drug complexes used in this disclosure are the above-mentioned drug-linker intermediates and Reacting with an anti-HER2 antibody that has a thiol group (also called a sulfidyl group). It can be produced by [method].

[0083] Anti-HER2 antibodies containing sulfidyl 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, tris(2-carboxyethyl)phosphorus for each interchain disulfide in an antibody. Using 0.3 to 3 molar equivalents of a reducing agent such as ethylenediamine hydrochloride (TCEP), The antibody is reacted with a buffer containing a chelating agent such as tetraacetic acid (EDTA). Furthermore, sulfidyl groups that have interchain disulfides that are partially or completely reduced within the antibody An anti-HER2 antibody possessing the following properties can be obtained.

[0084] Furthermore, 2-2 drug-linker intermediates per anti-HER2 antibody containing a sulfidyl group By using 20 molar equivalents, 2 to 8 drug molecules are combined with each antibody molecule. Anti-HER2 antibody-drug conjugates can be produced.

[0085] The average of the compounded drug molecules per anti-HER2 antibody molecule in the produced antibody-drug complex The average is, for example, at two wavelengths of 280 nm and 370 nm for antibody-drug complexes and their A method that calculates based on the measurement of UV absorption for the conjugation reaction precursor (UV method), or antibody- The drug complex was determined by HPLC analysis of the fragments obtained by treating the drug complex with a reducing agent. It can be determined by a method based on quantity (HPLC method).

[0086] Conjugation reaction between anti-HER2 antibody and drug-linker intermediate and antibody-drug complex The calculation of the average number of complex drug molecules per molecule is described in International Publication No. 2014 / 05768. Pamphlet No. 7, International Publication No. 2015 / 098099, International Publication No. 20 Pamphlet No. 15 / 115091, International Publication No. 2015 / 155998 International Publication No. 2017 / 002776, International Publication No. 2018 / 21213 This can be done by referring to the information in pamphlet No. 6, etc.

[0087] In this disclosure, the term "anti-HER2 antibody-drug complex" means, as defined in this disclosure, an antibody- This refers to an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-HER2 antibody.

[0088] The anti-HER2 antibody is preferably an amino acid consisting of amino acid residues 26-33 of SEQ ID NO: 1. CDRH1 consisting of an acid sequence, and the amino acid sequence consisting of amino acid residues 51-58 of SEQ ID NO: 1. CDRH2 consists of amino acid residues 97-109 of SEQ ID NO: 1 A heavy chain containing CDRH3 and amino acids consisting of amino acid residues 27-32 of SEQ ID NO: 2 CDRL1 consists of a sequence, and the amino acid sequence consists of amino acid residues 50-52 of SEQ ID NO: 2. The amino acid sequence consisting of amino acid residues 89-97 of CDRL2 and SEQ ID NO: 2 A light chain containing CDRL3, an antibody containing, and more preferably, the amino acid residue of SEQ ID NO: 1. A heavy chain containing a heavy chain variable region consisting of an amino acid sequence of groups 1 to 120, and the A of SEQ ID NO: 2 A light chain comprising a light chain variable region consisting of an amino acid sequence of amino acid residues 1 to 107, and Antibodies, and more preferably, heavy chains consisting of the amino acid sequence represented by SEQ ID NO: 1. An antibody comprising a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or SEQ ID NO: The heavy chain consists of amino acid residues 1-449 of 1, and all amino acid residues 1-21 of SEQ ID NO: 2. This antibody contains a light chain consisting of a sequence of 4 amino acids.

[0089] In anti-HER2 antibody-drug complexes, the number of complexed drug-linkers per antibody molecule The average number of units is preferably 2 to 8, more preferably 3 to 8, and even more preferably 7 to 8. More preferably 7.5 to 8 and even more preferably about 8.

[0090] The anti-HER2 antibody-drug conjugates used in this disclosure are referred to in International Publication No. 2015 / 11509. It can be created by referring to the information in Pamphlet No. 1, etc.

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

[0092] 4. CDK9 inhibitors In this disclosure, the term "CDK9 inhibitor" refers to cyclin-dependent kinase 9 (C) This refers to drugs that inhibit the kinase CDK9. It may selectively inhibit other kinases, or it may non-selectively inhibit CDK9, such as those other than CDK9. It also inhibits. Insofar as the CDK9 inhibitor is a drug having the characteristics described herein , but not limited to, a preferred example is the pamphlet for International Publication No. 2017 / 001354. This may include what is disclosed in the document.

[0093] Examples of CDK9 inhibitors that may be used in accordance with this disclosure include AZD4573 and BAY-1251. A selective inhibitor of CDK9, including 152 and BAY-1143572, and a non-CDK9 inhibitor. Selective inhibitors include CYC065, albocidib, AT7519, borsicrib, and ronisic. Includes rib and dinaciclib.

[0094] Preferably, the CDK9 inhibitor selectively inhibits CDK9 in this disclosure.

[0095] According to preferred embodiments of the CDK9 inhibitor used in this disclosure, the CDK9 inhibitor is , the following equation (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 H, C 1~3 It is alkyl, CN, or halogen; R 2 R is a 3- to 7-membered heterocycloalkyl or 3- to 7-membered cycloalkyl; 10、 OR 10 、SR 10 、S(O)R 10 、S(O)2R 10 、C(O)R 10 、C(O)O R 10 、OC(O)R 10 、OC(O)OR 10 、NH2、NHR 10 、N(R 10 )2 、NHC(O)H、NHC(O)R 10 、NR 10 C(O)H、NR 10 C(O)R 10 、NHS(O)2R 10 、NR 10 S(O)2R 10 、NHC(O)OR 10 、NR 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 、NR 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)2NR 10 C(O)OR 10 、C(O) Independently from the group consisting of H, C(O)OH, OH, CN, NO2, F, Cl, Br, and I Optionally substituted with 1 to 3 selected substituents; one or more ring CH2 groups, It can be optionally substituted with a corresponding number of -C(O) groups, and one or more ring sulfur or nitrogen atoms However, it may be selectively oxidized to form an S-oxide or an N-oxide; R 10 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 a Lucil, NH2, C(O)NH2, C(O)H, C(O)OH, OH, CN, NO2, F Independently selected from the group consisting of Cl, Br, and I; two R 10 The base is that they are connected Together with the atoms involved, they form a 3-6 membered cycloalkyl or heterocycloalkyl group. can; each of the above R 10 Alkyl, cycloalkyl, and heterocycloalkyl groups are CN, O H, halogen, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 a Lukil and NHC(O)-C 1~3 One or two substituents independently selected from alkyl groups It may be further replaced by; R 4 teeth, [ka] And, In this formula, X and Y, together with the atoms to which they are linked, in addition to bridging nitrogen, N, One or two selected from O and S It may contain heteroatoms, and the ring may be saturated or partially saturated. It also forms a 5-7 membered heterocycloalkyl ring; one or two ring CH2 groups, corresponding It can be optionally substituted with a number of -C(O) groups, and one or more ring sulfur or nitrogen atoms may be substituted. It can be selectively oxidized to form an S-oxide or N-oxide, and the ring has one or more carbon atoms on the ring carbon. or two R 10 By substituents, or on the cyclic nitrogen, R 12 It may be substituted with substituents; J is N or CR 11 and; R 11 H, C 1~3 It is alkyl; R 12 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 Alkyl, C(O)NH2, Independently selected from the group consisting of C(O)H; each R 12 Alkyl, cycloalkyl and he Terocycloalkyl groups include CN, OH, and halogens, C 1~3 Alkyl, NH2 and NH -C 1~3 Alkyl, NHC(O)-C 1~3 1 or 2 independently selected from alkyl (May be further substituted by a plurality of substituents) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0096] Further embodiments of CDK9 inhibitors include compounds of formula (I) and pharmaceutically acceptable compounds thereof It is a salt, and the substituents are defined as follows. Such specific substituents are used as needed. Depending on the context, used in any of the definitions, claims, or embodiments defined herein. obtain.

[0097] A In one embodiment, A is C(R5 )

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

[0099] R 2 In one embodiment, R 2 These are 3- to 7-membered cycloalkyl groups. In another embodiment, R 2 NHCOR 10 or R 10 3-7 member cycloal It's a kill. In another embodiment, R 2 NHCOR 10 It is a cyclohexyl that is substituted with [another compound]. In another embodiment, R 2 R 10 It is a cyclopropyl substituted with [a specific compound]. In another embodiment, R 2 These are 3- to 7-membered heterocycloalkyl groups. In another embodiment, R 2 NHCOR 10 Substituted with 3-7 member heterocycloalkyl groups That is the case. In another embodiment, R 2 It is piperidinil. In another embodiment, R 2 It is cyclobutyl. In another embodiment, R 2 R 10 It is cyclobutyl substituted with [a specific compound].

[0100] R 4 In one embodiment, R4 teeth, [ka] That is the case. In another embodiment, R 4 teeth, [ka] That is the case.

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

[0102] X and Y In one embodiment, X and Y, together with the atoms to which they are linked, form a 6-membered heterozygous It forms a chloroalkyl ring. In another embodiment, X and Y, together with the atom to which they are linked, are oxygen. It forms a six-membered heterocycloalkyl ring containing heteroatoms. In another embodiment, X and Y, together with the atom to which they are linked, are nitrogen. It forms a six-membered heterocycloalkyl ring containing heteroatoms. In another embodiment, X and Y, together with the atoms to which they are linked, form one CH2 This forms a six-membered heterocycloalkyl ring substituted with two methyl groups. In another embodiment, X and Y, together with the atoms to which they are linked, form a 5-membered heterozygous It forms a chloroalkyl ring. In another embodiment, X and Y, together with the atoms to which they are linked, form one CH2 This forms a five-membered heterocycloalkyl ring substituted with two methyl groups. In another embodiment, X and Y, together with the atoms to which they are linked, form a 7-membered heterozygous It forms a chloroalkyl ring. In another embodiment, X and Y, together with the atoms to which they are linked, form one CH2 This forms a 7-membered heterocycloalkyl ring substituted with two methyl groups.

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

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

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

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

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

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

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

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

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

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

[0113] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 NHC(O)R 10 It is a cyclohexyl substituted with; R 10 C 1~6 It is alkyl; R 4 teeth, [ka] and; J is C(R 11 ) and R 11 H is; X and Y, together with the atoms to which they are linked, form a five-membered heterocycloalkyl ring. To accomplish.

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

[0115] In another embodiment, A is C(R 5 ) and; R 5 is chloro; R 2 NHC(O)R 10 It is a cyclohexyl substituted with; R 10 C 1~6 It is alkyl; R 4 teeth, [ka] and; J is C(R11 ) and R 11 H is; X and Y, together with the atoms they are linked to, have one ring carbon and one or two R 1 0 It forms a piperidinyl ring that can be substituted with substituents.

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

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

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

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

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

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

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

[0123] In another embodiment, A is C(R5 ) and; R 5 is chloro; R 2 NHC(O)R 10 It is a cyclohexyl substituted with; R 4 teeth, [ka] and; X and Y, together with the atoms to which they are linked, form a 7-membered heterocycloalkyl ring. To accomplish.

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

[0125] In other embodiments, the CDK9 inhibitor used in this disclosure is a compound selected from the following: It is an object: (R)-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a Pyridine-3-yl)pyridine-2-yl)piperidine-3-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetra Hydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexa Carboxamide; (1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazo Ro[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexanecarboxa Mido; cis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a] Pyridine-3-yl)pyridine-2-yl)-3-hydroxycyclobutanecarboxami Do; (R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a Pyridine-3-yl)pyridine-2-yl)piperidine-3-carboxamide; cis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5- a) Pyridine-3-yl)pyridine-2-yl)cyclobutanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetra Hydroimidazo[1,2-a]pyridine-3-yl)pyridine-2-yl)cyclohexa Carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H -Pyrazolo[5,1-b][1,3]oxazine-3-yl)pyridine-2-yl)cy Roxencarboxamide; (1R,3S)-3-acetamido-N-(5-chloro- 4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyri Zin-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)cyclohexane Ruboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H -Pyrazolo[5,1-c][1,4]oxazine-3-yl)pyridine-2-yl)cy Roxencarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H -Pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)cyclohexane Carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6 ,7-Tetrahydropyrazolo[1,5-a]pyrazine-3-yl)pyridine-2-yl) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5, 6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl ) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetra Hydropyrazolo[1,5-a]pyrimidine-3-yl)pyridine-2-yl)cyclohex Sancarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)cyclohexyl Sancarboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-3-yl)pyridine-2-yl)-3-(1-hydroxycyclo Propancarboxamide) Cyclohexanecarboxamide; N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-p Roro[1,2-b]pyrazole-3-yl)pyridine-2-yl)carbamoyl)cyclo Hexyl oxetane-3-carboxamide; N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydr Ro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridin-2-yl)carbam Oxetane-3-carboxamide (Iyl)cyclohexyl)oxetane; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-3-((S)- 2-Hydroxypropanamide)cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-3-(1-Hyd Roxycyclopropanecarboxamide)Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6, 7-Dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl (L) Cyclohexanecarboxamide; (R)-N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6 -Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-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]pyrazole-3-yl)pyridine-2-yl) Carbamoyl cyclohexyl tetrahydrofuran-3-carboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)-5-fluoropyridine-2-yl (L) Cyclohexanecarboxamide; cis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b] Pyrazole-3-yl)pyridine-2-yl)-3-hydroxycyclobutanecarboxa Mido; cis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[ 1,2-b]pyrazole-3-yl)pyridine-2-yl)-3-hydroxycyclobuta Carboxamide; (1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazo Ro[1,5-a]pyridin-3-yl)pyrimidine-4-yl)cyclohexanecarbocy Samido; trans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1, 5-a) Pyridine-3-yl) Pyrimidine-4-yl) Cyclobutanecarboxamide; (1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)pyrimidine-4-yl)cyclohe Xancarboxamide; (1S,3R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-3-yl)pyridine-2-yl)-3-(2-cyanoacetamide ) Cyclohexanecarboxamide; tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tert Lahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamy Cyclohexyl carbamate; (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydro Pyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexanecal Boxamide; (1S,3R)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-3-yl)pyridine-2-yl)-3-(1-hydroxycyclop Ropancarboxamide) Cyclohexanecarboxamide; (R)-N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrah Dropyrazolo[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-tetrahydropyra Zoro[1,5-a]pyridine-3-yl)pyridine-2-yl)carbamoyl)cyclo Xyl)-3-methyloxetane-3-carboxamide; (S)-N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrah Dropyrazolo[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-tetrah Dropyrazolo[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]pyridine-3-yl)pyridine-2-yl)-3-((S)-2-hydroxy Propanamide) cyclohexanecarboxamide; (S)-N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrah Dropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl) Cyclohexyl tetrahydrofuran-3-carboxamide; (1S,3R)-3-acetamide-N-(5-cyano-4-(5,5-dimethyl-5, 6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl ) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-di Hydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl) cytoplasm Isomer 1 of lohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-di Hydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl) cytoplasm Isomer 2 of hexanecarboxamide; (1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5, 6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl ) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7- Tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclo Hexanecarboxamide; (S)-N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6 -Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-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]pyrazole-3-yl)pyridine-2-yl) Carbamoyl cyclohexyl tetrahydrofuran-2-carboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)-5-methylpyridine-2-yl ) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5, 6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl ) Cyclopentanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetra Hydro-[1,2,3]triazolo[1,5-a]pyridine-3-yl)pyridine-2- Il-cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro -5H-pyrrolo[1,2-a]imidazole-3-yl)-5-fluoropyridine-2- Il-cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7- Tetrahydropyrazolo[1,5-a]pyridine-3-yl)-5-fluoropyridine-2 -yl)cyclohexanecarboxamide; (1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetra) Hydropyrazolo[1,5-a]pyridine-3-yl)-5-fluoropyridine-2-yl ) Cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-3-(3-Hyd Roxypropanamide) cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-3-(cis-3 -Hydroxycyclobutanecarboxamide)Cyclohexanecarboxamide (1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazole-3-yl)-5-fluoropyridine-2-yl) Crohexane-1-carboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-3-yl)-5-fluoropyridine-2-yl)-3-(1-H (Droxycyclopropanecarboxamide) Cyclohexanecarboxamide; (1S,3R)-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H -Pyrrolo[1,2-a]imidazole-3-yl)pyridin-2-yl)-3-(1-H (Droxycyclopropanecarboxamide) Cyclohexanecarboxamide; N-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydr Ro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridin-2-yl)carb Moyl(cyclohexyl)oxetane-3-carboxamide; cis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[ 1,2-a]Imidazole-3-yl)pyridine-2-yl)-3-hydroxycyclobu Tancarboxamide; trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-di Hydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl) cytoplasm Isomer 1 of lohexanecarboxamide; trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-di Hydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl) cytoplasm Isomer 2 of hexanecarboxamide; trans-3-acetamide-N-(5-chloro-4-(4,5,6,7-tetrahydro Pyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexanecal Boxamide isomer 1; trans-3-acetamide-N-(5-chloro-4-(4,5,6,7-tetrahydro Pyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexanecal Boxamide isomer 2; (1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetra Lahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohex Sancarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl) Isomer 1 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl) Isomer 2 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetra Hydro-4H-pyrazolo[1,5-a]azepine-3-yl)pyridine-2-yl) cytoplasm Roxencarboxamide; N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyra Zoro[1,5-a]pyridine-3-yl)pyridine-2-yl)carbamoyl)cyclo Xyl)oxetane-3-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl) Isomer 1 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl) Isomer 2 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5, 6,7-Tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl )Isomer 1 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5, 6,7-Tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl )Isomer 2 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5, 6,7-Tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl )Isomer 1 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5, 6,7-Tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl )Isomer 2 of cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetra Lahydro-4H-pyrazolo[1,5-a]azepine-3-yl)pyridine-2-yl) Chlohexanecarboxamide; (1S,3R)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-3-yl)-5-methylpyridine-2-yl)-3-(2-Hyd Roxyacetamide)Cyclohexanecarboxamide; N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-p Roro[1,2-b]pyrazole-3-yl)-5-methylpyridine-2-yl)carbamate Oxetane-3-carboxamide (Iyl)cyclohexyl)oxetane; (1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetra Hydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl)cyclohexa Carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5 ,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)pyridine-2-yl (L) Cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyrate (Tyl)-1H-pyrazole-4-yl)pyridine-2-yl)cyclohexanecarbox Mido; (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5 -dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl) Isomer 1 of lysine-2-yl)cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5 -dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl) Isomer 2 of lysine-2-yl)cyclohexanecarboxamide; (1R,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydr Ro-4H-pyrrolo[1,2-b]pyrazole-3-yl)-5-fluoropyridine-2- Il-cyclohexanecarboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy- 2,2-dimethylpropyl)-1H-pyrazole-4-yl)pyridine-2-yl) cyclamine Rohexane-1-carboxamide; (1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5 -dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl) Lysine-2-yl)cyclohexane-1-carboxamide; (1R,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)-5-fluoropyridine-2-yl (L)Cyclohexane-1-carboxamide; and (1S,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole-3-yl)-5-fluoropyridine-2-yl (L)Cyclohexane-1-carboxamide and pharmaceutically acceptable salts thereof.

[0126] In preferred embodiments, the CDK9 inhibitor used in this disclosure has the following formula: [ka] The compound AZD4573, represented by [formula], or a pharmaceutically acceptable salt thereof.

[0127] In a more preferred embodiment, the CDK9 inhibitor used in this disclosure is given by the following formula: [ka] This is the compound AZD4573 in its free base form, represented by [formula].

[0128] CDK9 inhibitors, such as compounds of formula (I) including AZD4573, were introduced in International Publication No. 2017. The methods disclosed in pamphlet No. / 001354, etc., are investigated using methods known in the art. It can be manufactured.

[0129] 5. Combinations of antibody-drug complexes and CDK9 inhibitors In a first combined embodiment of this disclosure, an anti-HERP agent is combined with a CDK9 inhibitor. The antibody-drug complex has a drug-linker with the following formula: [ka] (In the formula, A represents the linkage site to the antibody, and is linked to the anti-HER2 antibody via thioether linkage.) It is an antibody-drug complex represented by (combined).

[0130] In another combination embodiment, the following applies to the first combination embodiment: The anti-HER2 antibody-drug conjugate is given by the following formula (I): [ka] (In the formula, A is C(R 5 ) or N; R 5 H, C 1~3 It is alkyl, CN, or halogen; R 2 R is a 3- to 7-membered heterocycloalkyl or 3- to 7-membered cycloalkyl; 10 , Ure 10 , SR 10 , S(O)R 10 S(O)2R 10 , C(O)R 10 , C(O)O R 10 ,OC(O)R 10 , OC(O)OR 10 NH2, NHR 10 , N(R 10 )2 , NHC(O)H, NHC(O)R 10 , NR 10 C(O)H, NR 10 C(O)R 10 NHS(O)2R 10 , NR 10 S(O)2R 10 , NHC(O)OR 10 , NR 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 , NR 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)2NR 10 C(O)OR 10 , C(O) Independently from the group consisting of H, C(O)OH, OH, CN, NO2, F, Cl, Br, and I Optionally substituted with 1 to 3 selected substituents; one or more ring CH2 groups, It can be optionally substituted with a corresponding number of -C(O) groups, and one or more ring sulfur or nitrogen atoms However, it may be selectively oxidized to form an S-oxide or an N-oxide; R 10 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, -OC 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 a Lucil, NH2, C(O)NH2, C(O)H, C(O)OH, OH, CN, NO2, F Independently selected from the group consisting of Cl, Br, and I; two R 10 The base is that they are connected Together with the atoms involved, they form a 3-6 membered cycloalkyl or heterocycloalkyl group. can; each of the above R 10 Alkyl, cycloalkyl, and heterocycloalkyl groups are CN, OH, halogen, C 1~3 Alkyl, -OC 1~3 Alkyl, NH2, NH-C 1~3 Alkyl and NHC(O)-C 1~3 One or two elements independently selected from alkyl groups It may be further substituted by substituents; R 4 teeth, [ka] and; In this formula, X and Y, together with the atoms they are linked to, are N in addition to the bridging nitrogen. , one or two selected from O and S It may contain heteroatoms, and the ring may be saturated or partially saturated. Alternatively, it may form a 5-7 membered heterocycloalkyl ring; one or two ring CH2 groups correspond It can be optionally substituted with a number of -C(O) groups, and one or more ring sulfur or nitrogen atoms The ring can be selectively oxidized to form an S-oxide or an N-oxide, and the ring is on the ring carbon. One or two R 10 By substituents, or on the cyclic nitrogen, R 12 It may be substituted with substituents. ; J is N or CR 11 and; R 11 H, C 1~3 It is alkyl; R 12 In each appearance, a 3-6 membered cycloalkyl or heterocycloalkyl group is present. group, C 1~6 Alkyl, C 1~6 Alkyl-OC 1~6 Alkyl, C(O)NH2, Independently selected from the group consisting of C(O)H; each R 12 Alkyl, cycloalkyl and he Terocycloalkyl groups include CN, OH, and halogens, C 1~3 Alkyl, NH2 and NH -C 1~3 Alkyl, NHC(O)-C 1~31 or 2 independently selected from alkyl (Can be further substituted with a plurality of substituents) Combined with a CDK9 inhibitor which is a compound represented by or a pharmaceutically acceptable salt thereof. It is possible.

[0131] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), A is C(R 5 ) is expressed by formula (I) as defined above. It can be combined with CDK9 inhibitors, which are compounds that can be used in combination.

[0132] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), A is C(R 5 ) and R 5 It is chloro, as defined above. It can be combined with CDK9 inhibitors.

[0133] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), A is C(R 5 ) and R 5 As defined above, is Electro It can be combined with CDK9 inhibitors.

[0134] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 CD as defined above, where the member is a 3-7 member cycloalkyl group. It can be used in combination with K9 inhibitors.

[0135] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 However, NHCOR 10 or R 103-7 member cycloal It is a kill agent, and can be combined with a CDK9 inhibitor as defined above;

[0136] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 However, the bases cyclopropyl, cyclobutyl, cyclopentyl, cyclo A CDK9 inhibitor selected from hexyl and cycloheptil as defined above, and They can be combined.

[0137] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 The above is determined by selecting from cyclopentyl and cyclohexyl. It can be combined with CDK9 inhibitors that can be used to treat the condition.

[0138] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 NHCOR 10 It is a cyclohexyl substituted with, as defined above. It can be combined with CDK9 inhibitors that can be used to treat the condition.

[0139] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 It is a 3- to 7-membered heterocycloalkyl, as defined above. It can be combined with CDK9 inhibitors.

[0140] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R 2 NHCOR 10 A 3- to 7-membered heterocycloalkyl that is substituted with It can be combined with a CDK9 inhibitor as defined above.

[0141] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In equation (I), R4 is [ka] It is used in combination with CDK9 inhibitors as defined above.

[0142] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is R4 [ka] And J is C(R 11 ) in combination with a CDK9 inhibitor as defined above. It is possible.

[0143] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is R4 [ka] And J is C(R 11 ) and R 11 CDK9 as defined above, where H is It can be combined with inhibitors.

[0144] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is In formula (I), X and Y, together with the atom to which they are linked, form a 5-membered heterozygous When combined with a CDK9 inhibitor that forms a cyclyl alkyl ring, as defined above It can be done.

[0145] In another combined embodiment, in formula (I), X and Y are the originals to which they are connected. Together with its offspring, it forms a 5-membered heterocycloalkyl group in which one CH2 is replaced by two methyl groups. A defined anti-HER2 antibody-drug conjugate that forms a ring.

[0146] In another combination embodiment, the anti-HER2 antibody-drug complex defined above is It can be combined with a CDK9 inhibitor as defined above, and the CDK9 inhibitor is as follows: formula: [ka] AZD4573, represented by [formula], or a pharmaceutically acceptable salt thereof.

[0147] In each of the above combined embodiments, the anti-HER2 antibody is SEQ ID NO: CDRH1 consists of the amino acid sequence represented by 3, and the amino acid represented by SEQ ID NO: 4 CDRH2 consists of a sequence and CDRH3 consists of an amino acid sequence represented by Sequence ID No. 5. CDRL1 and SEQ ID NO: 7 consist of a heavy chain containing the amino acid sequence represented by SEQ ID NO: 6. CDRL2 and SEQ ID NO: 8, which consist of amino acid sequences of amino acid residues 1-3, are shown. A light chain containing CDRL3 consisting of the amino acid sequence is provided. The above combination is implemented. In each of the different embodiments of the form, the anti-HER2 antibody is represented by SEQ ID NO: 9. A heavy chain containing a heavy chain variable region consisting of amino acid sequences, and an amino acid sequence represented by SEQ ID NO: 10 A light chain including a light chain variable region consisting of columns, and each of the above combination embodiments In another embodiment, the anti-HER2 antibody is derived from the amino acid sequence represented by SEQ ID NO: 1. It contains a heavy chain and a light chain consisting of the amino acid sequence represented by Sequence ID No. 2. In each of the other embodiments of the combined embodiment, the anti-HER2 antibody is as follows: A heavy chain consisting of the amino acid sequence represented by , and a chain consisting of the amino acid sequence represented by Sequence ID No. 2 It includes a light chain.

[0148] In particularly preferred combination embodiments of this disclosure, the anti-HER2 antibody-drug complex is Rustuzumab deruxtecan (DS-8201), a CDK9 inhibitor, has the following formula: [ka] This compound is represented by [formula] and is also identified as AZD4573.

[0149] 6. Combined therapeutic uses and methods The pharmaceutical product and its therapeutic use and method are described below, but hereby the anti-HER Two antibody-drug conjugates and a CDK9 inhibitor are administered in combination.

[0150] The pharmaceutical products and therapeutic uses and methods disclosed herein are anti-HER2 antibody-drug complexes and CD K9 inhibitors are individually included as active ingredients in different formulations, either simultaneously or at different times. It may be characterized by being administered, or by an antibody-drug complex and a CDK9 inhibitor being a single agent. It may be characterized by being contained as an active ingredient in a formula and administered as such.

[0151] In the pharmaceutical products and therapeutic methods disclosed herein, a single CDK9 inhibitor used herein is an anti- Can be administered in combination with a HER2 antibody-drug conjugate, or with two or more different CDKs. 9. Inhibitors may be administered in combination with antibody-drug conjugates.

[0152] The pharmaceutical products and therapeutic methods disclosed herein may be used to treat cancer, including breast cancer (triple cancer). (Including gastric and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (colon Also known as colorectal cancer, including colon cancer and rectal cancer), lung cancer (small cell lung cancer and non-small cell lung cancer) (including), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, biliary tract cancer Paget's disease (including bile duct cancer), pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer Cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, uterus Endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone marrow tumor, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic leukemia Bloody diseases, high-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-hemorrhagic leukemia Dikin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, chronic Lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, and follicular lymphoma Preferably used to treat at least one cancer selected from the group consisting of lymphomas. It may, more preferably, be used for breast cancer, gastric cancer, colorectal cancer, lung cancer (preferably non-small cell lung cancer), pancreatic cancer. Treatment of at least one cancer selected from the group consisting of visceral cancer, ovarian cancer, prostate cancer, and kidney cancer. It can be used for that purpose.

[0153] For example, tumor tissue is collected from cancer patients, fixed in formalin, and embedded in paraffin (FFPE). Prepare the specimen and then analyze it using methods such as immunohistochemistry (IHC), flow cytometry, or Testing of gene products (proteins) using Western blotting, or for example If hybridization is performed using the ISH method, quantitative PCR (q-PCR), or micro By subjecting the gene transcription to analysis using array analysis, or by using the data from cancer patients, Circulating tumor DNA (ctDNA) is recovered and analyzed using methods such as next-generation sequencing (NGS). By providing ctDNA to the test, the presence or absence of the HER2 tumor marker can be determined. obtain.

[0154] The pharmaceutical products and therapies described herein may be used for HER2-expressing cancers. It may be a cancer with overexpression (high or moderate) or a cancer with low HER2 expression.

[0155] In this disclosure, the term "HER2-overexpressing cancer" is used by those skilled in the art to describe HER2-overexpressing cancer. Insofar as it is recognized as such, it is not particularly limited. Preferred examples of HER2-overexpressing cancers include IHC. Cancers and IHCs that are given a score of 3+ for HER2 expression in the IHC method ER2 expression was given a score of 2+, and the in-situ hybridization method (ISH) was used. This may include cancers that are determined to be positive for HER2 expression in the present disclosure. Two-hybrid formation methods include fluorescence in vitro hybridization (FISH) and dual hybridization. This includes the DISH (Dual In-Side Hybrid Formation) method.

[0156] In this disclosure, the term "HER2-low expression cancer" is used by those skilled in the art to describe HER2-low expression cancer. Insofar as it is recognized as such, it is not particularly limited. Preferred examples of HER2-low-expressing cancers include IHC. In the method, HER2 expression was given a score of 2+, and in situ hybridization occurred. Cancers that are determined to be negative for HER2 expression by the law and cancers that are determined to be negative for HER2 expression by the IHC method This may include cancers that are currently given a score of 1+.

[0157] A method for scoring HER2 expression levels using the IHC method or an incite hybrid A method for determining whether HER2 expression is positive or negative by a formation method can be described by those skilled in the art. To the extent recognized, it is not particularly limited. Examples of this method include HER2 testing and guidelines for breast cancer. (Japanese Pathology Board for Optimal Us The 4th edition of e of HER2 for Breast Cancer (developed by e of HER2 for Breast Cancer) This may include the methods described in [reference].

[0158] Cancer, particularly in relation to the treatment of breast cancer, refers to HER2-overexpressing (high or moderate) or low-expressing breast cancer. Alternatively, it may be triple-negative breast cancer, and / or IHC3+, IHC2+, IHC1+. Alternatively, it may have an IHC > 0 and < 1+ HER2 status score.

[0159] The pharmaceutical products and treatments of this disclosure may be used preferably on mammals, but more preferably The word "mashiku" is used in reference to humans.

[0160] The antitumor effects of the pharmaceutical products and therapies disclosed herein are obtained by transplanting cancer cells into test animals. Prepare a test to measure the reduction in tumor volume or the life-extending effect of applying the pharmaceutical products and therapies disclosed herein. This can be confirmed by determining the antibody-drug complex used in this disclosure and The effects of combined use of CDK9 inhibitors are as follows: This can be confirmed by comparing the antitumor effects of CDK9 inhibitor monotherapy.

[0161] The antitumor effects of the pharmaceutical products and treatments disclosed herein are based on response evaluation. n Criteria in Solid Tumors (RECIST), WHO assessment Use one of the following methods: the Macdonald method, weight measurement, or other assessment approaches. This can be confirmed in clinical trials, with complete response (CR), partial response (PR); progressive disease ( PD), objective response rate (ORR), duration of response (DR), progression-free survival (PFS), overall survival rate The determination can also be made based on indicators such as (OS).

[0162] By using the above method, existing pharmaceutical products and treatments for cancer treatment can be compared to existing pharmaceutical products and therapies for cancer treatment. The superior antitumor effects of the pharmaceutical products and treatments disclosed herein can be confirmed.

[0163] The pharmaceutical products and therapies disclosed herein delay the development and inhibit the growth of cancer cells. These effects can further kill them. These effects can lead to cancer patients being affected by cancer Either the symptoms disappear, or the quality of life (QOL) of cancer patients is improved. It may be possible to achieve therapeutic effects by preserving the life of cancer patients. Even if pharmaceutical products and treatments do not completely eliminate cancer cells, they inhibit their growth. By harming or regulating, while achieving longer survival, the higher the level of cancer patients A high quality of life (QOL) can be achieved.

[0164] The pharmaceutical products disclosed herein are intended for use as systemic therapy in patients and, furthermore, for local application to cancer tissue. It is expected that the treatment will be effective when applied in the prescribed manner.

[0165] The pharmaceutical products of this disclosure may be administered containing at least one pharmaceutically appropriate ingredient. Pharmaceutically appropriate components are preferably antibody-drug complexes and CDK9 inhibitors used in this disclosure. Depending on the dosage and concentration of the agent, a selection of formulation additives commonly used in this field is made. Selected and applicable. Anti-HER2 antibody-drug conjugates used in this disclosure are, for example, HER2 Stidine buffers, vehicles such as sucrose and trehalose, and surfactants, For example, it can be administered as a pharmaceutical product containing polysorbate 80 and 20. Pharmaceutical products containing antibody-drug complexes used in the diagram are preferably administered by injection. It may, more preferably, be used as an aqueous injection or a lyophilized injection. It can be used as a lyophilized injectable.

[0166] The pharmaceutical product containing the anti-HER2 antibody-drug complex used in this disclosure is an aqueous injection. In this case, the aqueous injection is preferably diluted with a suitable diluent and then administered as an intravenous drip. It may be given. Examples of diluents may include dextrose solution, physiological saline, dextrose A dextrose solution may be preferably exemplified, and a 5% dextrose solution more preferably exemplified. It is possible.

[0167] If the pharmaceutical product of this disclosure is a lyophilized injectable, the lyophilized product is pre-dissolved in water for injection. The required amount of the dry injectable is preferably diluted with an appropriate diluent and then administered as an intravenous drip. It is possible. Examples of diluents include dextrose solution and physiological saline, and dextrose A dextrose solution may be preferably exemplified, and a 5% dextrose solution more preferably exemplified. It is possible.

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

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

[0170] The CDK9 inhibitors used in this disclosure are administered to humans as intravenous infusions at intervals of 1 to 180 days. It may be administered, preferably as an intravenous infusion at intervals of 1, 2, 3, or 4 weeks. The CDK9 inhibitors used in this disclosure may be administered in doses of 0.1 mg to 3000 mg. It can be administered as an intravenous drip in doses of g, preferably 10 mg to 100 mg per dose. It can be administered intravenously by drip infusion at doses of 1 mg to 20 mg per administration.

[0171] The size of the dose required for therapeutic treatment of a particular medical condition depends on the patient being treated, the route of administration, and The dosage will inevitably vary depending on the severity of the disease being treated. The range is 0.1 to 50 mg / kg. A weekly dose of a CDK9 inhibitor may be used. For example, the CDK9 inhibitor used in this disclosure If the compound is AZD4573 or a pharmaceutically acceptable salt thereof, then the CDK9 inhibitor is Preferably, 1 mg to 50 mg per dose, for example, 3 mg, 6 mg, 9 mg per dose. It can be administered intravenously once a week in doses of 12 mg, 15 mg, or 18 mg.

[0172] The pharmaceutical products and treatments described herein are used as adjuvant chemotherapy in combination with surgical procedures. The pharmaceutical products of this disclosure are administered for the purpose of reducing tumor size before surgery. To obtain (called neoadjuvant chemotherapy or neoadjuvant therapy), or to recur the tumor after surgery. It may be administered to prevent the onset of the disease (referred to as adjuvant chemotherapy or adjuvant therapy). [Examples]

[0173] This disclosure is described in detail with reference to the embodiments shown below. However, this disclosure is not limited to... These are not the only examples. Furthermore, this should never be interpreted restrictively.

[0174] Example 1: Preparation of antibody-drug complexes In accordance with the preparation method described in International Publication No. 2015 / 115091, and anti-H ER2 antibody (amino acid sequence represented by SEQ ID NO: 11 (amino acid residues 1-1 of SEQ ID NO: 1) A heavy chain consisting of 449) and an amino acid sequence consisting of all amino acid residues 1-214 of Sequence ID No. 2 Using a light chain consisting of and an antibody containing, the following formula: [ka] (In the formula, A represents the binding site to the antibody.) The drug-linker represented by is conjugated to the anti-HER2 antibody via a thioether linkage. We created an anti-HER2 antibody-drug conjugate (DS-8201: Trastuzumab Delux). Tecan). The DAR of the antibody-drug conjugate is 7.7 or 7.8.

[0175] Example 2: Preparation of CDK9 inhibitor According to the preparation method described in International Publication No. 2017 / 001354, Formula (I) CDK9 inhibitors are prepared. Specifically, (1S,3R)-3-acetamide-N- (5-Chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b Pyrazole-3-yl)pyridine-2-yl)cyclohexanecarboxamide; [ka] However, it can be prepared according to Example 14 of International Publication No. 2017 / 001354. .

[0176] Example 3: Antitumor Test CDK9 inhibitor AZD4573((1S,3R)-3-acetamido-N-(5-chloro -4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole) Antibody-drug conjugate with (-3-yl)pyridine-2-yl)cyclohexanecarboxamide) Combination of DS-8201 (trastuzumab / deruxtecan) method: Four types of HER2 cell lines - Three types of breast cancer as shown in Table 1 (SKBR3, MDA- MB-468 and KPL4) and one gastric cancer (NCI-N87) were subjected to 66-hour rest. Three logarithmic stepwise concentrations of DMSO or DS-8201 (3, 30 and 300 nucleotides) Treat with either g / mL, and at that point administer a vehicle or AZD4573 10-point Either of the 1 / 2 logarithmic continuous dilutions was added for a further 6 hours.

[0177] [Table 1]

[0178] After 6 hours of incubation with AZD4573, remove the culture medium and rinse twice with fresh phosphate-buffered saline. By adding PBS, removing it, and replacing the final washing solution with fresh medium, both drugs The items were washed away. Next, before evaluating cell viability using the CellTiter-Glo reagent... The cells were then incubated for an additional 18 hours. A dose-response curve was created, as shown in Figure 12. For that purpose, I used GraphPad Prism.

[0179] Preclinical breast and gastric cancer cell lines showed different reactions to DS-8201 across a range of doses. It shows activity, but of the four cell lines selected for this screening, it is the most sensitive. Even in highly susceptible individuals, complete loss of survival ability is not observed.

[0180] In two of the four cell lines tested (Figure 12: top row), AZD4573 showed The results of a 6-hour treatment followed by a 66-hour induction of DS-8201 showed a dose-dependent improvement in cell viability. The loss is amplified, thus demonstrating the advantages of the combination.

[0181] Therefore, the combination of DS-8201 with an acute CDK9 inhibitor using AZD4573 The combined study revealed an enhanced loss of viability in preclinical HER2 cancer cell lines. .

[0182] Example 4: Antitumor Test CDK9 inhibitor AZD4573((1S,3R)-3-acetamido-N-(5-chloro -4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole) Antibody-drug conjugate with (-3-yl)pyridine-2-yl)cyclohexanecarboxamide) Combination of DS-8201 (trastuzumab / deruxtecan) method: To evaluate the combined effect of AZD4573 (CDK9 inhibitor) and DS-8201 Therefore, HCC1954 breast cancer cells (HER2+) were subcutaneously introduced into 69 CB17-SCID mice. The cell line was transplanted. Tumor volume was monitored via caliper measurements, and the average tumor size was used. The mice were randomly divided. At the time of randomization, the group receiving DS-8201 was administered intravenously. AZD4573 was administered 24 hours after the DS-8201 treatment. The total dose of AZD4573 was Then, IP was administered after a 2-hour interval. The BID regimen was used for the 10 mg / kg dose. TID was used for a 5 mg / kg dose. This was done over a total of 3 cycles, and then weekly thereafter. AZD4573 was administered. Therefore, as shown by the vertical dotted line in Figure 13, the 0 Administer DS-8201 intravenously on day 1, and treat with AZD4573 on days 1, 8, and 15. went.

[0183] result: The tumor volume for treatment with DS-8201 and / or AZD4573 is shown in Figure 13. The data represents the change in tumor volume over time for the treatment group. As shown in Table 2, Bihik For the control group, tumor growth inhibition (TGI) was calculated using tumor measurement.

[0184] [Table 2]

[0185] The tumor dynamics growth curve (Figure 13) and TGI analysis (Table 2) show that AZD4573 is H This demonstrates a minimal tumor growth control as monotherapy in the CC1954 model.

[0186] Treatment with DS-8201 monotherapy at 3 mg / kg resulted in a total glycemic index (TGI) of 91.867%, and 10 months The TGI was 96.441% in g / kg. The most robust response was observed with AZD4573. DS-8201 10 mg / kg treatment group in combination with 10 mg / kg and 5 mg / kg Observed at 10 mg / kJ (99.829% TGI and 99.776% TGI, respectively), Maximum activity was observed with DS-8201 + 10 mg / kg BID AZD4573. (99.829% TGI).

[0187] The aforementioned specification document is sufficient to enable a person skilled in the art to carry out the embodiments. It is considered. The above description and examples detail a particular embodiment and are considered by the inventors. The best possible format is described. However, the above is described in detail in the text. Even if the embodiment is carried out in many ways, the claims may be any equivalent thereof It should be understood that this includes [something].

[0188] Free text in an array list 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 97-10 of SEQ ID NO: 1] 9] 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 of light chain CDRL2 (SAS) [= 5 amino acid residues of SEQ ID NO: 2] amino acid sequences containing [0-56] 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 the heavy chain variable region [= Amino acid residues 1-120 of SEQ ID NO: 1] SEQ ID NO: 10 - Amino acid sequence of the light chain variable region [= Amino acid residues 1-107 of SEQ ID NO: 2] ] SEQ ID NO: 11 - Amino acid sequence of the heavy chain [= Amino acid residues 1-449 of SEQ ID NO: 1]

Claims

1. For combined administration, an anti-HER2 antibody-drug conjugate and a CDK9 inhibitor are used. A pharmaceutical product containing the anti-HER2 antibody-drug complex having the following formula: 【Chemistry 1】 The drug-linker represented by (wherein A represents the binding site to the antibody) is bound to the thioether. A pharmaceutical product that is an antibody-drug conjugate that is combined with an anti-HER2 antibody via a compounding pathway.

2. A pharmaceutical product according to claim 1, wherein the CDK9 inhibitor is of the following formula (I): 【Chemistry 2】 (In the formula, A is C(R ５ ) or N; R ５ H, C １～３ It is alkyl, CN, or halogen; R ２ R is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl; １０ , OR １０ 、SR １０ 、S(O)R １０ 、S(O) ２ R １０ 、C(O)R １０ 、C(O)O R １０ 、OC(O)R １０ 、OC(O)OR １０ 、NH ２ 、NHR １０ 、N(R １０ ) ２ 、NXC(O)H、NXC(O)R １０ 、 １０ C(O)H、NR １０ C(O)R １０ 、NHS(O) ２ R １０ 、NR １０ S(O) ２ R １０ 、NHC(O)OR １０ 、NR １０ C(O)OR １０ NHC(O)NH ２ NHC(O)NHR １０ 、NHC(O)N(R １０ ) ２ NR １０ C(O)NH ２ NR １０ C(O)NHR １０ NR １０ C(O)N (R) １０ ) ２ C(O)NH ２ 、C(O)NHR １０ 、C(O)N(R １０ ) ２ 、C(O) )NHOH、C(O)NHOR １０ 、C(O)NHS(O) ２ R １０ 、C(O)NR １０ S (O) ２ R １０ 、S(O) ２ NH ２ 、S(O) ２ NHR １０ 、S(O) ２ N(R １０ ) ２ 、S(O) ２ NHC(O)OR １０ 、S(O) ２ NR １０ C(O)OR １０ 、C(O) H, C(O)OH, OH, CN, NO ２ Independently from the group consisting of F, Cl, Br, and I Optionally substituted with 1 to 3 selected substituents; one or more ring CH ２ The base, It can be optionally substituted with a corresponding number of -C(O) groups, and one or more ring sulfur or nitrogen atoms However, it may be selectively oxidized to form S-oxide or N-oxide; R １０ In each instance, a 3-6 member cycloalkyl or heterocycloalkyl group appears. group, C １～６ Alkyl, -O-C １～６ Alkyl, C １～６ Alkyl-O-C １～６ a ルキル、NH ２ 、C(O)NH ２ 、C(O)H、C(O)OH、OH、CN、NO ２ 、F , independently selected from the group consisting of Cl, Br and I; two R １０ The base is that they are connected Together with the atoms involved, they form a 3- to 6-membered cycloalkyl or heterocycloalkyl group. do; each of the above R １０ Alkyl, cycloalkyl, and heterocycloalkyl groups are CN, OH, halogen, C １～３ Alkyl, -O-C １～３ Alkyl, NH ２ NH-C １～３ Alkyl and NHC(O)-C １～３ One or two elements independently selected from alkyl groups It may be further substituted with substituents; R ４ teeth, 【Transformation 3】 And, In the formula, X and Y, together with the atoms to which they are linked, are N, O and bridging nitrogen. A 5-7 member heterocycloalkyl compound that may contain one or two heteroatoms selected from S. A ring is formed, and the ring may be saturated or partially saturated; one or two ring CH ２ The base is the corresponding number It can be optionally substituted with a -C(O) group, and one or more ring sulfur or nitrogen atoms are optional. It can be selectively oxidized to form an S-oxide or an N-oxide, and the ring has 1 on the ring carbon. Or two R １０ By substituents, or on the nitrogen ring, R １２ It may be substituted by substituents; J is N or CR １１ And; R １１ H, C １～３ It is alkyl; R １２ In each instance, a 3-6 member cycloalkyl or heterocycloalkyl group appears. Ru group, C １～６ alkyl, C １～６ alkyl - O - C １～６ alkyl, C(O)NH ２ , Independently selected from the group consisting of C(O)H; each R １２ Alkyl, cycloalkyl and he Terocycloalkyl groups consist of CN, OH, and halogens, C １～３ Alkyl, NH ２ and NH -C １～３ alkyl, NHC(O)-C １～３ 1 or 2 independently selected from alkyl (Further substitutions may be made by these substituents.) A pharmaceutical product which is a compound represented by or a pharmaceutically acceptable salt thereof.

3. In equation (I), A is C(R ５ The pharmaceutical product according to claim 2, which is the same as the one described in claim 2.

4. R ５ The pharmaceutical product according to claim 3, wherein the product is chloro.

5. R ５ The pharmaceutical product according to claim 3, wherein is fluoro.

6. In equation (I), R ２ The pharmaceutical product according to claim 2, wherein is a 3- to 7-membered cycloalkyl group 。

7. In equation (I), R ２ However, NHCOR １０ or R １０ 3-7 member cycloa that are replaced by The pharmaceutical product according to claim 2, which is Lukill.

8. R ２ However, the bases cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo A pharmaceutical product according to claim 6, selected from the group loheptil.

9. R ２ However, the pharmaceutical product according to claim 8, selected from cyclopentyl and cyclohexyl Product.

10. R ２ However, NHCOR １０ The pharmacopoeia according to claim 7, which is a cyclohexyl substituted with Product.

11. In equation (I), R ２ The medical device according to claim 2, wherein the member is a 3- to 7-membered heterocycloalkyl group. Pharmaceutical products.

12. In equation (I), R ２ ga NHCOR １０ Substituted with 3- to 7-membered heterocycloalkyl groups The pharmaceutical product according to claim 2.

13. In equation (I), R ４ but, 【Chemistry 4】 The pharmaceutical product according to claim 2.

14. J is C(R １１ The pharmaceutical product according to claim 13, which is the same as the pharmaceutical product according to claim 13.

15. R １１ The pharmaceutical product according to claim 14, wherein H is present.

16. In formula (I), X and Y, together with the atom to which they are linked, form a five-membered heterozygous The pharmaceutical product according to claim 2, which forms a cycloalkyl ring.

17. In formula (I), X and Y, together with the atom to which they are linked, form one CH ２ The following is described in claim 2, which forms a five-membered heterocycloalkyl ring substituted with two methyl groups. Listed pharmaceutical products.

18. The CDK9 inhibitor is given by the following formula: 【Transformation 5】 AZD4573 represented by, or a pharmaceutically acceptable salt thereof, as described in claim 2. A pharmaceutical product.

19. The aforementioned anti-HER2 antibody is CDRH1, which consists of the amino acid sequence represented by SEQ ID NO:

3. CDRH2, which consists of the amino acid sequence represented by SEQ ID NO: 4, and SEQ ID NO: 5 A heavy chain containing CDRH3 consisting of the amino acid sequence and an amino acid sequence represented by SEQ ID NO: 6 CDRL1 consists of a series of amino acid residues 1-3 of SEQ ID NO:

7. A light chain containing CDRL3, which consists of the amino acid sequence represented by CDRL2 and SEQ ID NO: 8 A pharmaceutical product according to any one of claims 1 to 18, wherein the antibody contains ,

20. The anti-HER2 antibody has a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO:

9. A heavy chain containing and a light chain variable region consisting of the amino acid sequence represented by Sequence ID No.

10. A pharmaceutical product according to any one of claims 1 to 18, wherein the antibody comprises a chain.

21. The anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by Sequence ID No. 1, and a sequence Claims 1 to 18, an antibody comprising a light chain consisting of an amino acid sequence represented by number 2. A pharmaceutical product as described in any one of the following items.

22. The anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11, and Claims 1 to 1 are antibodies comprising a light chain consisting of an amino acid sequence represented by column number 2. A pharmaceutical product as described in any one of item 8.

23. A pharmaceutical product according to any one of claims 1 to 22, wherein the anti-HER2 antibody-drug compound The combined product is given by the following formula: 【Transformation 6】 It is represented by, In the formula, the "antibody" is a compound of the drug-linker via a thioether bond. This represents an ER2 antibody, where n is the antibody molecule before it is complexed in the antibody-drug complex. This refers to a pharmaceutical product where the average number of units of the drug-linker is shown, and n is in the range of 7 to 8.

24. Claim 1, wherein the anti-HER2 antibody-drug complex is trastuzumab deruxtecan. A pharmaceutical product as described in any one of the following 23 items.

25. A combination comprising the anti-HER2 antibody-drug complex and the CDK9 inhibitor for simultaneous administration. A pharmaceutical product according to any one of claims 1 to 24.

26. For continuous or simultaneous administration, the anti-HER2 antibody-drug complex and the CDK9 inhibitor A pharmaceutical product according to any one of claims 1 to 24, which is a combination preparation containing the above.

27. A pharmaceutical product according to any one of claims 1 to 26, for the purpose of treating cancer.

28. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and biliary tract cancer. Cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, children Body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone Myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic Leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-leukemia Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma and follicular The pharmaceutical product according to claim 27, which is at least one selected from the group consisting of genital lymphomas. Product.

29. The pharmaceutical product according to claim 27, wherein the cancer is breast cancer.

30. The breast cancer has an IHC3+ HER2 status score, according to claim 29. Pharmaceutical products.

31. The pharmaceutical product according to claim 29, wherein the breast cancer is HER2-low expressing breast cancer.

32. The breast cancer has an IHC2+ HER2 status score, according to claim 29. Pharmaceutical products.

33. The breast cancer has an IHC1+ HER2 status score, according to claim 29. Pharmaceutical products.

34. Claim 29, the breast cancer has an IHC > 0 and < 1+ HER2 status score. The pharmaceutical products listed below.

35. The pharmaceutical product according to claim 29, wherein the breast cancer is triple-negative breast cancer.

36. The pharmaceutical product according to claim 27, wherein the breast cancer is gastric cancer.

37. The pharmaceutical product according to claim 27, wherein the breast cancer is colorectal cancer.

38. The pharmaceutical product according to claim 27, wherein the cancer is lung cancer.

39. The pharmaceutical product according to claim 38, wherein the lung cancer is non-small cell lung cancer.

40. The pharmaceutical product according to claim 27, wherein the cancer is pancreatic cancer.

41. The pharmaceutical product according to claim 27, wherein the cancer is ovarian cancer.

42. The pharmaceutical product according to claim 27, wherein the cancer is prostate cancer.

43. The pharmaceutical product according to claim 27, wherein the cancer is kidney cancer.

44. A pharmaceutical product according to any one of claims 1 to 26, for use in the treatment of cancer.

45. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and biliary tract cancer. Cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, children Body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone Myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic Leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-leukemia Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma and follicular The use of claim 44, which is at least one selected from the group consisting of sexual lymphomas. A pharmaceutical product for that purpose.

46. The pharmaceutical product for use according to claim 44, wherein the cancer is breast cancer.

47. The breast cancer described in claim 46 has an IHC3+ HER2 status score. A pharmaceutical product for use.

48. The pharmaceutical product for use according to claim 46, wherein the breast cancer is HER2-low expressing breast cancer.

49. The breast cancer described in claim 46 has an IHC2+ HER2 status score. A pharmaceutical product for use.

50. The breast cancer described in claim 46 has an IHC1+ HER2 status score. A pharmaceutical product for use.

51. Claim 4, the breast cancer has an IHC > 0 and < 1+ HER2 status score. A pharmaceutical product for use as described in item 6.

52. The pharmaceutically acceptable product for use according to claim 46, wherein the breast cancer is triple-negative breast cancer. Product.

53. The pharmaceutical product for use according to claim 44, wherein the cancer is gastric cancer.

54. The pharmaceutical product for use according to claim 44, wherein the cancer is colorectal cancer.

55. The pharmaceutical product for use according to claim 44, wherein the cancer is lung cancer.

56. The pharmaceutical product for use according to claim 55, wherein the lung cancer is non-small cell lung cancer.

57. The pharmaceutical product for use according to claim 44, wherein the cancer is pancreatic cancer.

58. The pharmaceutical product for use according to claim 44, wherein the cancer is ovarian cancer.

59. The pharmaceutical product for use according to claim 44, wherein the cancer is prostate cancer.

60. The pharmaceutical product for use according to claim 44, wherein the cancer is kidney cancer.

61. Combination anti-HER2 antibody-drug conjugates and CDK9 inhibitors for treating cancer In the manufacture of a drug for the administration of the anti-HER2 antibody-drug complex or the CDK9 The use of inhibitors, wherein the anti-HER2 antibody-drug complex and the CDK9 inhibitor are Use as described in any one of the requests 1 to 24.

62. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and biliary tract cancer. Cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, children Body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone Myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic Leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-leukemia Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma and follicular The use according to claim 61, which is at least one selected from the group consisting of sexual lymphomas.

63. The use according to claim 61, wherein the cancer is breast cancer.

64. The breast cancer described in claim 63 has an IHC3+ HER2 status score. For.

65. The use according to claim 63, wherein the breast cancer is a HER2-low expressing breast cancer.

66. The breast cancer described in claim 63 has an IHC2+ HER2 status score. For.

67. The breast cancer described in claim 63 has an IHC1+ HER2 status score. For.

68. Claim 63, the breast cancer has an IHC > 0 and < 1+ HER2 status score. Use as described above.

69. The use according to claim 63, wherein the breast cancer is triple-negative breast cancer.

70. The use according to claim 61, wherein the cancer is gastric cancer.

71. The use according to claim 61, wherein the cancer is colorectal cancer.

72. The use according to claim 61, wherein the cancer is lung cancer.

73. The use according to claim 72, wherein the lung cancer includes non-small cell lung cancer.

74. The use according to claim 61, wherein the cancer is pancreatic cancer.

75. The use according to claim 61, wherein the cancer is ovarian cancer.

76. The use according to claim 61, wherein the cancer is prostate cancer.

77. The use according to claim 61, wherein the cancer is kidney cancer.

78. The aforementioned drug is administered simultaneously with the anti-HER2 antibody-drug complex and the CDK9 inhibitor. The use according to any one of claims 60 to 76, wherein the composition contains a harmful agent.

79. The aforementioned drug is the anti-HER2 antibody-drug complex and the C for continuous or simultaneous administration. A combination preparation containing a DK9 inhibitor, as described in any one of claims 60 to 76. For.

80. A method for treating cancer, which can be combined with any of claims 1 to 24 for a subject requiring the treatment. This includes administering any of the anti-HER2 antibody-drug complexes and CDK9 inhibitors described in item 1. ,method.

81. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and biliary tract cancer. Cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, abdominal cancer, liver cancer, hepatocellular carcinoma, children Body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone Myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, acute myeloid leukemia, acute lymphoblastic Leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, Richter syndrome, B-cell non-leukemia Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, small lymphocytic lymphoma, multiple myeloma, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma and follicular The method according to claim 80, wherein at least one selected from the group consisting of genital lymphomas.

82. The method according to claim 80, wherein the cancer is breast cancer.

83. The breast cancer according to claim 82, wherein the breast cancer has an IHC3+ HER2 status score. Law.

84. The method according to claim 82, wherein the breast cancer is a HER2-low-expressing breast cancer.

85. The breast cancer according to claim 82, wherein the breast cancer has an IHC2+ HER2 status score. Law.

86. The breast cancer according to claim 82, wherein the breast cancer has an IHC1+ HER2 status score. Law.

87. Claim 82, the breast cancer has an IHC > 0 and < 1+ HER2 status score. Methods used.

88. The method according to claim 82, wherein the breast cancer is triple-negative breast cancer.

89. The method according to claim 80, wherein the cancer is gastric cancer.

90. The method according to claim 80, wherein the cancer is colorectal cancer.

91. The method according to claim 80, wherein the cancer is lung cancer.

92. The method according to claim 91, wherein the lung cancer is non-small cell lung cancer.

93. The method according to claim 80, wherein the cancer is pancreatic cancer.

94. The method according to claim 80, wherein the cancer is ovarian cancer.

95. The method according to claim 80, wherein the cancer is prostate cancer.

96. The method according to claim 80, wherein the cancer is kidney cancer.

97. This includes administering the anti-HER2 antibody-drug complex and the CDK9 inhibitor in succession. The method according to any one of claims 80 to 99.

98. This includes simultaneously administering the anti-HER2 antibody-drug complex and the CDK9 inhibitor. or the method according to any one of claims 80 to 96.

Images