WO2021260582A1 - Combination of antibody-drug conjugate and aurora b inhibitor - Google Patents

Combination of antibody-drug conjugate and aurora b inhibitor Download PDF

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WO2021260582A1
WO2021260582A1 PCT/IB2021/055551 IB2021055551W WO2021260582A1 WO 2021260582 A1 WO2021260582 A1 WO 2021260582A1 IB 2021055551 W IB2021055551 W IB 2021055551W WO 2021260582 A1 WO2021260582 A1 WO 2021260582A1
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cancer
amino
pharmaceutical product
antibody
alkyl
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PCT/IB2021/055551
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French (fr)
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Jerome Thomas Mettetal Ii
Stephen Thomas DURANT
Azadeh Cheraghchi Bashi ASTANEH
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Astrazeneca Uk Limited
Daiichi Sankyo Company, Limited
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Publication of WO2021260582A1 publication Critical patent/WO2021260582A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present disclosure relates to a pharmaceutical product for administration of a specific antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, in combination with an Aurora B inhibitor, and to a therapeutic use and method wherein the specific antibody-drug conjugate and the Aurora B inhibitor are administered in combination to a subject.
  • Aurora kinases are cell cycle regulated serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2 and mitosis and a role for human Aurora kinases in cancer has long been implicated. Aurora kinase inhibitors are disclosed, for example, in W02004/058781 .
  • ADCs Antibody-drug conjugates
  • ADCs which are composed of a cytotoxic drug conjugated to an antibody, can deliver the drug selectively to cancer cells, and are therefore expected to cause accumulation of the drug within cancer cells and to kill the cancer cells
  • trastuzumab deruxtecan which is composed of a HER2-targeting antibody and a derivative of exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108;
  • the antibody-drug conjugate used in the present disclosure (an anti-HER2 antibody-drug conjugate that includes a derivative of the topoisomerase I inhibitor exatecan) has been confirmed to exhibit an excellent antitumor effect in the treatment of certain cancers such as breast cancer and gastric cancer, when administered singly. Furthermore, an Aurora B inhibitor has been confirmed to exhibit an antitumor effect in the treatment of certain cancers. However, it is desired to provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers, such as enhanced efficacy, increased durability of therapeutic response and/or reduced dose-dependent toxicity.
  • the present disclosure provides a pharmaceutical product which can exhibit an excellent antitumor effect in the treatment of cancers, through administration of an anti-HER2 antibody-drug conjugate in combination with an Aurora B inhibitor.
  • the present disclosure also provides a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate and Aurora B inhibitor are administered in combination to a subject.
  • the present disclosure relates to the following [1] to [59]:
  • a pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor for administration in combination, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond;
  • Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • X is 0, S, S(O), S(0) 2 or NR 14 ;
  • m is 0, 1, 2 or 3;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and Ci-6alkyl which Ci-6alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further substituted
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2 -4alkenyl, C 2 -4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl, or a pharmaceutically acceptable salt thereof;
  • Ring A is a group of formula (a), (b), (c), (d) or (e): where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR 6 R 7 ) group of formula (I);
  • R 1 is Ci-salkyl substituted by phosphonooxy and R 2 is a group selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups, or R 2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylC 1-4 alkyl;
  • R 1 is 2-phosphonooxyethyl
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • nanoparticle comprises:
  • the pharmaceutical product according to any one of [1] to [22] wherein the product is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
  • the medicament is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
  • an anti-HER2 antibody-drug conjugate for use, in combination with an Aurora B inhibitor, in the treatment of cancer wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
  • the anti-HER2 antibody-drug conjugate for the use according to [48] wherein the cancer is as defined in any one of [26] to [41];
  • an Aurora B inhibitor for use, in combination with an anti-HER2 antibody-drug conjugate, in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
  • [56] a method of treating cancer comprising administering an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor as defined in any one of [1] to [22] in combination to a subject in need thereof; [57] the method according to [56], wherein the cancer is as defined in any one of [26] to [41]; and
  • the present disclosure provides a pharmaceutical product wherein an anti-HER2 antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, and an Aurora B inhibitor are administered in combination, and a therapeutic use and method wherein the specific antibody- drug conjugate and the Aurora B inhibitor are administered in combination to a subject.
  • the present disclosure can provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers.
  • Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ ID NO: 1]
  • Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 2).
  • SAS light chain CDRL2
  • Figure 12 is a diagram showing combination matrices obtained with high-throughput screens combining DS-8201 with AZD2811 (AZ11792866; Aurora B inhibitor) in a breast cancer cell line and a gastric cell line with high HER2 expression.
  • SI Systeme International de Unites
  • inhibitor refers to any statistically significant decrease in biological activity, including full blocking of the activity.
  • inhibition can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in biological activity.
  • Cellular proliferation can be assayed using art recognized techniques which measure rate of cell division, and/or the fraction of cells within a cell population undergoing cell division, and/or rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation) .
  • subject refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • subject and patient are used interchangeably herein in reference to a human subject.
  • pharmaceutical product refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered.
  • Such product can be sterile.
  • simultaneous administration is meant that the active ingredients are administered at the same time.
  • sequential administration is meant that the active ingredients are administered one after the other, in either order, at a time interval between the individual administrations. The time interval can be, for example, less than 24 hours, preferably less than 6 hours, more preferably less than 2 hours.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • a subject is successfully "treated” for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancers include but are not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma
  • Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
  • hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
  • cytotoxic agent as used herein is defined broadly and refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells (cell death), and/or exerts anti- neoplastic/anti-proliferative effects.
  • a cytotoxic agent prevents directly or indirectly the development, maturation, or spread of neoplastic tumor cells.
  • the term includes also such agents that cause a cytostatic effect only and not a mere cytotoxic effect.
  • chemotherapeutic agents as specified below, as well as other HER2 antagonists, anti-angiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, members of the cytokine family, radioactive isotopes, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin.
  • chemotherapeutic agent is a subset of the term “cytotoxic agent” comprising natural or synthetic chemical compounds.
  • compounds of the present disclosure may be administered to a patient to promote a positive therapeutic response with respect to cancer.
  • positive therapeutic response with respect to cancer treatment refers to an improvement in the symptoms associated with the disease.
  • an improvement in the disease can be characterized as a complete response.
  • complete response refers to an absence of clinically detectable disease with normalization of any previous test results.
  • an improvement in the disease can be categorized as being a partial response.
  • a "positive therapeutic response” encompasses a reduction or inhibition of the progression and/or duration of cancer, the reduction or amelioration of the severity of cancer, and/or the amelioration of one or more symptoms thereof resulting from the administration of compounds of the present disclosure.
  • such terms refer to one, two or three or more results following the administration of compounds of the instant disclosure:
  • the size of the cancer is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%, and
  • Clinical response can be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scan, x-radiographic imaging, computed tomographic (CT) scan, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistry, including but not limited to changes detectable by ELISA, RIA, chromatography, and the like.
  • MRI magnetic resonance imaging
  • CT computed tomographic
  • FACS fluorescence-activated cell sorter
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “tert-butyl” are specific for the branched chain version only. An analogous convention applies to other generic terms, for example “alkenyl” and “alkynyl”.
  • Cycloalkyl is a monocyclic, saturated alkyl ring and "aryl” is a monocyclic or bicyclic aromatic ring.
  • heteroaryl is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.
  • Heterocyclyl is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring may be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-; wherein a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring —NH is optionally substituted by acetyl, formyl, methyl or mesyl; and wherein a ring is optionally substituted by one or more halo.
  • Phosphonooxy is in one aspect a group of formula -P(0)(OH)2.
  • phosphonooxy also includes salts of this group such as those formed with alkali metal ions such as sodium or potassium ions or alkaline earth metal ions, for example calcium or magnesium ions.
  • substituents are chosen from “1 or 2", from “1, 2, or 3” or from “1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the sameor the substituents being chosen from two or more of the specified groups i.e. the substituents not being the same.
  • Suitable values for any R group (R 1 to R 14 in formula (I)) or any part or substituent for such groups include: for C 1-4 alkyl: methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl and tert-butyl; for C 1-6 alkyl: C 1-4 alkyl, pentyl, 2,2-dimethylpropyl,
  • alkyl cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for arylC 1-4 alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl; for halo: fluoro, chloro, bromo and iodo; for C 1-4 alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for Ci-6alkoxy: C 1-4 alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; for heteroaryl:pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl, ox
  • N-formylpiperazinyl N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5- dioximidazolidinyl, 2,2-dimethyl-l,3-dioxolanyl and 3,4- dimethylenedioxybenzyl .
  • the phrase "effective amount” means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical product will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient (s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of formula (I) for use in the treatment of cancer in combination with the antibody-drug conjugate is an amount such that the combination is sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer, to slow the progression of cancer, or to reduce in patients with symptoms of cancer the risk of getting worse.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compounds of formula (I) may encompass compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • 0 may be in any isotopic form, including 16 O and 18 O; and the like.
  • the present disclosure may use compounds of formula (I) as herein defined as well as salts thereof. Salts for use in pharmaceutical products will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the disclosure may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts.
  • acid addition salts include but are not limited to fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid.
  • salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • an alkali metal salt for example sodium or potassium
  • an alkaline earth metal salt for example calcium or magnesium
  • organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • the compounds of formula (I) may also be provided as in vivo hydrolysable esters.
  • An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
  • esters for carboxy include C 1-6 alkoxymethyl esters for example methoxymethyl, C 1-6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3-8 cycloalkcarbonyloxyC 1-6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl,
  • esters for example (5-methyl-l,3-dioxolen-2-one )ylmethyl, and C 1-6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this disclosure.
  • Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a- acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy groups.
  • Examples of a- acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy .
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include Ci- l oalkanoyl, for example acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-C 1-4 alkylcarbamoyl and N-(di-C 1-4 alkylaminoethyl)-N-C 1-4 alkylcarbamoyl (to give carbamates); di-C 1-4 alkylaminoacetyl and carboxyacetyl.
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, C 1-4 alkylaminomethyl and di- (Ci-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • esters include, for example, R A C(0)0C 1-6 alkyl-C0-, wherein R A is for example, benzyloxy-Ci-4alkyl, or phenyl.
  • Suitable substituents on a phenyl group in such esters include, for example, 4-C 1-4 alkylpiperazino-C 1-4 alkyl, piperazino- Ci-4alkyl and morpholino-Ci-4alkyl.
  • the antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which a drug- linker represented by the following formula:
  • A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
  • the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker".
  • the drug- linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.
  • the drug-linker of the present disclosure includes exatecan (IUPAC name: (IS,9S)-l-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H, 13H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro- 9-hydroxy-4-methy1- 1H,12H-benzo [de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-10,13 (9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component.
  • Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:
  • anti-HER2 antibody-drug conjugate used in the present disclosure can be also represented by the following formula:
  • the drug-linker is conjugated to an anti-HER2 antibody ('Antibody-') via a thioether bond.
  • n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to- Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule.
  • DAR Drug-to- Antibody Ratio
  • the anti-HER2 antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release a compound represented by the following formula:
  • This compound is inferred to be the original source of the antitumor activity of the antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097- 5108, Epub 2016 Mar 29).
  • the anti-HER2 antibody-drug conjugate used in the present disclosure is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039- 1046).
  • the bystander effect is exerted through a process whereby the antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target and the compound released then exerts an antitumor effect also on cancer cells which are present therearound and not expressing the target.
  • This bystander effect is exerted as an excellent antitumor effect even when the anti-HER2 antibody-drug conjugate is used in combination with an Aurora B inhibitor according to the present disclosure.
  • the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure may be derived from any species, and is preferably an anti-HER2 antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well known technique.
  • the anti-HER2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.
  • the antibody in the antibody-drug conjugate used in the present disclosure is an anti-HER2 antibody preferably having a characteristic of being capable of targeting cancer cells, and is preferably an antibody possessing, for example, a property of recognizing a cancer cell, a property of binding to a cancer cell, a property of internalizing in a cancer cell, and/or cytocidal activity against cancer cells.
  • the binding activity of the anti-HER2 antibody against cancer cells can be confirmed using flow cytometry.
  • the internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751- 761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol.
  • a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000).
  • the immunotoxin a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used.
  • the antitumor activity of the anti-HER2 antibody can be confirmed in vitro by determining inhibitory activity against cell growth.
  • a cancer cell line overexpressing HER2 as a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth.
  • the antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining change in the cancer cell.
  • the anti-HER2 antibody-drug conjugate exerts an antitumor effect
  • the anti-HER2 antibody should have the property of internalizing to migrate into cancer cells.
  • the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art.
  • the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo.
  • the origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like.
  • the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease.
  • antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained.
  • a method known in the art e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)
  • the antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified.
  • the antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen expressing cells or a cell line expressing the antigen.
  • the anti-HER2 antibody in the antibody-drug conjugate used the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody.
  • These antibodies can be produced using a known method.
  • chimeric antibody an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-
  • an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), and an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (WO 90/07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337) can be exemplified .
  • CDR complementarity determining region
  • human antibody an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology:Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et.
  • an antibody obtained by phage display the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science.
  • modified variants of the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure are also included.
  • the modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification.
  • Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or 0-linked carbohydrate chain, etc.
  • the biologically modified variant examples include variants obtained by post-translational modification (such as N-linked or 0-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell.
  • an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.
  • Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.
  • deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain variants obtained by amidation of deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included.
  • the type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved.
  • the two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full- length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom.
  • the ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-HER2 antibody according to the present disclosure and the culture conditions; however, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be exemplified as preferred.
  • IgG IgGl, IgG2, IgG3, IgG4
  • IgGl or IgG2 can be exemplified as preferred.
  • anti-HER2 antibody refers to an antibody which specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has an activity of internalizing in HER2-expressing cells by binding to HER2.
  • HER2 Human Epidermal Growth Factor Receptor Type 2
  • Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5821337) and pertuzumab (W001/00245), and trastuzumab can be exemplified as preferred.
  • a drug-linker intermediate for use in production of the anti-HER2 antibody-drug conjugate according to the present disclosure is represented by the following formula:
  • the drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanoyl]glycylglycyl-L-phenylalanyl-N- [(2- ⁇ [(IS,9S)- 9-ethyl-5-fluoro-9-hydroxy-4-methyl-1 0,13-dioxo- 2,3,9,10,13,15-hexahydro-lH,12H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl]amino ⁇ -2-oxoethoxy)methyl]glycinamide, and can be produced with reference to descriptions in WO2014/057687, WO2015/098099, W02015/115091, WO2015/155998,
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be produced by reacting the above- described drug-linker intermediate and an anti-HER2 antibody having a thiol group (also referred to as a sulfhydryl group).
  • the anti-HER2 antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an anti-HER2 antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.
  • a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody
  • TCEP tris(2- carboxyethyl)phosphine hydro
  • an anti-HER2 antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.
  • the average number of conjugated drug molecules per anti-HER2 antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).
  • UV method UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm
  • HPLC method a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent
  • anti-HER2 antibody-drug conjugate refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present disclosure is an anti- HER2 antibody.
  • the anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1 and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2 and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, and more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO:
  • a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2.
  • the average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be produced with reference to descriptions in W02015/115091 and so on.
  • the anti-HER2 antibody- drug conjugate is trastuzumab deruxtecan (DS-8201).
  • Aurora B inhibitor refers to an agent that inhibits the cell cycle regulated protein kinase Aurora B.
  • the Aurora B inhibitor in the present disclosure may selectively inhibit the kinase Aurora B, or may non-selectively inhibit Aurora B and inhibit also kinase(s) other than Aurora B.
  • the Aurora B inhibitor in the present disclosure is not particularly limited as long as it is an agent that has the described characteristics, and preferred examples thereof can include those disclosed in W02004/058781 and W02015/036792.
  • the Aurora B inhibitor in the present disclosure inhibits Aurora B selectively.
  • the Aurora B inhibitor is a compound represented by the following formula (I): wherein Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2 -4alkenyl, C 2 -4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • Additional embodiments of the Aurora B inhibitor are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which A, X, m, Z, R 3 , R 4 , R 5 , R 6 and R 7 are defined as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined herein.
  • Ring A in formula (I) is pyrrolyl, pyrazolyl, imidazolyl or triazolyl. In another embodiment, Ring A is a group of formula (a), (b), (c),
  • Ring A is pyrazolyl. In a more preferred embodiment, Ring A is a group of formula (a) as defined above.
  • X is NR 14 , 0 or S. In another embodiment, X is NR 14 . In yet another embodiment, X is NH. In one embodiment, m is 1, 2 or 3. In one embodiment, m is 1 or 2. In another embodiment, m is 0, 2 or 3. In another embodiment, m is 0, 1 or 2. In yet another embodiment, m is 1. In a further embodiment, m is
  • Z is —NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy.
  • Z is —NR 1 -R 2 .
  • R 1 is Ci-salkyl substituted by phosphonooxy. In another embodiment, R 1 is Ci-salkyl substituted by phosphonooxy and further substituted by 1 or 2 halo. In a further embodiment, R 1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 2- phosphonooxy-2-methylethyl, 3-phosphonooxy-1,1- dimethylpropyl, 3-phosphonooxypropyl and 4- phosphonooxybutyl .
  • R 1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 3- phosphonooxy-1,1-dimethylpropyl or 3-phosphonooxypropyl. In yet another embodiment, R 1 is 2-phosphonooxyethyl. In yet another embodiment, R 1 is hydroxyethyl.
  • R 2 is selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6 alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylCi- 4alkyl.
  • R 2 is hydrogen, allyl, 2- propynyl, methyl, ethyl, propyl, isopropyl, 2- methylpropyl, butyl, 2,2-dimethylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, 3,3,3-trifluoropropyl or 2-methoxyethyl .
  • R 2 is ethyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and Ci4alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups.
  • R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2- phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form 4- (phosphonooxymethyl)piperidinyl, 2- (phosphonooxymethyl)pyrrolidinyl, 4-(2- phosphonooxyethyl)piperazinyl, 3-
  • R 1 and R 2 together with the nitrogen to which they are attached form 2- (phosphonooxymethyl)pyrrolidinyl .
  • R 3 is C 1-4 alkoxy, halo or hydrogen. In a further embodiment, R 3 is C 1-4 alkoxy or hydrogen. In another embodiment, R 3 is methoxy. In another embodiment, R 3 is hydrogen. In yet a further embodiment, R 3 is fluoro.
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro.
  • R 4 is 3-fluorophenyl, 3-chlorophenyl, 3,5- difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl and 2,5- difluorophenyl .
  • R 4 is 3- fluorophenyl, 3,5-difluorophenyl and 2,3-difluorophenyl.
  • R 4 is 3-fluorophenyl.
  • R 4 is 3,5-difluorophenyl.
  • R 4 is 2,3-difluorophenyl.
  • R 5 is hydrogen or methyl. In another embodiment, R 5 is hydrogen.
  • R 6 is hydrogen, fluoro, chloro or methyl. In another embodiment, R 6 is hydrogen.
  • R 7 is hydrogen, fluoro, chloro or methyl. In another embodiment, R 7 is hydrogen.
  • R 8 is 2-phosphonooxyethyl.
  • R 9 is hydrogen, methyl or ethyl.
  • R 10 is hydrogen, methyl or ethyl.
  • R 11 is hydrogen, methyl or ethyl.
  • R 12 is hydrogen or methyl.
  • R 13 is hydrogen or methyl.
  • R 14 is hydrogen or methyl.
  • a preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or Ci_4alkyl substituted by phosphonooxy;
  • R 1 is Ci-salkyl substituted by phosphonooxy;
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups or R 2 is selected from C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6 cycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 Ci_ 4 alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C 2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
  • Another preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C 2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl; R 3 is C 1-4 alkoxy, halo or hydrogen;
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is C 1-4 alkoxy
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC 1-4 alkyl;
  • R 3 is hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is fluoro
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • Another preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom which ring is substituted by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted by 1 or 2 Ci- 4alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl; and R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl;
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • X is NH
  • 5 m is 0, 1 or 2;
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is C 1-4 alkoxy
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • Another preferred compound of formula (I) is any compound selected from:
  • a more preferred compound of formula (I) is a compound selected from:
  • a further preferred compound of formula (I) is:
  • a more preferred compound is any compound selected from: ⁇ 1— [3—( ⁇ 4—[(5— ⁇ 2—[(3-fluorophenyl)amino]-2-oxoethyl ⁇ -1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl ⁇ oxy)propyl]piperidin-4-yl ⁇ methyl dihydrogen phosphate;
  • a further preferred compound is any compound selected from:
  • Another preferred compound is any compound selected from: 2- [[3— ⁇ 4—[ ⁇ 5— ⁇ 2—[(3-fluorophenyl)amino]-2-oxoethyl ⁇ -1- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl ⁇ oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2- ⁇ (2,2-dimethylpropyl)[3— ⁇ 4—[ ⁇ 5— ⁇ 2— [(3- fluorophenyl)amino]-2-oxoethyl ⁇ -lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl ⁇ oxy)propyl]amino ⁇ ethyl dihydrogen phosphate;
  • a particularly preferred compound is any compound selected from:
  • An especially preferred compound of formula (I) is any compound selected from:
  • a further preferred compound is any compound selected from :
  • a further preferred compound is any compound selected from:
  • Another more preferred compound is any compound selected from :
  • a particularly preferred compound is any compound selected from:
  • Yet another preferred compound is any compound selected from:
  • Another preferred compound is any compound selected from: 2- ⁇ 4- [( ⁇ 4- [(5— ⁇ 2— [(2,3-difluorophenyl)amino]-2-oxoethyl ⁇ - lH-pyrazol-3-yl)amino]quinazolin-7- yl ⁇ oxy)methyl]piperidin-l-yl ⁇ ethyl dihydrogen phosphate; 2- [[3— ⁇ 4— [ ⁇ 5— ⁇ 2— [(2,3-difluorophenyl)amino]-2-oxoethyl ⁇ - lH-pyrazol-3-yl)amino]-quinazolin-7- yl ⁇ oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
  • Yet another preferred compound is any compound selected from :
  • a further particularly preferred compound is any compound selected from:
  • a further preferred compound of formula (I) is any one of:
  • the Aurora B inhibitor used in the disclosure is [AZD1152; barasertib] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • Aurora B inhibitor used in the disclosure is [AZD1152hqpa] represented by the following formula: or a pharmaceutically acceptable salt thereof, in the form of a nanoparticle.
  • the Aurora B inhibitor used in the disclosure is a nanoparticle [AZD2811] comprising:
  • a diblock poly(lactic) acid- poly(ethylene)glycol copolymer 60 to 78 weight percent a diblock poly(lactic) acid- poly(ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly(ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly(ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
  • Aurora B inhibitors such as compounds of formula (I), including AZD1152 and AZD1152hqpa, may be prepared by methods known in the art such as disclosed in W02004/058781.
  • the term "pharmaceutically acceptable salt" of the Aurora B inhibitor used in the present disclosure may be either an acid addition salt or a base addition salt.
  • the acid addition salt can include lower alkanesulfonates such as camsilate (camphorsulfonate), mesilate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosilate (p- toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrogen halide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate,
  • the base addition salt can include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkali earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, diethanolamine salt, N- benzyl-N- (2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl)aminomethane salt; and amino acid salts such as alginate.
  • alkali metal salts such as sodium salt, potassium salt, and lithium salt
  • alkali earth metal salts such as calcium salt and magnesium salt
  • the Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure may each exist as a solvate, and solvates of them are also included in the meaning of the Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure.
  • the anti-HER2 antibody-drug conjugate which is combined with the Aurora B inhibitor is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
  • the anti-HER2 antibody-drug conjugate as defined above for the first combination embodiment is combined with an Aurora B inhibitor which is a compound of formula (I): wherein
  • Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6C ycloalkyl and C 3-6C ycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a), (b), (c),
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a) as defined above.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), X is NH.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), in formula (I), R 1 is Ci-salkyl substituted by phosphonooxy and R 2 is a group selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3-6C ycloalkylC 1-4 alkyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 1 is 2-phosphonooxyethyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2- phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2— phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
  • Z is -NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2- phosphonooxyethyl, N-ethyl-N-
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 1 and R 2 together with the nitrogen to which they are attached form 2-(phosphonooxymethyl)pyrrolidinyl .
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 4 is 3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl .
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 3 is C 1-4 alkoxy, halo or hydrogen.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152; barasertib] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152hqpa] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle, the nanoparticle comprising:
  • diblock poly(lactic) acid- poly (ethylene)glycol copolymer 7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle [AZD2811].
  • the anti-HER2 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.
  • the anti-HER2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10.
  • the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
  • the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
  • the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the Aurora B inhibitor is a nanoparticle [AZD2811] comprising:
  • diblock poly(lactic) acid- poly (ethylene)glycol copolymer 7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
  • the pharmaceutical product and therapeutic use and method of the present disclosure may be characterized in that the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times, or characterized in that the antibody-drug conjugate and the Aurora B inhibitor are contained as active components in a single formulation and administered.
  • a single Aurora B inhibitor used in the present disclosure can be administered in combination with the anti-HER2 antibody-drug conjugate, or two or more different Aurora B inhibitors can be administered in combination with the antibody-drug conjugate.
  • the pharmaceutical product and therapeutic method of the present disclosure can be used for treating cancer, and can be preferably used for treating at least one cancer selected from the group consisting of breast cancer (including triple negative breast cancer and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colon and rectal cancer, and including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head-and-neck cancer (including salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma,
  • the presence or absence of HER2 tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient to prepare a formalin-fixed, paraffin- embedded (FFPE) specimen and subjecting the specimen to a test for gene products (proteins), for example, with an immunohistochemical (IHC) method, a flow cytometer, or Western blotting, or to a test for gene transcription, for example, with an in situ hybridization (ISH) method, a quantitative PCR method (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to a test with a method such as next-generation sequencing (NGS).
  • FFPE formalin-fixed, paraffin- embedded
  • IHC immunohistochemical
  • q-PCR quantitative PCR method
  • NGS next-generation sequencing
  • the pharmaceutical product and therapeutic method of the present disclosure can be used for HER2-expressing cancer, which may be HER2-overexpressing cancer (high or moderate) or may be HER2 low-expressing cancer.
  • the term "HER2- overexpressing cancer” is not particularly limited as long as it is recognized as HER2-overexpressing cancer by those skilled in the art.
  • Preferred examples of the HER2-overexpressing cancer can include cancer given a score of 3+ for the expression of HER2 in an IHC method, and cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in an in situ hybridization method (ISH).
  • ISH in situ hybridization method
  • the in situ hybridization method of the present disclosure includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH).
  • the term "HER2 low- expressing cancer” is not particularly limited as long as it is recognized as HER2 low-expressing cancer by those skilled in the art.
  • Preferred examples of the HER2 low- expressing cancer can include cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as negative for the expression of HER2 in an in situ hybridization method, and cancer given a score of 1+ for the expression of HER2 in an IHC method.
  • the method for scoring the degree of HER2 expression by the IHC method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in the 4th edition of the guidelines for HER2 testing, breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).
  • the cancer may be HER2-overexpressing (high or moderate) or low-expressing breast cancer, or triple negative breast cancer, and/or may have a HER2 status score of IHC 3+, IHC 2+, IHC 1+ or IHC >0 and ⁇ 1+.
  • the pharmaceutical product and therapeutic method of the present disclosure can be preferably used for a mammal, but are more preferably used for a human.
  • the antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed by transplanting cancer cells to a test subject animal to prepare a model and measuring reduction in tumor volume or life-prolonging effect by application of the pharmaceutical product and therapeutic method of the present disclosure. And then, the effect of combined use of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor can be confirmed by comparing antitumor effect with single administration of the antibody-drug conjugate used in the present disclosure and that of the Aurora B inhibitor.
  • the antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed in a clinical trial using any of an evaluation method with Response Evaluation Criteria in Solid Tumors (RECIST), a WHO evaluation method, a Macdonald evaluation method, body weight measurement, and other approaches, and can be determined on the basis of indexes of complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and so on.
  • RECIST Response Evaluation Criteria in Solid Tumors
  • a WHO evaluation method a Macdonald evaluation method
  • body weight measurement and other approaches
  • CR complete response
  • PR partial response
  • PD progressive disease
  • ORR objective response rate
  • DoR duration of response
  • PFS progression-free survival
  • OS overall survival
  • the pharmaceutical product and therapeutic method of the present disclosure can delay development of cancer cells, inhibit growth thereof, and further kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or achieve improvement in quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and therapeutic method of the present disclosure do not accomplish killing cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells.
  • QOL quality of life
  • the pharmaceutical product of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues.
  • the pharmaceutical product of the present disclosure can be administered containing at least one pharmaceutically suitable ingredient.
  • Pharmaceutically suitable ingredients can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration, or the like of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered, for example, as a pharmaceutical product containing a buffer such as histidine buffer, a vehicle such as sucrose and trehalose, and a surfactant such as Polysorbates 80 and 20.
  • the pharmaceutical product containing the antibody-drug conjugate used in the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection.
  • the aqueous injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
  • a required amount of the lyophilized injection dissolved in advance in water for injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
  • Examples of the administration route applicable to administration of the pharmaceutical product of the present disclosure can include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and intravenous routes are preferred.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered to a human with intervals of 1 to 180 days, can be preferably administered with intervals of a week, two weeks, three weeks, or four weeks, and can be more preferably administered with intervals of three weeks.
  • the anti- HER2 antibody-drug conjugate used in the present disclosure can be administered in a dose of about 0.001 to 100 mg/kg per administration, and can be preferably administered in a dose of 0.8 to 12.4 mg/kg per administration.
  • the anti-HER2 antibody-drug conjugate can be administered once every three weeks at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 5.4 mg/kg, 6.4 mg/kg, 7.4 mg/kg, or 8 mg/kg, and can be preferably administered once every three weeks at a dose of 5.4 mg/kg or 6.4 mg/kg.
  • the Aurora B inhibitor according to the present disclosure can be orally administered to a human once or twice in each one to seven days, and can be preferably orally administered once a day or twice per day.
  • the Aurora B inhibitor used in the present disclosure can be orally administered in a dose of 0.1 mg to 4000 mg per administration, and can be preferably administered in a dose of 2.5 mg to 600 mg per administration.
  • the Aurora B inhibitor used in the present disclosure can be administered to a human as an intravenous drip with intervals of 1 to 180 days, and can be preferably administered as an intravenous drip with intervals of a week, two weeks, three weeks, or four weeks.
  • the Aurora B inhibitor used in the present disclosure can be administered as an intravenous drip in a dose of 0.1 mg to 3000 mg per administration, and can be preferably administered as an intravenous drip in a dose of 10 mg to 100 mg per administration.
  • a formulation of an Aurora B inhibitor compound of formula (I) intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4000 mg of the active ingredient, compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of the active ingredient.
  • a daily dose of the Aurora B inhibitor in the range of 0.1-50 mg/kg may be employed.
  • the Aurora B inhibitor used in the present disclosure is AZD2811
  • the Aurora B inhibitor can be administered in a dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg per administration.
  • the total daily dose of AZD2811 is about 200 mg via intravenous administration.
  • the total daily dose is about 500 mg.
  • the total daily dose is about 600 mg.
  • the total daily dose is 300 mg.
  • AZD2811 is administered on day 1 and day 4 of a 28-day cycle.
  • AZD2811 is administered on day 1 of a 21-day cycle.
  • the pharmaceutical product and therapeutic method of the present disclosure can be used as adjuvant chemotherapy combined with surgery operation.
  • the pharmaceutical product of the present disclosure may be administered for the purpose of reducing tumor size before surgical operation (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or may be administered for the purpose of preventing recurrence of tumor after surgical operation (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).
  • an anti-HER2 antibody an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 (amino acid residues 1 to 449 of SEQ ID NO: 1) and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2)
  • an anti- HER2 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to the anti-HER2 antibody via a thioether bond was produced (DS-8201: trastuzumab deruxtecan).
  • the DAR of the antibody-drug conjugate is 7.7 or 7.8.
  • an Aurora B inhibitor of formula (I) is prepared. Specifically, 2-(3-((7-(3-(ethyl(2- hydroxyethyl)amino)propoxy)quinazolin-4-yl )amino)-1H- pyrazol-5-yl)-N- (3-fluorophenyl)acetamide:
  • a nanoparticle (AZD2811) of 2-(3-((7-(3- (ethyl (2-hydroxyethyl)amino)propoxy)quinazolin-4- yl)amino)-lH-pyrazol-5-yl)-N- (3-fluorophenyl)acetamide (AZD1152hqpa) is prepared.
  • a high-throughput combination screen was run, in which a breast cancer cell line and a gastric cell line with high HER2 expression (Table 1) were treated with combinations of DS-8201 and AZD2811 (Aurora B inhibitor).
  • the readout of the screen was a 7-day cell titer-glo cell viability assay, conducted as a 6 x 6 dose response matrix for each combination (5-point log serial dilution for DS-8201, and half log serial dilution for partners).
  • trastuzumab and exatecan were also screened in parallel with AZD2811. Combination activity was assessed based on a combination of the ⁇ Emax and HSA synergy scores.
  • row A shows matrices of measured cell viability signals.
  • X axes represent drug A (DS-8201), and Y axes represent drug B (AZD2811). Values in the box represent the ratio of cells treated with drug A + B compared to DMSO control at day 7. All values are normalised to cell viability values at day 0. Values between 0 and 100 represent % growth inhibition and values above 100 represent cell death.
  • row B shows HSA excess matrices. Values in the box represent excess values calculated by the HSA (Highest Single Agent) model.
  • Table 2 shows HSA synergy and Loewe additivity scores: Table 2
  • Dose Additivity predicts the expected response if the two compounds act on the same molecular target by means of the same mechanism. It calculates additivity based on the assumption of zero interaction between the compounds and it is independent from the nature of the dose-response relationship.
  • HSA Highest Single Agent
  • Excess Matrix For each well in the concentration matrix, the measured or fitted values are compared to the predicted non-synergistic values for each concentration pair. The predicted values are determined by the chosen model. Differences between the predicted and observed values may indicate synergy or antagonism, and are shown in the Excess Matrix. Excess Matrix values are summarized by the combination scores Excess Volume and Synergy
  • AZD2811 and DS-8201 in combination showed synergistic activity and increased cell death in HER2 + cell lines KPL4 and NCI-N87. Combination activity was observed at Emax (AZD28111 mM and DS-820110 ⁇ g/ml (0.064 mM)) and also at lower concentrations .
  • AZD2811 showed synergistic combination activity and increased cell death in HER2 high cell lines.
  • SEQ ID NO: 1 Amino acid sequence of a heavy chain of an anti-HER2 antibody
  • SEQ ID NO: 2 Amino acid sequence of a light chain of an anti-HER2 antibody

Abstract

A pharmaceutical product for administration of an anti HER2 antibody-drug conjugate in combination with an Aurora B inhibitor is provided. The anti-HER2 antibody drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents the connecting position to an antibody) is conjugated to an anti-HER2 antibody via a thioether bond. Also provided is a therapeutic use and method wherein the antibody-drug conjugate and the Aurora B inhibitor are administered in combination to a subject: Formula (I):

Description

COMBINATION OF ANTIBODY-DRUG CONJUGATE AND AURORA B INHIBITOR
[Technical Field]
The present disclosure relates to a pharmaceutical product for administration of a specific antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, in combination with an Aurora B inhibitor, and to a therapeutic use and method wherein the specific antibody-drug conjugate and the Aurora B inhibitor are administered in combination to a subject.
[Background]
Aurora kinases (Aurora A, Aurora B and Aurora C) are cell cycle regulated serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2 and mitosis and a role for human Aurora kinases in cancer has long been implicated. Aurora kinase inhibitors are disclosed, for example, in W02004/058781 .
Antibody-drug conjugates (ADCs) which are composed of a cytotoxic drug conjugated to an antibody, can deliver the drug selectively to cancer cells, and are therefore expected to cause accumulation of the drug within cancer cells and to kill the cancer cells (Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13; Alley, S. C., et al., Current Opinion in Chemical Biology (2010)
14, 529-537; Damle N. K. Expert Opin. Biol. Ther. (2004) 4, 1445-1452; Senter P. D., et al., Nature Biotechnology (2012) 30, 631-637; Burris HA., et al., J. Clin. Oncol. (2011) 29(4): 398-405).
One such antibody-drug conjugate is trastuzumab deruxtecan, which is composed of a HER2-targeting antibody and a derivative of exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108;
Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).
Despite the therapeutic potential of antibody-drug conjugates and Aurora kinase inhibitors, no literature is published that describes a test result demonstrating an excellent effect of combined use of the antibody-drug conjugate and an Aurora B inhibitor or any scientific basis suggesting such a test result. Moreover, in the absence of test results, a possibility exists that combined administration of the antibody-drug conjugate together with another cancer treating agent such as an Aurora B inhibitor could lead to negative interactions and/or sub-additive therapeutic outcomes, and thus an excellent or superior effect obtained by such combination treatment could not be expected.
Accordingly, a need remains for improved therapeutic compositions and methods, that can enhance efficacy of existing cancer treating agents, increase durability of therapeutic response and/or reduce dose-dependent toxicity. [Summary of Disclosure]
The antibody-drug conjugate used in the present disclosure (an anti-HER2 antibody-drug conjugate that includes a derivative of the topoisomerase I inhibitor exatecan) has been confirmed to exhibit an excellent antitumor effect in the treatment of certain cancers such as breast cancer and gastric cancer, when administered singly. Furthermore, an Aurora B inhibitor has been confirmed to exhibit an antitumor effect in the treatment of certain cancers. However, it is desired to provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers, such as enhanced efficacy, increased durability of therapeutic response and/or reduced dose-dependent toxicity.
The present disclosure provides a pharmaceutical product which can exhibit an excellent antitumor effect in the treatment of cancers, through administration of an anti-HER2 antibody-drug conjugate in combination with an Aurora B inhibitor. The present disclosure also provides a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate and Aurora B inhibitor are administered in combination to a subject.
Specifically, the present disclosure relates to the following [1] to [59]:
[1] a pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor for administration in combination, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:
Figure imgf000005_0001
wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond;
[2] the pharmaceutical product according to [1], wherein the Aurora B inhibitor is a compound of formula (I):
Figure imgf000005_0002
wherein
Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms; X is 0, S, S(O), S(0)2 or NR14 ; m is 0, 1, 2 or 3;
Z is a group selected from -NR1R2, phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R1 is a group selected from -COR8, -CONR8R9 and C1-6alkyl which C1-6alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 is a group selected from is a group selected from hydrogen, -COR10, -CONR10R11 and Ci-6alkyl which Ci-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups or -S(0)pR11 (where p is 0, 1 or 2) or phosphonooxy, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl; or R1 and R2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or -NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R3 is a group selected from hydrogen, halo, cyano, nitro, C1-6alkoxy, C1-6alkyl, -OR12, -CHR12R13, -0C(0)R12, - C (0)R12, -NR12C (0)R13, -C (0)NR12R13, -NR12S02R13 and -NR12R13;
R4 is hydrogen or a group selected from C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, aryl and arylC1-4alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
R5 is selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl;
R6 and R7 are independently selected from hydrogen, halo, C1-4alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
R8 is C1-4alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 is selected from hydrogen and C1-4alkyl;
R10 is selected from hydrogen and C1-4alkyl (optionally substituted by halo, C1-4alkoxy, S(0)q (where q is 0,1 or 2) or phosphonooxy);
R11, R12, R13 and R14 are independently selected from hydrogen, C1-4alkyl and heterocyclyl, or a pharmaceutically acceptable salt thereof;
[3] the pharmaceutical product according to [2], wherein, in formula (I), Ring A is a group of formula (a), (b), (c), (d) or (e):
Figure imgf000008_0001
where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR6R7) group of formula (I);
[4] the pharmaceutical product according to [3], wherein, in formula (I), Ring A is a group of formula (a) as defined in [3];
[5] the pharmaceutical product according to any one of [2] to [4], wherein, in formula (I), X is NH;
[6] the pharmaceutical product according to any one of [2] to [5], wherein, in formula (I), Z is -NR1R2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy;
[7] the pharmaceutical product according to any one of [2] to [6], wherein, in formula (I), R1 is Ci-salkyl substituted by phosphonooxy and R2 is a group selected from hydrogen and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylC1-4alkyl;
[8] the pharmaceutical product according to any one of [2] to [7], wherein, in formula (I), R1 is 2-phosphonooxyethyl;
[9] the pharmaceutical product according to any one of [2] to [6], wherein, in formula (I), Z is -NR1R2 and R1 and R2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N- ethyl-N- (2-phosphonooxyethyl)aminomethyl and N-(2— phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl;
[10] the pharmaceutical product according to [9], wherein, in formula (I), R1 and R2 together with the nitrogen to which they are attached form
2-(phosphonooxymethyl)pyrrolidinyl;
[11] the pharmaceutical product according to any one of [2] to [10], wherein, in formula (I), R4 is
3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl;
[12] the pharmaceutical product according to any one of [2] to [11], wherein, in formula (I), R3 is C1-4alkoxy, halo or hydrogen;
[13] the pharmaceutical product according to [2], wherein the compound of formula (I) is [AZD1152; barasertib] represented by the following formula:
Figure imgf000010_0002
or a pharmaceutically acceptable salt thereof;
[14] the pharmaceutical product according to [2], wherein the compound of formula (I) is [AZD1152hqpa] represented by the following formula:
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof;
[15] the pharmaceutical product according to [14], wherein the compound of formula (I) [AZD1152hqpa] is in the form of a nanoparticle;
[16] the pharmaceutical product according to [15], wherein the nanoparticle comprises:
15 to 25 weight percent, preferably about 20 weight percent, of the compound [AZD1152hqpa] represented by the following formula:
Figure imgf000011_0001
7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle [AZD2811]; [17] the pharmaceutical product according to any one of [1] to [16], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3 [= amino acid residues 26 to 33 of SEQ ID NO:
1], CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 [= amino acid residues 51 to
58 of SEQ ID NO: 1] and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5 [= amino acid residues 97 to 109 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 27 to 32 of SEQ ID NO: 2], CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7 [= amino acid residues 50 to 52 of SEQ ID NO: 2] and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8 [=amino acid residues 89 to 97 of SEQ ID NO: 2];
[18] the pharmaceutical product according to any one of
[1] to [16], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 [= amino acid residues 1 to 120 of SEQ ID NO: 1] and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 1 to 107 of SEQ ID NO: 2];
[19] the pharmaceutical product according to any one of [1] to [16], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2;
[20] the pharmaceutical product according to any one of
[1] to [16], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 1 to 449 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2; [21] the pharmaceutical product according to any one of [1] to [20], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula:
Figure imgf000013_0001
wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8;
[22] the pharmaceutical product according to any one of [1] to [21], wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201);
[23] the pharmaceutical product according to any one of [1] to [22] wherein the product is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
[24] the pharmaceutical product according to any one of [1] to [22] wherein the product is a combined preparation comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for sequential or simultaneous administration; [25] the pharmaceutical product according to any one of [1] to [24], wherein the product is for treating cancer;
[26] the pharmaceutical product according to [25], wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma;
[27] the pharmaceutical product according to [26], wherein the cancer is breast cancer;
[28] the pharmaceutical product according to [27], wherein the breast cancer has a HER2 status score of IHC 3+;
[29] the pharmaceutical product according to [27], wherein the breast cancer is HER2 low-expressing breast cancer;
[30] the pharmaceutical product according to [27], wherein the breast cancer has a HER2 status score of IHC 2+; [31] the pharmaceutical product according to [27], wherein the breast cancer has a HER2 status score of IHC
1+;
[32] the pharmaceutical product according to [27], wherein the breast cancer has a HER2 status score of IHC >0 and <1+;
[33] the pharmaceutical product according to [27], wherein the breast cancer is triple-negative breast cancer;
[34] the pharmaceutical product according to [25], wherein the cancer is gastric cancer;
[35] the pharmaceutical product according to [25], wherein the cancer is colorectal cancer;
[36] the pharmaceutical product according to [25], wherein the cancer is lung cancer;
[37] the pharmaceutical product according to [36], wherein the lung cancer is non-small cell lung cancer;
[38] the pharmaceutical product according to [25], wherein the cancer is pancreatic cancer;
[39] the pharmaceutical product according to [25], wherein the cancer is ovarian cancer;
[40] the pharmaceutical product according to [25], wherein the cancer is prostate cancer;
[41] the pharmaceutical product according to [25], wherein the cancer is kidney cancer;
[42] a pharmaceutical product as defined in any one of [1] to [24], for use in treating cancer; [43] the pharmaceutical product for the use according to [42], wherein the cancer is as defined in any one of [26] to [41];
[44] use of an anti-HER2 antibody-drug conjugate or an Aurora B inhibitor in the manufacture of a medicament for administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor in combination, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22], for treating cancer;
[45] the use according to [44], wherein the cancer is as defined in any one of [26] to [41];
[46] the use according to [44] or [45] wherein the medicament is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
[47] the use according to [44] or [45] wherein the medicament is a combined preparation comprising the anti- HER2 antibody-drug conjugate and the Aurora B inhibitor, for sequential or simultaneous administration;
[48] an anti-HER2 antibody-drug conjugate for use, in combination with an Aurora B inhibitor, in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
[49] the anti-HER2 antibody-drug conjugate for the use according to [48], wherein the cancer is as defined in any one of [26] to [41]; [50] the anti-HER2 antibody-drug conjugate for the use according to [48] or [49], wherein the use comprises administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor sequentially;
[51] the anti-HER2 antibody-drug conjugate for the use according to [48] or [49], wherein the use comprises administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor simultaneously;
[52] an Aurora B inhibitor for use, in combination with an anti-HER2 antibody-drug conjugate, in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
[53] the Aurora B inhibitor for the use according to [52], wherein the cancer is as defined in any one of [26] to [41];
[54] the Aurora B inhibitor for the use according to [52] or [53], wherein the use comprises administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor sequentially;
[55] the Aurora B inhibitor for the use according to [52] or [53], wherein the use comprises administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor simultaneously;
[56] a method of treating cancer comprising administering an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor as defined in any one of [1] to [22] in combination to a subject in need thereof; [57] the method according to [56], wherein the cancer is as defined in any one of [26] to [41]; and
[58] the method according to [56] or [57], wherein the method comprises administering the anti-HER2 antibody- drug conjugate and the Aurora B inhibitor sequentially; and
[59] the method according to [56] or [57], wherein the method comprises administering the anti-HER2 antibody- drug conjugate and the Aurora B inhibitor simultaneously.
[Advantageous Effects of Disclosure]
The present disclosure provides a pharmaceutical product wherein an anti-HER2 antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, and an Aurora B inhibitor are administered in combination, and a therapeutic use and method wherein the specific antibody- drug conjugate and the Aurora B inhibitor are administered in combination to a subject. Thus, the present disclosure can provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers.
[Brief Description of Drawings]
[Figure 1] Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ
ID NO: 1). [Figure 2] Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 2).
[Figure 3] Figure 3 is a diagram showing the amino acid sequence of a heavy chain CDRH1 (SEQ ID NO: 3 [= amino acid residues 26 to 33 of SEQ ID NO: 1]).
[Figure 4] Figure 4 is a diagram showing the amino acid sequence of a heavy chain CDRH2 (SEQ ID NO: 4 [= amino acid residues 51 to 58 of SEQ ID NO: 1]).
[Figure 5] Figure 5 is a diagram showing the amino acid sequence of a heavy chain CDRH3 (SEQ ID NO: 5 [= amino acid residues 97 to 109 of SEQ ID NO: 1]).
[Figure 6] Figure 6 is a diagram showing the amino acid sequence of a light chain CDRL1 (SEQ ID NO: 6 [= amino acid residues 27 to 32 of SEQ ID NO: 2]).
[Figure 7] Figure 7 is a diagram showing an amino acid sequence comprising the amino acid sequence of a light chain CDRL2 (SAS) (SEQ ID NO: 7 [= amino acid residues 50 to 56 of SEQ ID NO: 2]).
[Figure 8] Figure 8 is a diagram showing the amino acid sequence of a light chain CDRL3 (SEQ ID NO: 8 [= amino acid residues 89 to 97 of SEQ ID NO: 2]).
[Figure 9] Figure 9 is a diagram showing the amino acid sequence of a heavy chain variable region (SEQ ID NO: 9 [= amino acid residues 1 to 120 of SEQ ID NO: 1]).
[Figure 10] Figure 10 is a diagram showing the amino acid sequence of a light chain variable region (SEQ ID NO: 10 [= amino acid residues 1 to 107 of SEQ ID NO: 2]). [Figure 11] Figure 11 is a diagram showing the amino acid sequence of a heavy chain (SEQ ID NO: 11 [= amino acid residues 1 to 449 of SEQ ID NO: 1]).
[Figure 12] Figure 12 is a diagram showing combination matrices obtained with high-throughput screens combining DS-8201 with AZD2811 (AZ11792866; Aurora B inhibitor) in a breast cancer cell line and a gastric cell line with high HER2 expression.
In order that the present disclosure can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to specific compositions or method steps, as such can vary. As used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more, " and "at least one" can be used interchangeably herein.
Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B, " "A or B, " "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.
Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.
It is understood that wherever aspects are described herein with the language "comprising", otherwise analogous aspects described in terms of "consisting of" and/or "consisting essentially of" are also provided.
The terms "inhibit", "block", and "suppress" are used interchangeably herein and refer to any statistically significant decrease in biological activity, including full blocking of the activity. For example, "inhibition" can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in biological activity. Cellular proliferation can be assayed using art recognized techniques which measure rate of cell division, and/or the fraction of cells within a cell population undergoing cell division, and/or rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation) .
The term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.
The term "pharmaceutical product" refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered. Such product can be sterile. By "simultaneous administration" is meant that the active ingredients are administered at the same time. By "sequential administration" is meant that the active ingredients are administered one after the other, in either order, at a time interval between the individual administrations. The time interval can be, for example, less than 24 hours, preferably less than 6 hours, more preferably less than 2 hours.
Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.
The terms "cancer", "tumor", "cancerous", and "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers include but are not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
The term "cytotoxic agent" as used herein is defined broadly and refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells (cell death), and/or exerts anti- neoplastic/anti-proliferative effects. For example, a cytotoxic agent prevents directly or indirectly the development, maturation, or spread of neoplastic tumor cells. The term includes also such agents that cause a cytostatic effect only and not a mere cytotoxic effect. The term includes chemotherapeutic agents as specified below, as well as other HER2 antagonists, anti-angiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, members of the cytokine family, radioactive isotopes, 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 agent" comprising natural or synthetic chemical compounds.
In accordance with the methods or uses of the present disclosure, compounds of the present disclosure may be administered to a patient to promote a positive therapeutic response with respect to cancer. The term "positive therapeutic response" with respect to cancer treatment refers to an improvement in the symptoms associated with the disease. For example, an improvement in the disease can be characterized as a complete response. The term "complete response" refers to an absence of clinically detectable disease with normalization of any previous test results.
Alternatively, an improvement in the disease can be categorized as being a partial response. A "positive therapeutic response" encompasses a reduction or inhibition of the progression and/or duration of cancer, the reduction or amelioration of the severity of cancer, and/or the amelioration of one or more symptoms thereof resulting from the administration of compounds of the present disclosure. In specific aspects, such terms refer to one, two or three or more results following the administration of compounds of the instant disclosure:
(1) a stabilization, reduction or elimination of the cancer cell population; (2) a stabilization or reduction in cancer growth;
(3) an impairment in the formation of cancer;
(4) eradication, removal, or control of primary, regional and/or metastatic cancer;
(5) a reduction in mortality;
(6) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate;
(7) an increase in the response rate, the durability of response, or number of patients who respond or are in remission;
(8) a decrease in hospitalization rate,
(9) a decrease in hospitalization lengths,
(10) the size of the cancer is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%, and
(11) an increase in the number of patients in remission.
(12) a decrease in the number of adjuvant therapies (e.g., chemotherapy or hormonal therapy) that would otherwise be required to treat the cancer.
Clinical response can be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scan, x-radiographic imaging, computed tomographic (CT) scan, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistry, including but not limited to changes detectable by ELISA, RIA, chromatography, and the like. In addition to these positive therapeutic responses, the subject undergoing therapy can experience the beneficial effect of an improvement in the symptoms associated with the disease.
As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "tert-butyl" are specific for the branched chain version only. An analogous convention applies to other generic terms, for example "alkenyl" and "alkynyl".
"Cycloalkyl" is a monocyclic, saturated alkyl ring and "aryl" is a monocyclic or bicyclic aromatic ring.
Unless otherwise specified "heteroaryl" is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.
"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring may be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-; wherein a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring —NH is optionally substituted by acetyl, formyl, methyl or mesyl; and wherein a ring is optionally substituted by one or more halo.
"Phosphonooxy " is in one aspect a group of formula -P(0)(OH)2. However the term "phosphonooxy" also includes salts of this group such as those formed with alkali metal ions such as sodium or potassium ions or alkaline earth metal ions, for example calcium or magnesium ions.
Where optional substituents are chosen from "1 or 2", from "1, 2, or 3" or from "1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the sameor the substituents being chosen from two or more of the specified groups i.e. the substituents not being the same.
Compounds of the present disclosure have been named with the aid of computer software (ACD/Name version 10.06).
Suitable values for any R group (R1 to R14 in formula (I)) or any part or substituent for such groups include: for C1-4alkyl: methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl and tert-butyl; for C1-6alkyl: C1-4alkyl, pentyl, 2,2-dimethylpropyl,
3-methylbutyl and hexyl; for C2-4alkenyl: vinyl, allyl and 1-propenyl; for C2-6alkenyl:C2-4alkenyl, 1-butenyl, 2-butenyl, 3- butenyl, 2-methylbut-2-enyl, 3-methylbut-l-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl; for C2-4alkynyl:ethynyl, 1-propynyl, 2-propynyl and 3-butynyl; for C2-6alkynyl:C2-4alkynyl, 2-pentynyl, hexynyl and l-methylpent-2-ynyl; for C3-6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for C3-6cycloalkylCi.alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for arylC1-4alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl; for halo: fluoro, chloro, bromo and iodo; for C1-4alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for Ci-6alkoxy: C1-4alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; for heteroaryl:pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl and pyrazinyl and preferably thiazolyl, pyridyl, imidazolyl and pyrimidinyl; for heteroarylC1-4alkyl: pyridylmethyl, pyridylethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl; for heterocyclyl: furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuryl, piperidinyl, N- acetylpiperidinyl, N-methylpiperidinyl,
N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5- dioximidazolidinyl, 2,2-dimethyl-l,3-dioxolanyl and 3,4- dimethylenedioxybenzyl .
It should be noted that examples given for terms used in the description are not limiting.
As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical product will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient (s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
In particular, an effective amount of a compound of formula (I) for use in the treatment of cancer in combination with the antibody-drug conjugate is an amount such that the combination is sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer, to slow the progression of cancer, or to reduce in patients with symptoms of cancer the risk of getting worse.
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Within the present disclosure, it is to be understood that, insofar as certain compounds of formula (I) herein defined may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms or sulphur atoms, the disclosure includes in its definition any such optically active or racemic form which possesses the Aurora B kinase inhibitory activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using standard laboratory techniques.
Within the present disclosure it is to be understood that a compound of formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the disclosure encompasses any tautomeric form which has Aurora B inhibitory activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
It will be understood that compounds of formula (I) may encompass compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; 0 may be in any isotopic form, including 16O and 18O; and the like.
It is also to be understood that certain compounds of formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the disclosure encompasses all such solvated forms which have Aurora B inhibitory activity.
The present disclosure may use compounds of formula (I) as herein defined as well as salts thereof. Salts for use in pharmaceutical products will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts.
Pharmaceutically acceptable salts of the disclosure may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid. In addition where compounds of formula (I) are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
The compounds of formula (I) may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkcarbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl,
(1,3-dioxolen-2-one)ylmethyl esters for example (5-methyl-l,3-dioxolen-2-one )ylmethyl, and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this disclosure. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a- acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy groups. Examples of a- acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy . A selection of in vivo hydrolysable ester forming groups for hydroxy include Ci- loalkanoyl, for example acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-C1-4alkylcarbamoyl and N-(di-C1-4 alkylaminoethyl)-N-C1-4alkylcarbamoyl (to give carbamates); di-C1-4alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C1-4alkylaminomethyl and di- (Ci-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
Other interesting in vivo hydrolysable esters include, for example, RAC(0)0C1-6alkyl-C0-, wherein RA is for example, benzyloxy-Ci-4alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4-C1-4alkylpiperazino-C1-4alkyl, piperazino- Ci-4alkyl and morpholino-Ci-4alkyl.
[Description of Embodiments]
Hereinafter, preferred modes for carrying out the present disclosure are described. The embodiments described below are given merely for illustrating one example of a typical embodiment of the present disclosure and are not intended to limit the scope of the present disclosure.
1. Antibody-drug conjugate
The antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which a drug- linker represented by the following formula:
Figure imgf000036_0001
wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
In the present disclosure, the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker". The drug- linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.
The drug-linker of the present disclosure includes exatecan (IUPAC name: (IS,9S)-l-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H, 13H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro- 9-hydroxy-4-methy1- 1H,12H-benzo [de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-10,13 (9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component. Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:
Figure imgf000037_0001
The anti-HER2 antibody-drug conjugate used in the present disclosure can be also represented by the following formula:
Figure imgf000037_0002
Here, the drug-linker is conjugated to an anti-HER2 antibody ('Antibody-') via a thioether bond. The meaning of n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to- Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule. After migrating into cancer cells, the anti-HER2 antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release a compound represented by the following formula:
Figure imgf000038_0001
This compound is inferred to be the original source of the antitumor activity of the antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097- 5108, Epub 2016 Mar 29).
The anti-HER2 antibody-drug conjugate used in the present disclosure is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039- 1046). The bystander effect is exerted through a process whereby the antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target and the compound released then exerts an antitumor effect also on cancer cells which are present therearound and not expressing the target. This bystander effect is exerted as an excellent antitumor effect even when the anti-HER2 antibody-drug conjugate is used in combination with an Aurora B inhibitor according to the present disclosure.
2. Antibody in antibody-drug conjugate
The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure may be derived from any species, and is preferably an anti-HER2 antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well known technique. The anti-HER2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.
The antibody in the antibody-drug conjugate used in the present disclosure is an anti-HER2 antibody preferably having a characteristic of being capable of targeting cancer cells, and is preferably an antibody possessing, for example, a property of recognizing a cancer cell, a property of binding to a cancer cell, a property of internalizing in a cancer cell, and/or cytocidal activity against cancer cells.
The binding activity of the anti-HER2 antibody against cancer cells can be confirmed using flow cytometry. The internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751- 761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268- 5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used.
The antitumor activity of the anti-HER2 antibody can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing HER2 as a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining change in the cancer cell.
Since the compound conjugated in the anti-HER2 antibody-drug conjugate exerts an antitumor effect, it is preferred but not essential that the anti-HER2 antibody itself should have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and also preferred that the anti-HER2 antibody should have the property of internalizing to migrate into cancer cells.
The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art. For example, the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo.
The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like.
In this case, the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease.
Alternatively, antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained.
The antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen expressing cells or a cell line expressing the antigen.
The anti-HER2 antibody in the antibody-drug conjugate used the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody. These antibodies can be produced using a known method.
As the chimeric antibody, an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-
6855, (1984)).
As the humanized antibody, an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), and an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (WO 90/07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337) can be exemplified .
As the human antibody, an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology:Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.) can be exemplified. As an alternative, an antibody obtained by phage display, the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science.
(2002)43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), p.427-431, etc.) can be exemplified.
In the present disclosure, modified variants of the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or 0-linked carbohydrate chain, etc. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or 0-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant. Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.
Further, by regulating the modification of a glycan which is linked to the antibody according to the present disclosure (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of a glycan of antibodies, those disclosed in W099/54342, WOOO/61739, W002/31140, WO2007/133855, W02013/120066, etc. are known. However, the technique is not limited thereto. In the anti-HER2 antibody according to the present disclosure, antibodies in which the modification of a glycan is regulated are also included.
It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the anti-HER2 antibody according to the present disclosure, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full- length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-HER2 antibody according to the present disclosure and the culture conditions; however, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be exemplified as preferred.
As isotypes of the anti-HER2 antibody according to the present disclosure, for example, IgG (IgGl, IgG2, IgG3, IgG4) can be exemplified, and IgGl or IgG2 can be exemplified as preferred.
In the present disclosure, the term "anti-HER2 antibody" refers to an antibody which specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has an activity of internalizing in HER2-expressing cells by binding to HER2. Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5821337) and pertuzumab (W001/00245), and trastuzumab can be exemplified as preferred.
3. Production of antibody-drug conjugate
A drug-linker intermediate for use in production of the anti-HER2 antibody-drug conjugate according to the present disclosure is represented by the following formula:
Figure imgf000047_0001
The drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanoyl]glycylglycyl-L-phenylalanyl-N- [(2-{[(IS,9S)- 9-ethyl-5-fluoro-9-hydroxy-4-methyl-1 0,13-dioxo- 2,3,9,10,13,15-hexahydro-lH,12H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced with reference to descriptions in WO2014/057687, WO2015/098099, W02015/115091, WO2015/155998,
W02019/044947 and so on. The anti-HER2 antibody-drug conjugate used in the present disclosure can be produced by reacting the above- described drug-linker intermediate and an anti-HER2 antibody having a thiol group (also referred to as a sulfhydryl group).
The anti-HER2 antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an anti-HER2 antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.
Further, by using 2 to 20 molar equivalents of the drug-linker intermediate per anti-HER2 antibody having a sulfhydryl group, an anti-HER2 antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.
The average number of conjugated drug molecules per anti-HER2 antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).
Conjugation between the anti-HER2 antibody and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate can be performed with reference to descriptions in WO2014/057687,
WO2015/098099, W02015/115091, WO2015/155998,
WO2017/002776, WO2018/212136, and so on.
In the present disclosure, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present disclosure is an anti- HER2 antibody.
The anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1 and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2 and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, and more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO:
1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2.
The average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.
The anti-HER2 antibody-drug conjugate used in the present disclosure can be produced with reference to descriptions in W02015/115091 and so on.
In preferred embodiments, the anti-HER2 antibody- drug conjugate is trastuzumab deruxtecan (DS-8201).
4. Aurora B inhibitor In the present disclosure, the term "Aurora B inhibitor" refers to an agent that inhibits the cell cycle regulated protein kinase Aurora B. The Aurora B inhibitor in the present disclosure may selectively inhibit the kinase Aurora B, or may non-selectively inhibit Aurora B and inhibit also kinase(s) other than Aurora B. The Aurora B inhibitor in the present disclosure is not particularly limited as long as it is an agent that has the described characteristics, and preferred examples thereof can include those disclosed in W02004/058781 and W02015/036792.
Preferably, the Aurora B inhibitor in the present disclosure inhibits Aurora B selectively.
According to preferred embodiments of the Aurora B inhibitor used in the present disclosure, the Aurora B inhibitor is a compound represented by the following formula (I):
Figure imgf000051_0001
wherein Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
X is 0, S, S(0), S(0)2 or NR14 ; m is 0, 1, 2 or 3;
Z is a group selected from -NR1R2, phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R1 is a group selected from -COR8, -CONR8R9 and C1-6alkyl which C1-6alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 is a group selected from is a group selected from hydrogen, -COR10, -CONR10R11 and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups or -S(0)pR11 (where p is 0, 1 or 2) or phosphonooxy, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl; or R1 and R2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or -NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R3 is a group selected from hydrogen, halo, cyano, nitro, C1-6alkoxy, C1-6alkyl, -OR12, -CHR12R13, -0C(0)R12, - C (0)R12, -NR12C (0)R13, -C (0)NR12R13, -NR12S02R13 and -NR12R13;
R4 is hydrogen or a group selected from C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, aryl and arylC1-4alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
R5 is selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl;
R6 and R7 are independently selected from hydrogen, halo, C1-4alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
R8 is C1-4alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 is selected from hydrogen and C1-4alkyl;
R10 is selected from hydrogen and C1-4alkyl (optionally substituted by halo, C1-4alkoxy, S(0)q (where q is 0,1 or 2) or phosphonooxy);
R11, R12, R13 and R14 are independently selected from hydrogen, C1-4alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
Additional embodiments of the Aurora B inhibitor are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which A, X, m, Z, R3, R4, R5, R6 and R7 are defined as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined herein.
In one embodiment, Ring A in formula (I) is pyrrolyl, pyrazolyl, imidazolyl or triazolyl. In another embodiment, Ring A is a group of formula (a), (b), (c),
(d) or (e):
Figure imgf000054_0001
where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR6R7) group of formula (I). In a preferred embodiment, Ring A is pyrazolyl. In a more preferred embodiment, Ring A is a group of formula (a) as defined above.
In one embodiment, X is NR14, 0 or S. In another embodiment, X is NR14. In yet another embodiment, X is NH. In one embodiment, m is 1, 2 or 3. In one embodiment, m is 1 or 2. In another embodiment, m is 0, 2 or 3. In another embodiment, m is 0, 1 or 2. In yet another embodiment, m is 1. In a further embodiment, m is
2.
In one embodiment Z is —NR1R2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy. In another embodiment, Z is —NR1-R2.
In one embodiment, R1 is Ci-salkyl substituted by phosphonooxy. In another embodiment, R1 is Ci-salkyl substituted by phosphonooxy and further substituted by 1 or 2 halo. In a further embodiment, R1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 2- phosphonooxy-2-methylethyl, 3-phosphonooxy-1,1- dimethylpropyl, 3-phosphonooxypropyl and 4- phosphonooxybutyl . In yet another embodiment, R1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 3- phosphonooxy-1,1-dimethylpropyl or 3-phosphonooxypropyl. In yet another embodiment, R1 is 2-phosphonooxyethyl. In yet another embodiment, R1 is hydroxyethyl.
In one embodiment, R2 is selected from hydrogen and C1-6alkyl which C1-6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylCi- 4alkyl. In another embodiment, R2 is hydrogen, allyl, 2- propynyl, methyl, ethyl, propyl, isopropyl, 2- methylpropyl, butyl, 2,2-dimethylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, 3,3,3-trifluoropropyl or 2-methoxyethyl . In yet another embodiment, R2 is ethyl.
In one embodiment, R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and Ci4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C1-4alkyl groups. In another embodiment, R1 and R2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2- phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl. In a further embodiment, R1 and R2 together with the nitrogen to which they are attached form 4- (phosphonooxymethyl)piperidinyl, 2- (phosphonooxymethyl)pyrrolidinyl, 4-(2- phosphonooxyethyl)piperazinyl, 3-
(phosphonooxy)pyrrolidinyl, 3-(phosphonooxy)piperidinyl, 2-{N-ethyl-N- (2- phosphonooxyethyl)aminomethyl]pyrrolidinyl,
4-(phosphonooxy)piperidinyl, N-(2- phosphonooxyethyl)aminomethyl ]pyrrolidinyl, 4-(2- phosphonooxyethyl)piperidinyl, 2-(2- phosphonooxyethyl)pyrrolidinyl and 2-(2- phosphonooxyethyl)piperidinyl . In yet another embodiment, R1 and R2 together with the nitrogen to which they are attached form 4-(phosphonooxymethyl)piperidinyl, 2- (phosphonooxymethyl)pyrrolidinyl, 2-(2- phosphonooxyethyl)pyrrolidinyl and 3-
(phosphonooxy)piperidinyl . In a further embodiment, R1 and R2 together with the nitrogen to which they are attached form 2- (phosphonooxymethyl)pyrrolidinyl .
In one embodiment, R3 is C1-4alkoxy, halo or hydrogen. In a further embodiment, R3 is C1-4alkoxy or hydrogen. In another embodiment, R3 is methoxy. In another embodiment, R3 is hydrogen. In yet a further embodiment, R3 is fluoro.
In one embodiment, R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro. In another embodiment, R4 is 3-fluorophenyl, 3-chlorophenyl, 3,5- difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl and 2,5- difluorophenyl . In a further embodiment, R4 is 3- fluorophenyl, 3,5-difluorophenyl and 2,3-difluorophenyl. In a further embodiment, R4 is 3-fluorophenyl. In a further embodiment, R4 is 3,5-difluorophenyl. In yet another embodiment, R4 is 2,3-difluorophenyl.
In one embodiment, R5 is hydrogen or methyl. In another embodiment, R5 is hydrogen.
In one embodiment, R6 is hydrogen, fluoro, chloro or methyl. In another embodiment, R6 is hydrogen.
In one embodiment, R7 is hydrogen, fluoro, chloro or methyl. In another embodiment, R7 is hydrogen.
In one embodiment, R8 is 2-phosphonooxyethyl.
In one embodiment, R9 is hydrogen, methyl or ethyl.
In one embodiment, R10 is hydrogen, methyl or ethyl.
In one embodiment, R11 is hydrogen, methyl or ethyl.
In one embodiment, R12 is hydrogen or methyl.
In one embodiment, R13 is hydrogen or methyl.
In one embodiment, R14 is hydrogen or methyl.
A preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a), (b), (c), (d) or
(e) as defined above;
X is NH; m is 0, 1, 2 or 3;
Z is —NR1R2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or Ci_4alkyl substituted by phosphonooxy; R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and C1-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl; or R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 Ci_4alkyl groups;
R3 is C1-4alkoxy, halo or hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen or methyl; and
R6 and R7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a), (b), (c), (d) or
(e) as defined above;
X is NH; m is 1, 2 or 3;
Z is —NR1R2;
R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl;
R3 is C1-4alkoxy, halo or hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen or methyl; and
R6 and R7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
Another preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a) as defined above;
X is NH; m is 1, 2 or 3;
Z is —NR1R2;
R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl; R3 is C1-4alkoxy, halo or hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and R6 and R7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
Yet another preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a) as defined above;
X is NH; m is 1 or 2;
Z is —NR1R2;
R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and C1-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl;
R3 is C1-4alkoxy;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and R6 and R7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds is of formula
(I) wherein: Ring A is a group of formula (a) as defined above;
X is NH; m is 1, 2 or 3;
Z is —NR1R2;
R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and C1-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl;
R3 is hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and R6 and R7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a) as defined above;
X is NH; m is 1 or 2;
Z is —NR1R2;
R1 is Ci-salkyl substituted by phosphonooxy;
R2 is selected from hydrogen and C1-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C1-4alkoxy groups, or R2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC1-4alkyl;
R3 is fluoro;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and R6 and R7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
Another preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a), (b), (c), (d) or
(e) as defined above;
X is NH; m is 0, 1 or 2;
Z is —NR1R2
R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom which ring is substituted by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted by 1 or 2 Ci- 4alkyl groups;
R3 is C1-4alkoxy, halo or hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen or methyl; and R6 and R7 are independently hydrogen, fluoro, chloro or methyl;
R8 is 2-phosphonooxyethyl; and R9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a) as defined above;
X is NH;
5 m is 0, 1 or 2;
Z is -NR4R2
R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C1-4alkyl groups;
R3 is C1-4alkoxy, halo or hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen or methyl; and
R6 and R7 are independently hydrogen, fluoro, chloro or methyl;
R8 is 2-phosphonooxyethyl; and R9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds is of formula (I) wherein:
Ring A is a group of formula (a) as defined above;
X is NH; m is 0, 1 or 2;
Z is —NR1R2
R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C1-4alkyl groups;
R3 is C1-4alkoxy;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and
R6 and R7 are each hydrogen;
R8 is 2-phosphonooxyethyl; and R9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds is of formula
(I) wherein: Ring A is a group of formula (a) as defined above;
X is NH; m is 0, 1 or 2;
Z is —NR1R2
R1 and R2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or —NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C1-4alkyl groups;
R3 is hydrogen;
R4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
R5 is hydrogen; and
R6 and R7 are each hydrogen;
R8 is 2-phosphonooxyethyl; and R9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
Another preferred compound of formula (I) is any compound selected from:
{1—[3— ({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-4-yl }methyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ {5—{2— [(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{(2R)-l-[3-({4-[ {5—{2— [(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ {5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate;
2—{4— [(5-12- [(3,5-difluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2-{ (2,2-dimethylpropyl)[3— {{4— [{5—{2— [(3- fluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
1— [3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-3-yl dihydrogen phosphate;
{ (2R)-l-[3-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (2-methoxyethyl)amino]ethyl dihydrogen phosphate;
2-{[3— ({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;2- {(cyclobutylmethyl) [3—({4—[(5—{2—[(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (3,3,3-trifluoropropyl)amino]ethyl dihydrogen phosphate;
2-{allyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclobutyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclopentyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclopropyl [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{(cyclopropylmethyl) [3—{{4—[{5—{2—[(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphateand
2-{cyclobutyl [3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A more preferred compound of formula (I) is a compound selected from:
2-{4- [({4- [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)methyl]piperidin-l-yl }ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
3-{ [3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}- 3-methylbutyl dihydrogen phosphate;
2-{ (2S)-l-[3-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }ethyl dihydrogen phosphate; { (2R)-l-[3-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3—({4—[(5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (butyl)amino]ethyl dihydrogen phosphate;
2-{cyclopentyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
{ (2S)-l-[3-({4-[{5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{ (2S)-l-[3-(14-[{5—{2—[(3-fluorophenyl)amino]-2- oxoethyll-IH-pyrazol-3-yl )amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-{cyclopentyl [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2-{ [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}-2- methylpropyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
{ (2R)-l-[3-({4-[{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
3- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]propyl dihydrogen phosphate2- [ [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl](2- methoxyethyl)amino]ethyl dihydrogen phosphate;
2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (ethyl)amino]ethyl dihydrogen phosphate;
{ (2R)-l-[4-({4-[(5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-ylamino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; 2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)butyl] (methyl)amino]ethyl dihydrogen phosphate;and { (2,5)-l-[4-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further preferred compound of formula (I) is:
2-{ethyl [3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A more preferred compound is any compound selected from: {1— [3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-4-yl }methyl dihydrogen phosphate;
{ (2)-l-[3-({4-[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-
1-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2-{ (2,2-dimethylpropyl)[3—{4—[{5—{2—[(3- fluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
1— [3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-3-yl dihydrogen phosphate; 2-{ [3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (3,3,3-trifluoropropyl)amino]ethyl dihydrogen phosphate;
2-{cyclopropyl [3—{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclobutyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
{ (2S)-l-[3-({4-[{5—{2— [(3-iluorophenyl)amino]-2- oxoethyl}-l-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-{cyclopentyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2-{ [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}-2- methylpropyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;{ (2R)-1-[(3—{{4—[{5—{2—[(3-fluorophenyl)amino]-
2-oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
3- [[3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]propyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl](2- methoxyethyl)amino]ethyl dihydrogen phosphate; and
2-{ethyl [3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further preferred compound is any compound selected from:
{1— [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-4-yl }methyl dihydrogen phosphate; { (2)-l-[3-({4-[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-
1-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate;2-{ (2,2-dimethylpropyl)[3—({4—[(5—{2— [(3- fluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
1— [3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-3-yl dihydrogen phosphate;
2-{ [3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2- [[3—({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (3,3,3-trifluoropropyl)amino]ethyl dihydrogen phosphate;
2-{cyclopropyl [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; and 2-{cyclobutyl [3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
Another preferred compound is any compound selected from: 2- [[3—{{4—[{5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2-{ (2,2-dimethylpropyl)[3—{{4—[{5—{2— [(3- fluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2-{ [3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (3,3,3-trifluoropropyl)amino]ethyl dihydrogen phosphate;
2-{cyclopropyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; and 2-{cyclobutyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A particularly preferred compound is any compound selected from:
{ (2S)-l-[3-({4-[{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lpyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-{cyclopentyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2-{ [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}-2- methylpropyl dihydrogen phosphate;
2- [[2— {{4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
{ (2R)-l-[3-({4-[{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
3- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]propyl dihydrogen phosphate; and
2- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl](2- methoxyethyl)amino]ethyl dihydrogen phosphate;
Or a pharmaceutically acceptable salt thereof.
An especially preferred compound of formula (I) is any compound selected from:
2-{cyclopentyl [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2-{ [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}-2- methylpropyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
3- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino] propyl dihydrogen phosphate; and
2- [[3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl) amino] quinazolin-7- yl} oxy) propyl] (2- methoxyethyl) amino] ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further preferred compound is any compound selected from :
2- [[3— {{4— [{5—{2— [(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl }oxy) propyl] (ethyl)amino]ethyl dihydrogen phosphate;
{ (2S)-l-[3-({4-[{5—{2— [(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; { (2R)-1-[3-(14-[(5-12-[(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyqumazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate; and
2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further preferred compound is any compound selected from:
2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2- [[3—{{4—[{5—{2—[(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate; and
2- [[3— {{4— [{5—{2— [(3,5-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazol-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
Another more preferred compound is any compound selected from :
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; { (2R)-l-[3-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yloxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (2-methoxyethyl)amino]ethyl dihydrogen phosphate;
2-{(cyclobutylmethyl) [3— ({4— [(5—{2— [(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2-{allyl [3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclobutyl [3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclopentyl [3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{(cyclopropyhnethyl) [3— {{4— [{5—{2— [(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2—{4— [({4-[(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)methyl]piperidin-l-yl }ethyl dihydrogen phosphate; 2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate; 2-[[3— ({4—[(5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
3-{[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}- 3-methylbutyl dihydrogen phosphate;
2-{(2S)-l-[3-({4-[ {5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }ethyl dihydrogen phosphate;
{(2R)-l-[3-({4-[ {5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (butyl)amino]ethyl dihydrogen phosphate;
2-{cyclopentyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ {5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; 2- [[4— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (propyl)amino]ethyl dihydrogen phosphate;
2-[ [4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (ethyl)amino]ethyl dihydrogen phosphate;
{ (2R)-l-[4-[{4-[(5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; 2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)butyl] (methyl)amino]ethyl dihydrogen phosphate; and
{ (2S)-l-[4-({4-[{5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A particularly preferred compound is any compound selected from:
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; { (2R)-I- [3- (14- [(5-12- [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-[[3— ({4—[(5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (2-methoxyethyl)amino]ethyl dihydrogen phosphate;
2-{(cyclobutylmethyl) [3—{{4—[{5—{2—[(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2-{allyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclobutyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclopentyl [3—{{4—[{5—{2—[(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; and 2-{(cyclopropylmethyl) [3—({4—[(5—{2—[(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
Yet another preferred compound is any compound selected from:
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquillazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (prop-2-yn-l-yl)amino]ethyl dihydrogen phosphate;
2-[[3— {{4—[{5—{2—[(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl] (2-methoxyethyl)amino]ethyl dihydrogen phosphate;
2-{(cyclobutylmethyl) [3—{{4—[{5—{2—[(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate;
2-{allyl [3— ({4— [(5- [2- [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclobutyl [3— ({4— [(5- [2- [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-{cyclopentyl [3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate; and 2-{ (cyclopropylmethyl)[3— ({4— [(5—{2— [(2,3- difluorophenyl)amino]-2-oxoethyl }-lH-pyrazol-3-yl)amino]- 6-methoxyquinazolin-7-yl }oxy)propyl]amino}ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
Another preferred compound is any compound selected from: 2-{4- [({4- [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)methyl]piperidin-l-yl }ethyl dihydrogen phosphate; 2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate; 3-{[3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}- 3-methylbutyl dihydrogen phosphate;
2-{(2S)-l-[3-({4-[ (5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }ethyl dihydrogen phosphate;
{(2R)-l-[3-({4-[ (5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2- [[3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (butyl)amino]ethyl dihydrogen phosphate;
2-{cyclopentyl [3— {{4— [(5- [2- [(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ {5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (propyl)amino]ethyl dihydrogen phosphate;
2- [[4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (ethyl)amino]ethyl dihydrogen phosphate; {(2R)-l-[4-({4-[ (5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; 2- [[4— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)butyl] (methyl)amino]ethyl dihydrogen phosphate; and
{(2S)-l-[4-({4-[ {5—{2— [(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
Yet another preferred compound is any compound selected from :
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lHpyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (isopropyl)amino]ethyl dihydrogen phosphate;
3-{[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7-yl }oxy)propyl]amino}- 3-methylbutyl dihydrogen phosphate;
2- [[3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (propyl)amino]ethyl dihydrogen phosphate; 2- [[3— ({4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl] (butyl)amino]ethyl dihydrogen phosphate;
2-{cyclopentyl [3— {{4— [{5—{2— [(2,3-difluorophenyl)amino]- 2-oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]amino }ethyl dihydrogen phosphate;
2-[ [4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (propyl)amino]ethyl dihydrogen phosphate;
2-[ [4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl] (ethyl)amino]ethyl dihydrogen phosphate; and 2-[ [4— {{4— [(5—{2— [(2,3-difluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)amino]quinazolin-7- yl}oxy)butyl] (methyl)amino]ethyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further particularly preferred compound is any compound selected from:
{1— [3— {{4— [{5—{2— [(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-4-yl }methyl dihydrogen phosphate;
{ (2S)-1- [3- (f4- [(5-12- [(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{ (2R)-l-[3-({4-[{5—{2— [(3,5-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ (5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
1—[3— ({4—[(5—{2—[(3-fluorophenyl)amino]-2-oxoethyl}-1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]piperidin-3-yl dihydrogen phosphate;
{(2R)-l-[3-({4-[ (5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
2-{(2S)-l-[3-({4-[ (5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }ethyl dihydrogen phosphate; {(2R)-l-[3-({4-[ (5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ (5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{(2S)-l-[3-({4-[ (5—{2—[(3-Quorophenyl)ainino]-2- oxoethyl}-l-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; { (2R)-l-[3-({4-[(5—{2—[(3-fluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)propyl]pyrrolidin-2-yl }methyl dihydrogen phosphate;
{ (2R)-l-[4-({4-[(5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; and
{ (2S)-l-[4-({4-[(5—{2—[(2,3-difluorophenyl)amino]-2- oxoethyl}-lH-pyrazol-3-yl)amino]-quinazolin-7- yl}oxy)butyl]pyrrolidin-2-yl }methyl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
A further preferred compound of formula (I) is any one of:
N- (2,3-difluorophenyl)—2—{3—[(7-{[1-(2- hydroxyethyl)piperidin-4-yl ]methoxy}quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N- (2,3-difluorophenyl)-2-{3-[(7—{3—[(3-hydroxy-l,1- dimethylpropyl)amino]propoxy }quinazolin-4-yl)amino]-1H- pyrazol-5-yl}acetamide;
N- (2,3-difluorophenyl)-2-{3-[(7-{3-[(259-2-(2- hydroxyethyl)pyrrolidin-l-yl ]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N- (2,3-difluorophenyl)—2—{3—[(7—{3—[(2- hydroxyethyl) (butyl)amino]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide; 2—{3— [(7—{3—[cyclopentyl(2-hydroxyethyl)amino]propoxy}- quinazolin-4-yl)amino]-lH-pyrazol-5-yl }-N (2,3- difluorophenyl)acetamide;
N-(2,3-difluorophenyl)—2— {3—[(7—{3—[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl ]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N-(3-fluorophenyl)-2- {3-[(7-{3-[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl ]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
2—{3— [(7—{3—[cyclopentyl(2-hydroxyethyl)amino]propoxy}- quinazolin-4-yl)amino]-lH-pyrazol-5-yl }-N- (3- fluorophenyl)acetamide;
N-(3-fluorophenyl)—2— {3—[(7—{3—[ethyl(2- hydroxyethyl)amino]propoxy }-quinazolin-4-yl)amino]-1H- pyrazol-5-yl}acetamide;N- (3-fluorophenyl)—2—{3— [(7—{3—
[(2-hydroxy-1,1-dimethylethyl )amino]propoxy}quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N-(3-fluorophenyl)—2— {3—[(7—{3—[(2- hydroxyethyl) (propyl)amino]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N-(3-fluorophenyl)—2— {3—[(7—{3—[(2R)-2- (hydroxymethyl)pyrrolidin-l-yl ]propoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N-(2,3-difluorophenyl)—2— {3—[(7—{4—[(2- hydroxyethyl) (propyl)amino]butoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide; N- (3-fluorophenyl)—2—{3—[(7—{4—[ethyl(2- hydroxyethyl)amino]butoxy }-quinazolin-4-yl)amino]-1H- pyrazol-5-yl}acetamide;
N (2,3-difluorophenyl)-2-{3-[(7—{4—[(2R)-2- (hydroxymethyl)pyrrolidin-l-yl ]butoxy}-quinazolin-4- yl)amino]-lH-pyrazol-5-yl }acetamide;
N (2,3-difluorophenyl)—2—{3—[(7—{4—[(2- hydroxyethyl) (methyl)amino]butoxy}quinazolin-4-yl)amino]- lH-pyrazol-5-yl }acetamide;N-(2,3-difluorophenyl)—2—{3—
[ (7—{4—[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]butoxy}- quinazolin-4-yl)amino]-lH-pyrazol-5-yl }acetamide;
2—{3— [(7—{3—[ethyl(3-hydroxypropyl)amino]propoxy}- quinazolin-4-yl)amino]-lH-pyrazol-5-yl }-N- (3- fluorophenyl)acetamide;
N- (3-fluorophenyl)-2-{3-[{7—{3—[(2-hydroxyethyl)(2- methoxyethyl)amino]propoxy }quinazolin-4-yl)amino]-1H- pyrazol-5-yl}acetamide; and
2—{3— [(7—{3—[ethyl(2-hydroxyethyl)amino]propoxy}-6- fluoroquinazolin-4-yl)amino]-lH-pyrazol-5-yl }-N-(3- fluorophenyl)acetamide; or a pharmaceutically acceptable salt thereof.
In an especially preferred embodiment the Aurora B inhibitor used in the disclosure is [AZD1152; barasertib] represented by the following formula:
Figure imgf000095_0002
or a pharmaceutically acceptable salt thereof.
In another especially preferred embodiment the Aurora B inhibitor used in the disclosure is [AZD1152hqpa] represented by the following formula:
Figure imgf000095_0001
or a pharmaceutically acceptable salt thereof, in the form of a nanoparticle.
In a particularly especially preferred embodiment the Aurora B inhibitor used in the disclosure is a nanoparticle [AZD2811] comprising:
15 to 25 weight percent, preferably about 20 weight percent, of the compound [AZD1152hqpa] represented by the following formula:
Figure imgf000096_0001
7 to 15 weight percent of pamoic acid; and
60 to 78 weight percent a diblock poly(lactic) acid- poly(ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly(ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly(ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
Aurora B inhibitors such as compounds of formula (I), including AZD1152 and AZD1152hqpa, may be prepared by methods known in the art such as disclosed in W02004/058781. Nanoparticles comprising compounds of formula (I), including nanoparticle AZD2811 which comprises AZD1152hqpa, may be prepared by methods known in the art such as disclosed in WO2015/036792.
The term "pharmaceutically acceptable salt" of the Aurora B inhibitor used in the present disclosure may be either an acid addition salt or a base addition salt. Examples of the acid addition salt can include lower alkanesulfonates such as camsilate (camphorsulfonate), mesilate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosilate (p- toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrogen halide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate, and aspartate. Examples of the base addition salt can include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkali earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, diethanolamine salt, N- benzyl-N- (2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl)aminomethane salt; and amino acid salts such as alginate.
The Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure may each exist as a solvate, and solvates of them are also included in the meaning of the Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure.
5. Combination of antibody-drug conjugate and Aurora B inhibitor
In a first combination embodiment of the disclosure, the anti-HER2 antibody-drug conjugate which is combined with the Aurora B inhibitor is an antibody-drug conjugate in which a drug-linker represented by the following formula:
Figure imgf000098_0001
wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above for the first combination embodiment is combined with an Aurora B inhibitor which is a compound of formula (I):
Figure imgf000099_0001
wherein
Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
X is 0, S, S(0), S(0)2 or NR14 ; m is 0, 1, 2 or 3;
Z is a group selected from -NR1R2, phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups; R1 is a group selected from -COR8, -CONR8R9 and C1-6alkyl which C1-6alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 is a group selected from is a group selected from hydrogen, -COR10, -CONR10R11 and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups or -S(0)pR11 (where p is 0, 1 or 2) or phosphonooxy, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl; or R1 and R2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or -NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R3 is a group selected from hydrogen, halo, cyano, nitro, C1-6alkoxy, C1-6alkyl, -OR12, -CHR12R13, -0C(0)R12, - C (0)R12, -NR12C (0)R13, -C (0)NR12R13, -NR12S02R13 and -NR12R13;
R4 is hydrogen or a group selected from C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, aryl and arylC1-4alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl; R5 is selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl;
R6 and R7 are independently selected from hydrogen, halo, C1-4alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
R8 is C1-4alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 is selected from hydrogen and C1-4alkyl;
R10 is selected from hydrogen and C1-4alkyl (optionally substituted by halo, C1-4alkoxy, S(0)q (where q is 0,1 or 2) or phosphonooxy);
R11, R12, R13 and R14 are independently selected from hydrogen, C1-4alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a), (b), (c),
(d) or (e) :
Figure imgf000101_0001
(d) (e) where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR6R7) group of formula (I).
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a) as defined above.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), X is NH.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR1R2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), in formula (I), R1 is Ci-salkyl substituted by phosphonooxy and R2 is a group selected from hydrogen and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6CycloalkylC1-4alkyl. In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R1 is 2-phosphonooxyethyl.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR1R2 and R1 and R2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2- phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2— phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R1 and R2 together with the nitrogen to which they are attached form 2-(phosphonooxymethyl)pyrrolidinyl .
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R4 is 3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl .
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R3 is C1-4alkoxy, halo or hydrogen.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152; barasertib] represented by the following formula:
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152hqpa] represented by the following formula:
Figure imgf000104_0002
or a pharmaceutically acceptable salt thereof.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle.
In another combination embodiment, the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle, the nanoparticle comprising:
15 to 25 weight percent, preferably about 20 weight percent, of the compound [AZD1152hqpa] represented by the following formula:
Figure imgf000105_0001
7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle [AZD2811]. In an embodiment of each of the combination embodiments described above, the anti-HER2 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8. In another embodiment of each of the combination embodiments described above, the anti-HER2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10. In another embodiment of each of the combination embodiments described above, the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2. In another embodiment of each of the combination embodiments described above, the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2. In a particularly preferred combination embodiment of the disclosure, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the Aurora B inhibitor is a nanoparticle [AZD2811] comprising:
15 to 25 weight percent, preferably about 20 weight percent, of the compound [AZD1152hqpa] represented by the following formula:
Figure imgf000107_0001
7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
6. Therapeutic combined use and method
Described in the following are a pharmaceutical product and a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate according to the present disclosure and an Aurora B inhibitor are administered in combination.
The pharmaceutical product and therapeutic use and method of the present disclosure may be characterized in that the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times, or characterized in that the antibody-drug conjugate and the Aurora B inhibitor are contained as active components in a single formulation and administered.
In the pharmaceutical product and therapeutic method of the present disclosure, a single Aurora B inhibitor used in the present disclosure can be administered in combination with the anti-HER2 antibody-drug conjugate, or two or more different Aurora B inhibitors can be administered in combination with the antibody-drug conjugate.
The pharmaceutical product and therapeutic method of the present disclosure can be used for treating cancer, and can be preferably used for treating at least one cancer selected from the group consisting of breast cancer (including triple negative breast cancer and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colon and rectal cancer, and including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head-and-neck cancer (including salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma, and can be more preferably used for treating at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer (preferably non small cell lung cancer), pancreatic cancer, ovarian cancer, prostate cancer, and kidney cancer.
The presence or absence of HER2 tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient to prepare a formalin-fixed, paraffin- embedded (FFPE) specimen and subjecting the specimen to a test for gene products (proteins), for example, with an immunohistochemical (IHC) method, a flow cytometer, or Western blotting, or to a test for gene transcription, for example, with an in situ hybridization (ISH) method, a quantitative PCR method (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to a test with a method such as next-generation sequencing (NGS).
The pharmaceutical product and therapeutic method of the present disclosure can be used for HER2-expressing cancer, which may be HER2-overexpressing cancer (high or moderate) or may be HER2 low-expressing cancer.
In the present disclosure, the term "HER2- overexpressing cancer" is not particularly limited as long as it is recognized as HER2-overexpressing cancer by those skilled in the art. Preferred examples of the HER2-overexpressing cancer can include cancer given a score of 3+ for the expression of HER2 in an IHC method, and cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in an in situ hybridization method (ISH). The in situ hybridization method of the present disclosure includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH).
In the present disclosure, the term "HER2 low- expressing cancer" is not particularly limited as long as it is recognized as HER2 low-expressing cancer by those skilled in the art. Preferred examples of the HER2 low- expressing cancer can include cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as negative for the expression of HER2 in an in situ hybridization method, and cancer given a score of 1+ for the expression of HER2 in an IHC method. The method for scoring the degree of HER2 expression by the IHC method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in the 4th edition of the guidelines for HER2 testing, breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).
The cancer, particularly in regard to the treatment of breast cancer, may be HER2-overexpressing (high or moderate) or low-expressing breast cancer, or triple negative breast cancer, and/or may have a HER2 status score of IHC 3+, IHC 2+, IHC 1+ or IHC >0 and <1+.
The pharmaceutical product and therapeutic method of the present disclosure can be preferably used for a mammal, but are more preferably used for a human.
The antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed by transplanting cancer cells to a test subject animal to prepare a model and measuring reduction in tumor volume or life-prolonging effect by application of the pharmaceutical product and therapeutic method of the present disclosure. And then, the effect of combined use of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor can be confirmed by comparing antitumor effect with single administration of the antibody-drug conjugate used in the present disclosure and that of the Aurora B inhibitor.
The antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed in a clinical trial using any of an evaluation method with Response Evaluation Criteria in Solid Tumors (RECIST), a WHO evaluation method, a Macdonald evaluation method, body weight measurement, and other approaches, and can be determined on the basis of indexes of complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and so on.
By using the above methods, the superiority in antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure to existing pharmaceutical products and therapeutic methods for cancer treatment can be confirmed.
The pharmaceutical product and therapeutic method of the present disclosure can delay development of cancer cells, inhibit growth thereof, and further kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or achieve improvement in quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and therapeutic method of the present disclosure do not accomplish killing cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells.
The pharmaceutical product of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues.
The pharmaceutical product of the present disclosure can be administered containing at least one pharmaceutically suitable ingredient. Pharmaceutically suitable ingredients can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration, or the like of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor. The anti-HER2 antibody-drug conjugate used in the present disclosure can be administered, for example, as a pharmaceutical product containing a buffer such as histidine buffer, a vehicle such as sucrose and trehalose, and a surfactant such as Polysorbates 80 and 20. The pharmaceutical product containing the antibody-drug conjugate used in the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection.
In the case that the pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in the present disclosure is an aqueous injection, the aqueous injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion. Examples of the diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
In the case that the pharmaceutical product of the present disclosure is a lyophilized injection, a required amount of the lyophilized injection dissolved in advance in water for injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion. Examples of the diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
Examples of the administration route applicable to administration of the pharmaceutical product of the present disclosure can include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and intravenous routes are preferred.
The anti-HER2 antibody-drug conjugate used in the present disclosure can be administered to a human with intervals of 1 to 180 days, can be preferably administered with intervals of a week, two weeks, three weeks, or four weeks, and can be more preferably administered with intervals of three weeks. The anti- HER2 antibody-drug conjugate used in the present disclosure can be administered in a dose of about 0.001 to 100 mg/kg per administration, and can be preferably administered in a dose of 0.8 to 12.4 mg/kg per administration. For example, the anti-HER2 antibody-drug conjugate can be administered once every three weeks at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 5.4 mg/kg, 6.4 mg/kg, 7.4 mg/kg, or 8 mg/kg, and can be preferably administered once every three weeks at a dose of 5.4 mg/kg or 6.4 mg/kg.
The Aurora B inhibitor according to the present disclosure can be orally administered to a human once or twice in each one to seven days, and can be preferably orally administered once a day or twice per day. The Aurora B inhibitor used in the present disclosure can be orally administered in a dose of 0.1 mg to 4000 mg per administration, and can be preferably administered in a dose of 2.5 mg to 600 mg per administration. The Aurora B inhibitor used in the present disclosure can be administered to a human as an intravenous drip with intervals of 1 to 180 days, and can be preferably administered as an intravenous drip with intervals of a week, two weeks, three weeks, or four weeks. The Aurora B inhibitor used in the present disclosure can be administered as an intravenous drip in a dose of 0.1 mg to 3000 mg per administration, and can be preferably administered as an intravenous drip in a dose of 10 mg to 100 mg per administration. For example, a formulation of an Aurora B inhibitor compound of formula (I) intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4000 mg of the active ingredient, compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of the active ingredient. For further information on Routes of Administration and Dosage Regimes, reference may be made to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose required for the therapeutic treatment of a particular disease state will necessarily be varied depending on the subject treated, the route of administration and the severity of the illness being treated. A daily dose of the Aurora B inhibitor in the range of 0.1-50 mg/kg may be employed. For example, in the case that the Aurora B inhibitor used in the present disclosure is AZD2811, the Aurora B inhibitor can be administered in a dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg per administration. In embodiments, the total daily dose of AZD2811 is about 200 mg via intravenous administration. In embodiments, the total daily dose is about 500 mg. In further embodiments, the total daily dose is about 600 mg. In further embodiments, the total daily dose is 300 mg. In further embodiments, AZD2811 is administered on day 1 and day 4 of a 28-day cycle. In further embodiments, AZD2811 is administered on day 1 of a 21-day cycle.
The pharmaceutical product and therapeutic method of the present disclosure can be used as adjuvant chemotherapy combined with surgery operation. The pharmaceutical product of the present disclosure may be administered for the purpose of reducing tumor size before surgical operation (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or may be administered for the purpose of preventing recurrence of tumor after surgical operation (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).
[Examples]
The present disclosure is specifically described in view of the examples shown below. However, the present disclosure is not limited to these. Further, it is by no means to be interpreted in a limited way.
Example 1:_ Production of antibody-drug conjugate
In accordance with a production method described in W02015/115091 and using an anti-HER2 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 (amino acid residues 1 to 449 of SEQ ID NO: 1) and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2), an anti- HER2 antibody-drug conjugate in which a drug-linker represented by the following formula:
Figure imgf000118_0001
wherein A represents the connecting position to an antibody, is conjugated to the anti-HER2 antibody via a thioether bond was produced (DS-8201: trastuzumab deruxtecan). The DAR of the antibody-drug conjugate is 7.7 or 7.8.
Example 2:_ Production of Aurora B inhibitor
In accordance with a production method described in W02004/058781, an Aurora B inhibitor of formula (I) is prepared. Specifically, 2-(3-((7-(3-(ethyl(2- hydroxyethyl)amino)propoxy)quinazolin-4-yl )amino)-1H- pyrazol-5-yl)-N- (3-fluorophenyl)acetamide:
Figure imgf000119_0001
(AZD1152hqpa) can be prepared according to Example 39(a) of W02004/058781 .
In accordance with a production method described in W02015/036792, a nanoparticle (AZD2811) of 2-(3-((7-(3- (ethyl (2-hydroxyethyl)amino)propoxy)quinazolin-4- yl)amino)-lH-pyrazol-5-yl)-N- (3-fluorophenyl)acetamide (AZD1152hqpa) is prepared.
Example 3:_ Antitumor test
Combination of antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) with Aurora B inhibitor AZD2811 (nanoparticle comprising 2-(3-((7-(3-(ethyl(2- hydroxyethyl)amino)propoxy)quinazolin-4-yl )amino)-1H- pyrazol-5-yl)-N- (3-fluorophenyl)acetamide (AZD1152hqpa)).
Method:
A high-throughput combination screen was run, in which a breast cancer cell line and a gastric cell line with high HER2 expression (Table 1) were treated with combinations of DS-8201 and AZD2811 (Aurora B inhibitor).
Table 1
Figure imgf000120_0001
The readout of the screen was a 7-day cell titer-glo cell viability assay, conducted as a 6 x 6 dose response matrix for each combination (5-point log serial dilution for DS-8201, and half log serial dilution for partners). In addition, trastuzumab and exatecan (DNA topoisomerase I inhibitor) were also screened in parallel with AZD2811. Combination activity was assessed based on a combination of the ΔEmax and HSA synergy scores.
Results:
Results are shown in Figure 12 and Table 2.
In Figure 12, row A) shows matrices of measured cell viability signals. X axes represent drug A (DS-8201), and Y axes represent drug B (AZD2811). Values in the box represent the ratio of cells treated with drug A + B compared to DMSO control at day 7. All values are normalised to cell viability values at day 0. Values between 0 and 100 represent % growth inhibition and values above 100 represent cell death.
In Figure 12, row B) shows HSA excess matrices. Values in the box represent excess values calculated by the HSA (Highest Single Agent) model.
Table 2 shows HSA synergy and Loewe additivity scores: Table 2
Figure imgf000121_0001
Loewe Dose Additivity predicts the expected response if the two compounds act on the same molecular target by means of the same mechanism. It calculates additivity based on the assumption of zero interaction between the compounds and it is independent from the nature of the dose-response relationship.
HSA (Highest Single Agent) [Berenbaum 1989] quantifies the higher of the two single compound effects at their corresponding concentrations. The combined effect is compared with the effect of each single agent at the concentration used in the combination. Excess over the highest single agent effect indicates cooperativity. HSA does not require the compounds to affect the same target.
Excess Matrix: For each well in the concentration matrix, the measured or fitted values are compared to the predicted non-synergistic values for each concentration pair. The predicted values are determined by the chosen model. Differences between the predicted and observed values may indicate synergy or antagonism, and are shown in the Excess Matrix. Excess Matrix values are summarized by the combination scores Excess Volume and Synergy
Score.
As seen from Figure 12 and Table 2, AZD2811 and DS-8201 in combination showed synergistic activity and increased cell death in HER2 + cell lines KPL4 and NCI-N87. Combination activity was observed at Emax (AZD28111 mM and DS-820110 μg/ml (0.064 mM)) and also at lower concentrations .
The results demonstrate that Aurora B inhibition using AZD2811 enhances the antitumor efficacy of DS-8201 in high HER2-expressing cell lines in vitro. AZD2811 showed synergistic combination activity and increased cell death in HER2 high cell lines.
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiments may be practiced in many ways and the claims include any equivalents thereof. Free Text of Sequence Listing
SEQ ID NO: 1 - Amino acid sequence of a heavy chain of an anti-HER2 antibody
SEQ ID NO: 2 - Amino acid sequence of a light chain of an anti-HER2 antibody
SEQ ID NO: 3 - Amino acid sequence of a heavy chain CDRH1 [= amino acid residues 26 to 33 of SEQ ID NO: 1]
SEQ ID NO: 4 - Amino acid sequence of a heavy chain CDRH2 [= amino acid residues 51 to 58 of SEQ ID NO: 1]
SEQ ID NO: 5 - Amino acid sequence of a heavy chain CDRH3 [= amino acid residues 97 to 109 of SEQ ID NO: 1]
SEQ ID NO: 6 - Amino acid sequence of a light chain CDRL1 [= amino acid residues 27 to 32 of SEQ ID NO: 2]
SEQ ID NO: 7 - Amino acid sequence comprising an amino acid sequence of a light chain CDRL2 (SAS) [= amino acid residues 50 to 56 of SEQ ID NO: 2]
SEQ ID NO: 8 - Amino acid sequence of a light chain CDRL3 [= amino acid residues 89 to 97 of SEQ ID NO: 2]
SEQ ID NO: 9 - Amino acid sequence of a heavy chain variable region [= amino acid residues 1 to 120 of SEQ ID NO: 1]
SEQ ID NO: 10 - Amino acid sequence of a light chain variable region [= amino acid residues 1 to 107 of SEQ ID NO: 2]
SEQ ID NO: 11 - Amino acid sequence of a heavy chain [= amino acid residues 1 to 449 of SEQ ID NO: 1]

Claims

1. A pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor for administration in combination, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:
Figure imgf000124_0001
wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
2. The pharmaceutical product according to claim 1, wherein the Aurora B inhibitor is a compound of
formula (I):
Figure imgf000125_0001
wherein
Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
X is 0, S, S(0), S(0)2 or NR14 ; m is 0, 1, 2 or 3;
Z is a group selected from -NR1R2, phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups; R1 is a group selected from -COR8, -CONR8R9 and C1-6alkyl which C1-6alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R2 is a group selected from is a group selected from hydrogen, -COR10, -CONR10R11 and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups or -S(0)pR11 (where p is 0, 1 or 2) or phosphonooxy, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl; or R1 and R2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C1-4alkyl which C1-4alkyl is substituted by phosphonooxy or -NR8R9, and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C1-4alkyl groups;
R3 is a group selected from hydrogen, halo, cyano, nitro, C1-6alkoxy, C1-6alkyl, -OR12, -CHR12R13, -0C(0)R12, - C (0)R12, -NR12C (0)R13, -C (0)NR12R13, -NR12S02R13 and -NR12R13;
R4 is hydrogen or a group selected from C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, aryl and arylC1-4alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl; R5 is selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC1-4alkyl;
R6 and R7 are independently selected from hydrogen, halo, C1-4alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
R8 is C1-4alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
R9 is selected from hydrogen and C1-4alkyl;
R10 is selected from hydrogen and C1-4alkyl (optionally substituted by halo, C1-4alkoxy, S(0)q (where q is 0,1 or 2) or phosphonooxy);
R11, R12, R13 and R14 are independently selected from hydrogen, C1-4alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical product according to claim 2, wherein, in formula (I), Ring A is a group of formula
Figure imgf000127_0001
where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR6R7) group of formula (I).
4. The pharmaceutical product according to claim 3, wherein, in formula (I), Ring A is a group of formula (a) as defined in claim 3.
5. The pharmaceutical product according to any one of claims 2 to 4, wherein, in formula (I), X is NH.
6. The pharmaceutical product according to any one of claims 2 to 5, wherein, in formula (I), Z is -NR1R2 or a
5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C1-4alkyl substituted by phosphonooxy.
7. The pharmaceutical product according to any one of claims 2 to 6, wherein, in formula (I), R1 is Ci-salkyl substituted by phosphonooxy and R2 is a group selected from hydrogen and C1-6alkyl which C1-6alkyl is optionally substituted by 1,2 or 3 halo or C1-4alkoxy groups, or R2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylC1-4alkyl.
8. The pharmaceutical product according to any one of claims 2 to 7, wherein, in formula (I), R1 is 2-phosphonooxyethyl .
9. The pharmaceutical product according to any one of claims 2 to 6, wherein, in formula (I), Z is -NR1-R2 and R1 and R2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N- ethyl-N- (2-phosphonooxyethyl)aminomethyl and N-(2— phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
10. The pharmaceutical product according to claim 9, wherein, in formula (I), R1 and R2 together with the nitrogen to which they are attached form
2-(phosphonooxymethyl)pyrrolidinyl .
11. The pharmaceutical product according to any one of claims 2 to 10, wherein, in formula (I), R4 is
3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl.
12. The pharmaceutical product according to any one of claims 2 to 11, wherein, in formula (I), R3 is C1-4alkoxy, halo or hydrogen.
13. The pharmaceutical product according to claim 2, wherein the compound of formula (I) is [AZD1152; barasertib] represented by the following formula:
Figure imgf000130_0001
or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical product according to claim 2, wherein the compound of formula (I) is [AZD1152hqpa] represented by the following formula:
Figure imgf000130_0002
or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical product according to claim 14, wherein the compound of formula (I) [AZD1152hqpa] is in the form of a nanoparticle.
16. The pharmaceutical product according to claim 15, wherein the nanoparticle comprises:
15 to 25 weight percent, preferably about 20 weight percent, of the compound [AZD1152hqpa] represented by the following formula:
Figure imgf000131_0001
7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle [AZD2811].
17. The pharmaceutical product according to any one of claims 1 to 16, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.
18. The pharmaceutical product according to any one of claims 1 to 16, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10.
19. The pharmaceutical product according to any one of claims 1 to 16, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
20. The pharmaceutical product according to any one of claims 1 to 16, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
21. The pharmaceutical product according to any one of claims 1 to 20, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula:
Figure imgf000133_0001
wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8.
22. The pharmaceutical product according to any one of claims 1 to 21, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201).
23. The pharmaceutical product according to any one of claims 1 to 22, wherein the product is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration.
24. The pharmaceutical product according to any one of claims 1 to 22, wherein the product is a combined preparation comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for sequential or simultaneous administration.
25. The pharmaceutical product according to any one of claims 1 to 24, wherein the product is for treating cancer.
26. The pharmaceutical product according to claim 25, wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.
27. The pharmaceutical product according to claim 26, wherein the cancer is breast cancer.
28. The pharmaceutical product according to claim 27, wherein the breast cancer has a HER2 status score of IHC 3+.
29. The pharmaceutical product according to claim 27, wherein the breast cancer is HER2 low-expressing breast cancer.
30. The pharmaceutical product according to claim 27, wherein the breast cancer has a HER2 status score of IHC 2+.
31. The pharmaceutical product according to claim 27, wherein the breast cancer has a HER2 status score of IHC 1+.
32. The pharmaceutical product according to claim 27, wherein the breast cancer has a HER2 status score of IHC >0 and <1+.
33. The pharmaceutical product according to claim 27, wherein the breast cancer is triple-negative breast cancer.
34. The pharmaceutical product according to claim 25, wherein the cancer is gastric cancer.
35. The pharmaceutical product according to claim 25, wherein the cancer is colorectal cancer.
36. The pharmaceutical product according to claim 25, wherein the cancer is lung cancer.
37. The pharmaceutical product according to claim 36, wherein the lung cancer is non-small cell lung cancer.
38. The pharmaceutical product according to claim 25, wherein the cancer is pancreatic cancer.
39. The pharmaceutical product according to claim 25, wherein the cancer is ovarian cancer.
40. The pharmaceutical product according to claim 25, wherein the cancer is prostate cancer.
41. The pharmaceutical product according to claim 25, wherein the cancer is kidney cancer.
42. A pharmaceutical product as defined in any one of claims 1 to 23, for use in treating cancer.
43. The pharmaceutical product for the use according to claim 42, wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.
44. The pharmaceutical product for the use according to claim 42, wherein the cancer is breast cancer.
45. The pharmaceutical product for the use according to claim 44, wherein the breast cancer has a HER2 status score of IHC 3+.
46. The pharmaceutical product for the use according to claim 44, wherein the breast cancer is HER2 low- expressing breast cancer.
47. The pharmaceutical product for the use according to claim 44, wherein the breast cancer has a HER2 status score of IHC 2+.
48. The pharmaceutical product for the use according to claim 44, wherein the breast cancer has a HER2 status score of IHC 1+.
49. The pharmaceutical product for the use according to claim 44, wherein the breast cancer has a HER2 status score of IHC >0 and <1+.
50. The pharmaceutical product for the use according to claim 44, wherein the breast cancer is triple-negative breast cancer.
51. The pharmaceutical product for the use according to claim 42, wherein the cancer is gastric cancer.
52. The pharmaceutical product for the use according to claim 42, wherein the cancer is colorectal cancer.
53. The pharmaceutical product for the use according to claim 42, wherein the cancer is lung cancer.
54. The pharmaceutical product for the use according to claim 53, wherein the lung cancer is non-small cell lung cancer.
55. The pharmaceutical product for the use according to claim 42, wherein the cancer is pancreatic cancer.
56. The pharmaceutical product for the use according to claim 42, wherein the cancer is ovarian cancer.
57. The pharmaceutical product for the use according to claim 42, wherein the cancer is prostate cancer.
58. The pharmaceutical product for the use according to claim 42, wherein the cancer is kidney cancer.
59. Use of an anti-HER2 antibody-drug conjugate or an Aurora B inhibitor in the manufacture of a medicament for administration of the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor in combination, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of claims 1 to 22, for treating cancer.
60. The use according to claim 59, wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.
61. The use according to claim 59, wherein the cancer is breast cancer.
62. The use according to claim 61, wherein the breast cancer has a HER2 status score of IHC 3+.
63. The use according to claim 61, wherein the breast cancer is HER2 low-expressing breast cancer.
64. The use according to claim 61, wherein the breast cancer has a HER2 status score of IHC 2+.
65. The use according to claim 61, wherein the breast cancer has a HER2 status score of IHC 1+.
66. The use according to claim 61, wherein the breast cancer has a HER2 status score of IHC >0 and <1+.
67. The use according to claim 61, wherein the breast cancer is triple-negative breast cancer.
68. The use according to claim 59, wherein the cancer is gastric cancer.
69. The use according to claim 59, wherein the cancer is colorectal cancer.
70. The use according to claim 59, wherein the cancer is lung cancer.
71. The use according to claim 70, wherein the lung cancer is non-small cell lung cancer.
72. The use according to claim 59, wherein the cancer is pancreatic cancer.
73. The use according to claim 59, wherein the cancer is ovarian cancer.
74. The use according to claim 59, wherein the cancer is prostate cancer.
75. The use according to claim 59, wherein the cancer is kidney cancer.
76. The use according to any one of claims 59 to 75 wherein the medicament is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration.
77. The use according to any one of claims 59 to 75 wherein the medicament is a combined preparation comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for sequential or simultaneous administration .
78. A method of treating cancer comprising administering an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor as defined in any one of claims 1 to 22 in combination to a subject in need thereof.
79. The method according to claim 78, wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.
80. The method according to claim 78, wherein the cancer is breast cancer.
81. The method according to claim 80, wherein the breast cancer has a HER2 status score of IHC 3+.
82. The method according to claim 80, wherein the breast cancer is HER2 low-expressing breast cancer.
83. The method according to claim 80, wherein the breast cancer has a HER2 status score of IHC 2+.
84. The method according to claim 80, wherein the breast cancer has a HER2 status score of IHC 1+.
85. The method according to claim 80, wherein the breast cancer has a HER2 status score of IHC >0 and <1+.
86. The method according to claim 80, wherein the breast cancer is triple-negative breast cancer.
87. The method according to claim 78, wherein the cancer is gastric cancer.
88. The method according to claim 78, wherein the cancer is colorectal cancer.
89. The method according to claim 78, wherein the cancer is lung cancer.
90. The method according to claim 89, wherein the lung cancer is non-small cell lung cancer.
91. The method according to claim 78, wherein the cancer is pancreatic cancer.
92. The method according to claim 78, wherein the cancer is ovarian cancer.
93. The method according to claim 78, wherein the cancer is prostate cancer.
94. The method according to claim 78, wherein the cancer is kidney cancer.
95. The method according to any one of claims 78 to 94, wherein the method comprises administering the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor sequentially.
96. The method according to any one of claims 78 to 94, wherein the method comprises administering the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor simultaneously .
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