WO2018158175A1 - Combinaison d'inhibiteurs de bub1 - Google Patents

Combinaison d'inhibiteurs de bub1 Download PDF

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Publication number
WO2018158175A1
WO2018158175A1 PCT/EP2018/054630 EP2018054630W WO2018158175A1 WO 2018158175 A1 WO2018158175 A1 WO 2018158175A1 EP 2018054630 W EP2018054630 W EP 2018054630W WO 2018158175 A1 WO2018158175 A1 WO 2018158175A1
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cancer
alkyl
methyl
indazol
amino
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PCT/EP2018/054630
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English (en)
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Gerhard Siemeister
Wilhelm Bone
Anne Mengel
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Bayer Pharma Aktiengesellschaft
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to combinations of at least two components, component A and component B, component A being a Bub1 inhibitor of general formula (I) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a pharmaceutically acceptable salt, or a mixture of same, and component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from a taxane, such as docetaxel or paclitaxel, or combinations thereof, for use in the treatment or prophylaxis of a disease, particularly for the treatment of cancer, more particularly for the treatment of breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor- resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC), Non-Small Cell Lung Cancer (NSCLC), melanoma, colorectal cancer, such as colorec
  • Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particularly for the treatment of cancer, more particularly for the treatment of breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Non-Small Cell Lung Cancer (NSCLC), Castration- Resistant Prostate Cancer (CRPC), melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • NSCLC Non-Smal
  • Yet another aspect of the present invention relates to methods of treatment or prophylaxis of a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC), Non-Small Cell Lung Cancer (NSCLC), melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Res
  • kits comprising a combination of:
  • TNBC Triple-negative breast cancer
  • NSCLC Non-Small Cell Lung Cancer
  • melanoma colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma,
  • Another aspect of the present invention relates to a combination as defined herein, for use in the treatment or prophylaxis of a cancer selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC), Non-Small Cell Lung Cancer (NSCLC) melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from a taxane, such as docetaxel or paclit
  • Another aspect of the present invention relates to a combination as defined herein, for use in a method to sensitize cancer cells selected from breast cancer, such as Triple- negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Non-Small Cell Lung Cancer (NSCLC), Castration- Resistant Prostate Cancer (CRPC), melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, to paclitaxel or docetaxel.
  • TNBC Triple- negative breast cancer
  • NSCLC Non-Small Cell Lung Cancer
  • CRPC
  • BACKGROUND Cell cycle deregulation represents one of the classical hallmarks of cancer [Hanahan D and Weinberg RA, Cell 100, 57, 2000; Hanahan D and Weinberg RA, Cell 144, 646, 201 1 ] and consequently cell cycle arrest is the predominant mode of action of a lot of the cancer drugs on the market including ' anti-mitotics ' such as taxanes and vinca alkaloids which stablize respectively depolymerize tubuline and thus compromize the function of the mitotic spindle.
  • ' anti-mitotics ' such as taxanes and vinca alkaloids which stablize respectively depolymerize tubuline and thus compromize the function of the mitotic spindle.
  • cell cycle checkpoint regulation offers a novel approach to cancer treatment: inactivation of cell cycle checkpoints is considered to drive tumor cells into cell divison despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy.
  • the spindle assembly checkpoint controls the accurate attachment of mircrotubules of the spindle device to the kinetochors (the attachment site for microtubules) of the duplicated chromosomes.
  • the SAC is active as long as unattached kinetochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors [for recent review see Musacchio A, Curr. Biol. 25, R1002-R1018, 2015].
  • the SAC signal is initiated by multipolar-spindle 1 (Mpsl )-mediated phosphorlyation of Met-Glu-Leu-Thr (MELT) motifs on the kinetochore scaffold 1 (KNL-1 ) protein to generate docking sites for budding uninhibited by benzimidazole 1 (Bub1 )/Bub3 dimers.
  • Mpsl multipolar-spindle 1
  • MELT Met-Glu-Leu-Thr
  • Bub1 kinetochore scaffold 1
  • Bub3 dimers The N-terminal non-catalytic part of Bub1 represents a scaffold for the assembly of mitotic arrest deficient 1 (MAD1 )/MAD2, BubR1 and centromere protein E (CENP-E) proteins.
  • MCC diffusible mitotic checkpoint complex
  • APC/C ubiquitin ligase anaphase-promoting complex/cyclosome
  • Bub1 kinase phosphorylates histone H2A at Thr120 within the centromeric region of the duplicated chromosomes thereby creating binding sites for shugoshin proteins (Sgo) 1 and 2, which protect centromeric cohesin from premature degradation, and for the chromosomal passenger complex consisting of INCENP, survivin, borealin and Aurora B (AurB) [Kawashima et al. Science 327, 172, 2010; Watanabe Y, Cold Spring Harb. Symp. Quant. Biol. 75, 419, 2010]. Specific inhibition of Bub1 kinase activity results in reduced levels of Sgo1 and Sgo2 at mitotic centromeres.
  • AurB fails to concentrate at the centromeres and was instead found to be spread over the chromosome arms [Baron et al. eLife 5, e12187, 2016].
  • AurB activity localized at the centromeric region is essential for the resolution of microtubule - kinetochore attachment errors such as syntelic and merotelic attachments.
  • Dyslocatization of AurB due to Bub1 kinase inactivation strongly compromizes the cells ability to resolve attachment errors and results in an increased rate of chromosome aligment defects [Ricke et al. J. Cell Biol. 199, 931 , 2012], in particular in presence of attachment error inducing agents such as microtubule stabilizers paclitaxel or docetaxel.
  • TNBC Triple-negative breast cancer
  • the present invention provides combinations of at least two components, component A and component B, component of general formula (I),
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 '
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 , or,
  • V and Y represent N, and W and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from : Ci -Ce-alkyl, Ci-C 6 -haloalkyl, C3-C 6 -cycloalkyl,
  • R 2 represents, independently of each other, halogen or a group selected from: Ci -C 3 -alkyl, C3-C 4 -cycloalkyl, Ci-C 3 -haloalkyl, Ci -C 3 -alkoxy,
  • R 3 represents a group selected from:
  • said C 2 -C 6 -hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent hydrogen (glycine) or a group selected from:
  • -CH 3 (alanine), -C(H)(CH 3 ) 2 (valine), -(CH 2 ) 2 CH 3 (norvaline), -CH 2 C(H)(CH 3 ) 2 (leucine), - C(H)(CH 3 )CH 2 CH 3 (isoleucine), -(CH 2 ) 3 CH 3 (norleucine), -C(CH 3 ) 3 (2-fert-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH 2 ) 3 NH 2 (ornithine), -(CH 2 ) 4 NH 2 (lysine), -(CH 2 ) 2 C(H)(OH)CH 2 NH 2 (hydroxylysine), -CH 2 OH (serine), -(CH 2 ) 2 OH (homoserine), -C(H)(OH)CH 3 (threonine), -(CH 2 ) 3
  • R 8 represents hydrogen or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl,
  • component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from a taxane, such as docetaxel or paclitaxel, or combinations thereof, for use in the treatment or prophylaxis of a disorder selected from Triple-negative breast cancer (TNBC), Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • a taxane such as docetaxel or paclitaxel, or combinations thereof
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • the present invention also provides combinations of at least two components, component A and component B as described herein, for use in the treatment or prophylaxis of a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocarcinoma
  • cervical cancer such as cervical adenocarcinoma
  • gastric (stomach) cancer pancreatic cancer, such as pancreatic carcinoma
  • bladder cancer such
  • the present invention covers uses of a combination as defined herein, for the preparation of a medicament for the treatment or prophylaxis of a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • breast cancer such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer
  • prostate cancer such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • the present invention also covers uses of a combination as defined herein, for the preparation of a medicament for the treatment or prophylaxis of a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocarcinoma
  • cervical cancer such as cervical adenocarcinoma
  • gastric (stomach) cancer pancreatic cancer, such as pancreatic carcinoma
  • bladder cancer such as bladder
  • the present invention covers methods of treatment or prophylaxis of a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination as defined herein.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • the present invention also covers methods of treatment or prophylaxis of a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination as defined herein.
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocarcinoma
  • cervical cancer such as cervical adenocarcinoma
  • gastric (stomach) cancer pancreatic cancer, such as pan
  • kits comprising a combination as defined herein, and, optionally, one or more further pharmaceutical agents C; in which optionally both or either of said compound of general formula (I) and anti-hyperproliferative, cytotoxic and/or cytostatic agent are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, for use in the treatment or prophylaxis of a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • kits comprising a combination as defined herein, and, optionally, one or more further pharmaceutical agents C; in which optionally both or either of said compound of general formula (I) and anti-hyperproliferative, cytotoxic and/or cytostatic agent are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, for use in the treatment or prophylaxis of a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinom
  • compositions containing a combination as defined herein for use in the treatment or prophylaxis of a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof, together with a pharmaceutically acceptable ingredients.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocarcinoma
  • cervical cancer such as cervical adenocarcinoma
  • gastric (stomach) cancer pancreatic cancer, such as pancreatic carcinoma
  • bladder cancer such as bladder
  • the present invention covers combinations of at least two components, component A and component B, wherein component A and component B are as defined herein, for use in the treatment or prophylaxis of a cancer selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from a taxane, such as docetaxel or paclitaxel.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • the present invention also covers combinations of at least two components, component A and component B, wherein component A and component B are as defined herein, for use in the treatment or prophylaxis of a cancer selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, together with a pharmaceutically acceptable ingredients.
  • a cancer selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adeno
  • the present invention covers, combinations of at least two components, component A and component B, wherein component A and component B are as defined herein, for use in a method to sensitize cancer cells selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Non-Small Cell Lung Cancer (NSCLC) and Castration- Resistant Prostate Cancer (CRPC) and/or metastases thereof, to paclitaxel or docetaxel.
  • TNBC Triple-negative breast cancer
  • NSCLC Non-Small Cell Lung Cancer
  • CRPC Castration- Resistant Prostate Cancer
  • the present invention covers, combinations of at least two components, component A and component B, wherein component A and component B are as defined herein, for use in a method to sensitize cancer cells selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof, to paclitaxel or docetaxel.
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocarcinoma
  • cervical cancer such as cervical adenocarcinoma
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W,
  • Y and Z represents CR 2
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 , R 1 represents a group selected from :
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C3-C 4 -cycloalkyl,
  • R 2 represents, independently of each other, halogen or a group selected from: Ci-C 3 -alkyl, C 3 -C 4 -cycloalkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy,
  • Ci-C -alkoxy Ci-C -haloalkoxy, C 3 -C -cycloalkyl
  • R 3 represents a group selected from :
  • said C 2 -C 6 -hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent hydrogen (glycine) or a group selected from:
  • -CH 3 (alanine), -C(H)(CH 3 ) 2 (valine), -(CH 2 ) 2 CH 3 (norvaline), -CH 2 C(H)(CH 3 ) 2 (leucine), - C(H)(CH 3 )CH 2 CH 3 (isoleucine), -(CH 2 ) 3 CH 3 (norleucine), -C(CH 3 ) 3 (2-fert-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH 2 ) 3 NH 2 (ornithine), -(CH 2 ) 4 NH 2 (lysine), -(CH 2 )2C(H)(OH)CH 2 NH2 (hydroxylysine), -CH 2 OH (serine), -(CH 2 ) 2 OH (homoserine), -C(H)(OH)CH 3 (threonine), -(CH 2 ) 3
  • R 8 represents hydrogen or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl,
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W,
  • Y and Z represents CR 2
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from :
  • Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, and C 3 -C4-cycloalkyl
  • R 2 represents, independently of each other, halogen or a group selected from: Ci-C 3 -alkyl, C 3 -C 4 -cycloalkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy,
  • R 3 represents a group selected from :
  • said C 2 -C 6 -hydroxyalkyl group being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent a group selected from:
  • R 8 represents hydrogen or a group selected from:
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 or,
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 , R 1 represents a Ci-C 3 -alkyl group,
  • R 2 represents, independently of each other, halogen or a group selected from: Ci-C 3 -alkyl, C3-C 4 -cycloalkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy,
  • R 3 represents a group selected from :
  • R 5 and R 7 independently of each other represent a group selected from :
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2
  • V represents N
  • W, Y and Z independently of each other represent CH or CR 2
  • R 1 represents a methyl group
  • R 2 represents, independently of each other, fluorine, chlorine or a group selected from:
  • R 3 represents a group selected from :
  • R 5 represents -CH 3 (alanine)
  • R 7 represents -(CH 2 ) 4 NH2 (lysine), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2
  • V represents N
  • W, Y and Z independently of each other represent CH or CR 2
  • R 1 represents a methyl group
  • R 2 represents, independently of each other, fluorine, chlorine or a group selected from:
  • R 3 represents a -(CH 2 ) 2 OH group, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • component A is a Bub1 kinase inhibitor of formula (I) supra, selected from the group consisting of :
  • component A is a Bub1 kinase inhibitor of formula (I) supra, wherein the component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 - yl)methyl]phenoxy ⁇ ethanol,
  • component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 AVICI indazol-1 -yl)methyl]phenoxy ⁇ ethanol,
  • component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 H- 15 indazol-1 -yl)methyl]phenoxy ⁇ ethanol.
  • component B is docetaxel. In accordance to a preferred embodiment of the first aspect, component B is paclitaxel.
  • the cancer is breast cancer and/or metastases thereof, such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • antiestrogen resistant breast cancer antiestrogen resistant breast cancer
  • aromatase inhibitor-resistant breast cancer and/or metastases thereof such as Triple-negative breast cancer (TNBC), antiestrogen resistant breast cancer and aromatase inhibitor-resistant breast cancer and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • antiestrogen resistant breast cancer antiestrogen resistant breast cancer
  • aromatase inhibitor-resistant breast cancer and/or metastases thereof aromatase inhibitor-resistant breast cancer and/or metastases thereof.
  • the cancer is prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and/or metastases thereof.
  • CRPC Castration- Resistant Prostate Cancer
  • the cancer is Triple-negative breast cancer (TNBC) and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • the cancer is Castration-Resistant Prostate Cancer (CRPC) and/or metastases thereof.
  • CRPC Castration-Resistant Prostate Cancer
  • the cancer is Non-Small Cell Lung Cancer 35 (NSCLC) and/or metastases thereof.
  • NSCLC Non-Small Cell Lung Cancer 35
  • the cancer is melanoma and/or metastases thereof.
  • the cancer is colorectal cancer, such as colorectal adenocarcinoma and/or metastases thereof.
  • the cancer is glioblastoma/neuroglioma and/or metastases thereof.
  • the cancer is ovarian cancer, such as ovarian adenocarcinoma and/or metastases thereof.
  • the cancer is cervical cancer, such as cervical adenocarcinoma and/or metastases thereof.
  • the cancer is gastric (stomach) cancer and/or metastases thereof.
  • the cancer is pancreatic cancer, such as pancreatic carcinoma and/or metastases thereof.
  • the cancer is bladder cancer, such as bladder transitional cell carcinoma and/or metastases thereof.
  • bladder cancer such as bladder transitional cell carcinoma and/or metastases thereof.
  • Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position.
  • each definition is independent. For example, whenever R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 V, W, Y and/or Z occur more than one time for any compound of formula (I) each definition of R ⁇ R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , V, W, Y and Z is independent.
  • halogen atom halo- or Hal-
  • fluorine chlorine, bromine or iodine atom.
  • Ci-C 6 -alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2- methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 - dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2- ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 ,1
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C 4 -alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • Ci-C 4 -alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms
  • Si-C3-alkyl e.g. a methyl, ethyl, n-propyl- or iso-propyl group
  • Ci-C 6 -haloalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C 6 -alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Ci-C 6 -haloalkyl group is, for example, -CF 3 , - CHF 2 , -CH 2 F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH 2 F) 2 .
  • Ci -C 6 -alkoxy is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
  • Particularly preferred is "Ci -C 4 -alkoxy” e.g.
  • Ci-C 4 -haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci -C 4 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said Ci-C 4 -haloalkoxy group is, for example, - OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
  • Ci-C 6 -hydroxyalkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci -C 6 -alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3- hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.
  • a hydroxymethyl e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl,
  • Ci-C3-hydroxyalkyl e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3- dihydroxypropan-2-yl.
  • C2-C 6 -hydroxyalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, in which one or more hydrogen atoms is replaced by a hydroxy group, e.g.
  • Cs-Ce-cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C 3 -C 6 - cycloalkyi").
  • Said C3-C 6 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • C3-C 6 -cycloalkyloxy is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon group of formula -O-cycloalkyI, in which the term “cycloalkyi” is defined supra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
  • Ci-C 6 as used throughout this text, e.g. in the context of the definition of "Ci- Ce-alkyl", “Ci-C 6 -haloalkyl”, “Ci-C 6 -hydroxyalkyl”, “Ci-C 6 -alkoxy”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “Ci-Ce” is to be interpreted as any sub-range comprised therein, e.g.
  • C 2 -C 6 as used throughout this text, e.g. in the context of the definition of "C 2 - Ce-hydroxyalkyl”, is to be understood as meaning a hydroxyalkyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 2 -C 6 , C 2 -C 5 , C3-C4, particularly C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , C 2 -C 6 .
  • C3-C 6 as used throughout this text, e.g. in the context of the definition of "C3-C 6 -cycloalkyl”, is to be understood as meaning a cycloalkyi group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -C 5 , C3-C5 , C3-C4 , C 4 -C 6 , C 5 -C 6 ; particularly
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ", is to be understood as meaning that at least one of V, W, Y and Z represents CR 2 , and the remaining, independently from each other, represent CH or CR 2 , as it is known to a skilled person.
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 and the remaining represent CH; according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR 2 , wherein two of V, W, Y and Z, independently of each other, represent CR 2 and the remaining represent CH; still according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR 2 , wherein three of V, W, Y and Z, independently of each other, represent CR 2 and the remaining represents CH, for example.
  • the invention also includes all suitable isotopic variations of a compound (i.e. component A, B or C(when present)) used in the combination of the present invention.
  • An isotopic variation of a compound is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l,
  • isotopic variations of a compound used in the combination of the present invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds used in the combination of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds used in the combination of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure: , for example, in which * indicates atoms to which the rest of the molecule can be bound.
  • Preferred compounds used in the combination are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds used in the combination of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds used in the combination of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound used in the combination of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds used in the combination of the present invention may exist as tautomers.
  • the present invention includes all possible tautomers of the compounds used in the combination of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds used in the combination of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds used in the combination as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds used in the combination of the present invention can exist as a hydrate, or as a solvate, wherein the compounds contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds used in the combination of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds used in the combination of the present invention may be, for example, an acid-addition salt of a compound bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)- benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, per
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds used in the combination of the invention are prepared by reacting the compounds with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds used in the combination of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound used in the combination of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci -C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-Ci-C 6 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound used in the combination of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds used in the combination of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • pharmacokinetic profile means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
  • Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
  • the term "combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of- parts.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein component A and component B are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said component A and the said component B are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said component A and the said component B are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said component A and the said component B (and optionally component C) are present in more than one unit.
  • non-fixed combination or kit-of-parts is a combination wherein the said component A and the said component B (and optionally component C) are present separately, for example in different and separate pharmaceutical compositions.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • standard of care drug(s) is meant to be understood a drug selected froma taxane, such as docetaxel or paclitaxel, or combinations thereof.
  • resistant is applied interchangeably with “refractory”.
  • resistant or “insensitive” to "treatment with stardard of care drugs” is meant to define a cancer disease, particularly breat cancer such as, Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) or Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof, in which the treatment with a drug selected from a taxane, such as docetaxel or paclitaxel, or combinations thereof,
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • antiestrogen-resistant breast cancer refers to breast cancers for which treatment with antiestrogens, such as tamoxifen, raloxifene, toremifene, and fulvestrant, is not therapeutically effective, for failing to:
  • aromatase inhibitor-resistant breast cancer refers to breast cancers for which treatment with aromatase inhibitors, such as Anastrozole (Arimidex®), Exemestane (Aromasin®), and Letrozole (Femara®), is not therapeutically effective, for failing to:
  • the resistance and/or insensitivity may be intrinsic (to the patient) or acquired.
  • the methods, combinations, uses and kits of the present invention cover both intrinsic and acquired resistance and/or insensitivity to standard of care drugs as defined herein.
  • embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another.
  • Features discussed with one embodiment or aspect of the invention are meant to be disclosed also in connection with other embodiments or aspects of the invention shown herein. If, in one case, a specific feature is not disclosed with one embodiment or aspect of the invention, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment or aspect of the invention. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment or spect of the invention, but that just for purposes of clarity and to keep the length of this specification manageable.
  • Component A can be selected from inhibitors of BUB1 -kinase or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof specifically or generically disclosed e.g. in the publications as mentioned above which are incorporated herein by reference.
  • Component A is selected from the group of Bub1 inhibitors generically or specifically disclosed in WO 2016/042084, which are incorporated by reference herein.
  • component A is is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 - yl)methyl]phenoxy ⁇ ethanol,
  • said component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5-methoxy- 4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 -yl)methyl]phenoxy ⁇ ethanol or a pharmaceutically acceptable salt thereof.
  • component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5-methoxy-4-[(3- methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 -yl)methyl]phenoxy ⁇ ethanol.
  • component A is selected from the group of Bub1 inhibitors described generically or specifically in:
  • a preferred embodiment of the present invention covers combinations comprising the Compound A1 or a pharmaceutically acceptable salt thereof and a taxane selected from docetaxel and paclitaxel. It is to be understood that the present invention relates also to any combination of the embodiments of component A described above.
  • Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component A is administered intravenously, intraperitoneally or orally.
  • Compound A1 is administered preferably orally.
  • Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from a taxane, such as docetaxel or paclitaxel, or combinations thereof.
  • a taxane such as docetaxel or paclitaxel, or combinations thereof.
  • Suitable dose(s), administration regime(s) and administration route(s) for taxanes include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Breast Cancer version 2.2016, the NCCN Guidelines for Prostate Cancer version 2.2017 and the NCCN Guidelines for Non-Small Cell Lung Cancer version 4.2017, which are included herein by reference in their entirety.
  • cytotoxic refers to an agent which can be administered to kill or eliminate a cancer cell.
  • cytostatic refers to an agent which can be administered to restrain tumor proliferation rather than induce cytotoxic cytoreduction yielding an elimination of the cancer cell from the total viable cell population of the patient.
  • anti-hyperproliferative refers to an agent which can inhibit the survival or multiplication of the tumor cells with high proliferation rate.
  • chemotherapeutic agents described herein e.g., docetaxel and paclitaxel are considered cytotoxic, cytostatic agent, or anti-hyper-proliferative agents depending on individual tumor types. These anti-hyperproliferative, cytotoxic and cytostatic agents have gained wide spread use as chemotherapeutics in the treatment of various cancer types and are well known.
  • Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Docetaxel is sold under the tradename Taxotere® by Sanofi-Aventis (1 ,7 ⁇ ,10 ⁇ - trihydroxy-9-oxo-53,20-epoxytax-1 1 -ene-2a,4,13a-triyl 4-acetate 2-benzoate 13- ⁇ (2 ,3S)-3-[(fert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate ⁇ , CAS No. 1 14977-28-5).
  • Docetaxel belongs to the taxanes chemotherapy drug class and is a semi-synthetic analogue of paclitaxel (Taxol®). It is an anti-mitotic chemotherapy medication that works by interfering with cell division.
  • cytotoxic activity of docetaxel is believed to be exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny. Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Docetaxel is administered by intravenous injection or by other appropriate infusion techniques.
  • Paclitaxel is sold under the tradename Taxol® by the Bristol-Myers Squibb Company.
  • Paclitaxel ((2a,4a,53,73,103,13a)-4,10-bis(acetyloxy)-13- ⁇ [(2R,3S)- 3-(benzoylamino)- 2-hydroxy-3-phenylpropanoyl]oxy ⁇ - 1 ,7-dihydroxy-9-oxo-5,20-epoxytax-1 1 -en-2-yl benzoate - CAS No: 33069-62-4) has the empirical formula C47H51 N014 and a molecular weight of 853.9. It is highly lipophilic in water.
  • Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubles from tubulin dimers and stabilizes microtubules by preventing depolymerization. While not bound by a theory, it is believed that this stability results in the inhibition in the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Also, paclitaxel is believed to induce abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Paclitaxel is administered by intravenous injection or by other appropriate infusion techniques.
  • Protein-bound paclitaxel (Tradename: Abraxane® ) is an injectable formulation of paclitaxel, a mitotic inhibitor drug used in the treatment of breast cancer, lung cancer (NSCLC) and pancreatic cancer.
  • paclitaxel is bonded to albumin as a delivery vehicle. It is also called nab-paclitaxel (with the “nab” syllable derived from “nanoparticle albumin-bound”) or paclitaxel albumin-bound.
  • paclitaxel is meant to cover both paclitaxel and protein-bound paclitaxel.
  • component B is paclitaxel or protein-bound paclitaxel and is collectively referred to as "paclitaxel”.
  • component B is paclitaxel only (i.e. ((2a,4a,53,73,103,13a)-4,10-bis(acetyloxy)-13- ⁇ [(2R,3S)- 3-(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy ⁇ - 1 ,7-dihydroxy-9-oxo-5,20-epoxytax-1 1 -en-2-yl benzoate - CAS No : 33069-62-4) .
  • component B is protein- bound paclitaxel only.
  • component C being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers.
  • a list of such readily available agents is being provided further below.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component B preferably is administered by the more appropriate route within the knowledge of the skilled person. Suitable route(s) are included in NCCN Guidelines for NSCLC Version 2.2013, which is included herein by reference in its entirety. Component C being administered as the case may be.
  • Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • Components of this invention can also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the component in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example dimethyl dial
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the pharmaceutical compositions can be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • Components of the invention can also be administered in the form of suppositories for rectal administration of the drug. These components can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
  • a component of the present invention can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations " PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .
  • compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellents (examples include but are not limited to carbon dioxide, CCI2F2, air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antim
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not
  • compositions according to the present invention can be illustrated as follows:
  • Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
  • a sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof according to the combination as referred to above are components A.
  • the compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit Bub1 kinase and are expected to be commercially applicable in the therapy of diseases (e.g. cancer).
  • component B is especially suitable to have effects on tumor diseases.
  • the combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof.
  • Such cancer types include, but are not limited, to breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor- resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) or Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • Additional cancer types include, but are not limited to, melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • component B of the present combinations is preferably docetaxel and component A is preferably compound A1 .
  • docetaxel is a preferred component B and compound A1 is a preferred component A in the methods and uses disclosed herein in which the cancer type is cervical cancer such as cervical adenocarcinoma and/or metastases thereof.
  • Preferred uses of the combinations of the invention are for the treatment of Triple- negative breast cancer (TNBC) and/or metastases thereof.
  • TNBC Triple- negative breast cancer
  • Preferred uses of the combinations of the invention are for the treatment of Castration- Resistant Prostate Cancer (CRPC) and/or metastases thereof.
  • CRPC Castration- Resistant Prostate Cancer
  • Preferred uses of the combinations of the invention are for the treatment of NSCLC and/or metastases thereof.
  • Preferred uses of the combinations of the invention are for the treatment of advanced or recurrent TNBC and/or metastases thereof.
  • Preferred uses of the combinations of the invention are for the treatment of advanced or recurrent CRPC and/or metastases thereof.
  • Preferred uses of the combinations of the invention are for the treatment of advanced or recurrent NSCLC and/or metastases thereof.
  • the cancer is TNBC and/or metastases thereof.
  • the cancer is CRPC and/or metastases thereof. In an embodiment of the present invention the cancer is NSCLC and/or metastases thereof.
  • the cancer is recurrent NSCLC and/or metastases thereof.
  • the cancer is advanced NSCLC and/or metastases thereof.
  • the cancer is colorectal adenocarcinoma and/or metastases thereof. In an embodiment of the present invention the cancer is glioblastoma/neuroglioma and/or metastases thereof.
  • the cancer is ovarian adenocarcinoma and/or metastases thereof.
  • the cancer is cervical adenocarcinoma and/or metastases thereof.
  • the cancer is gastric (stomach) cancer and/or metastases thereof.
  • the cancer is pancreatic carcinoma and/or metastases thereof.
  • the cancer is bladder transitional cell carcinoma and/or metastases thereof.
  • the cancer is NSCLC and/or metastases thereof at any stage as defined in The Revised International System for Staging Lung Cancer, adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 1 1 1 (6): 1710-7, 1997 ; Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70., which are included herein by reference in their entirety).
  • the breast cancer such as the Triple-negative breast cancer (TNBC), antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer
  • the prostate cancer such as Castration-Resistant Prostate Cancer (CRPC) or the Non- Small Cell Lung Cancer (NSCLC) and/or metastases thereof is resistant and/or insensitive to treatment with standard of care drugs.
  • TNBC Triple-negative breast cancer
  • CRPC Castration-Resistant Prostate Cancer
  • NSCLC Non- Small Cell Lung Cancer
  • the melanoma, colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof is resistant and/or insensitive to treatment with standard of care drugs.
  • Techniques and methods to determine whether a cancer is resistant and/or insensitive to treatment with standard of care drugs are readily available to the skilled person, such as the methods provided in the Experimental Section of the present application.
  • Suitable techniques include in vitro and in vivo methods.
  • inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
  • Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof and an amount of component B of this invention; which is effective to treat a disorder selected from breast cancer, such as Triple-negative breast cancer (TNBC), antiestrogen- resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as Castration- Resistant Prostate Cancer (CRPC) and Non-Small Cell Lung Cancer (NSCLC) and/or metastases thereof.
  • TNBC Triple-negative breast cancer
  • CRPC Castration- Resistant Prostate Cancer
  • NSCLC Non-Small Cell Lung Cancer
  • This invention also includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof and an amount of component B of this invention; which is effective to treat a disorder selected from melanoma, colorectal cancer, such as colorectal adenocarcinoma, glioblastoma/neuroglioma, ovarian cancer, such as ovarian adenocarcinoma, cervical cancer, such as cervical adenocarcinoma, gastric (stomach) cancer, pancreatic cancer, such as pancreatic carcinoma, and bladder cancer, such as bladder transitional cell carcinoma, and/or metastases thereof.
  • colorectal cancer such as colorectal adenocarcinoma, glioblastoma/neuroglioma
  • ovarian cancer such as ovarian adenocar
  • treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredients to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 30 mg/kg body weight per day.
  • the total amount of the active ingredients per dose will generally range from about 1 mg to about 500 mg per dose, and preferably from about 20 mg to about 200 mg per dose.
  • Clinically useful dosing schedules of a compound will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the hyper-proliferative, cytotoxic or cytostatic agent taxane such as docetaxel or paclitaxel, or combinations thereof, can be administered to a patient at a dosage which can range from about 0.1 to about 300 mg/kg of total body weight.
  • the agents can also be administered in conventional amounts routinely used in cancer chemotherapy, particularly in breast cancer, such as TNBC, antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as CRPC and NSCLC and/or metastases thereof.
  • 100 - 175 mg/m 2 paclitaxel are administered once every 3 weeks, or alternatively 75-90 mg/m 2 paclitaxel once weekly, the latter being preferred.
  • 60 - 100 mg/m 2 docetaxel are administered once every 3 weeks, or alternatively 30-40 mg/m 2 docetaxel once weekly.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compounds employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • Suitable dose(s), administration regime(s) and administration route(s) for taxanes, such as docetaxel or paclitaxel; or combinations thereof include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Breast Cancer 2.2016, in the NCCN Guidelines for Prostate Cancer 2.2017 and in the NCCN Guidelines for NSCLC Version 4.2017 which is included herein by reference in its entirety. Further, suitable dose(s), administration regime(s) and administration route(s) for taxanes, such as docetaxel or paclitaxel; or combinations thereof may be readily determined by standard techniques known to the skilled person.
  • the dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.
  • the administered dosage of the compound(s) may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
  • the agents can be administered by any of the conventional routes of administration for these compounds.
  • the preferred route of administration for the hyper- proliferative/cytotoxic/cytostatic agents using this invention is typically by injection which is the same route of administration used for the agent alone.
  • Any of the hyper- proliferative, cytotoxic or cytostatic agents can be administered in combination with an Bub1 inhibitor of general formula (I) by any of the mentioned routes of administration.
  • the Bub1 inhibitor of general formula (I) can be administered simultaneously with the hyper-proliferative, cytotoxic or cytostatic agent. This can be performed by administering a single formulation which contains both the Bub1 inhibitor of general formula (I) and the hyper-proliferative/cytotoxic/cytostatic agent or administering the Bub1 inihibitor of general formula (I) compound and the hyperproliferative/cytotoxic/cytostatic agents in independent formulations at the same time to a patient.
  • the Bub1 inhibitor of general formula (I) can be administered in tandem with the hyper-proliferative/cytotoxic/cytostatic agent.
  • the Bub1 inhibitor of general formula (I) can be administered prior to the hyper-proliferative/cytotoxic/cytostatic agent.
  • the Bub1 inihibitor of general formula (I) can be administered once or more times per day up to 28 consecutive days, or once or more times per week up to 4 consecutive weeks followed by administration of the hyper-proliferative, cytotoxic or cytostatic agent.
  • the hyper-proliferative, cytotoxic or cytostatic agent can be administered first followed by adminstration of the Bub1 inihibitor of general formula (I).
  • the choice of sequence administration of the Bub1 inihibitor of general formula (I) relative to the hyper-proliferative/cytotoxic/cytostatic agent may vary for different agents. Also, the hyper-proliferative/cytotoxic or cytostatic agent can be administered using any regimen which is conventionally used for these agents.
  • the Bub1 inihibitor of general formula (I) and the hyper-proliferative/cytotoxic/cytostatic agent can be administered once or more times per day on the day of administration.
  • the combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth, more especially on breast cancer, such as TNBC, antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer, prostate cancer, such as CRPC or NSCLC and/or metastases thereof, even more preferably on TNBC, CRPC or NSCLC and/or metastases thereof.
  • breast cancer such as TNBC, antiestrogen-resistant breast cancer and aromatase inhibitor-resistant breast cancer
  • prostate cancer such as CRPC or NSCLC and/or metastases thereof, even more preferably on TNBC, CRPC or NSCLC and/or metastases thereof.
  • the combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents C (i.e. component C) where the resulting combination of components A, B and C causes no unacceptable adverse effects.
  • the combinations of components A and B of this invention can be combined with component C, i.e. one or more further pharmaceutical agents, such as known anti- angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.
  • Component C can be one or more pharmaceutical agents such as 131 1-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalu
  • Optional anti-hyper-proliferative agents which can be added as component C to the combination of components A and B of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference.
  • anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference.
  • cytotoxic and/or cytostatic agents as component C in combination with a combination of components A and B of the present invention will serve to: (1 ) yield better efficacy in reducing the growth of a tumor and/or metastasis or even eliminate the tumor and/ or metastasis as compared to administration of either agent alone,
  • Component B is available from commercial sources. Alternatively Component B may be prepared using any of the methods available in the art. 2. Biological in vitro Experiments:
  • H4 glioblastoma/neuroglioma ATCC HTB-148 700
  • Tumor cells were propagated in a humidified 37 ⁇ in cubator in their respective growth medium supplemented 10% fetal calf serum.
  • a compound A for analysis of combination effects between a compound A and a compound B, cells were plated in 384-well plates at the cell numbers per well as indicated in 2.1 (Study design).
  • IC50 values inhibiting concentration at 50% of maximal effect
  • DMSO vehicle
  • IC50 isobolograms were plotted with the actual concentrations of the two compounds on the x- and y-axis, and the combination index (CI) was calculated according to the median-effect model of Chou- Talalay [Chou T.C. Pharmacol. Rev. 58, 621 , 2006].
  • a CI of ⁇ 0.8 was defined as more than additive (synergistic) interaction, and a CI of >1 .2 was defined as antagonistic interaction.
  • CI50 interpretation code CI50 ⁇ 0.8, synergism; 0.8 ⁇ CI50 ⁇ 1 .2, additivity; CI 5 o>1.2, antagonism.
  • Table 1 summarizes the data for Compound A1 plus paclitaxel.
  • Table 1 Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and paclitaxel.
  • Table 2 summarizes the data for Compound A1 plus docetaxel.
  • Table 2 Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and docetaxel.
  • Animals were randomly assigned to experimental groups, twelve animals per group. At the initiation of the treatment, animals were tattooed and each cage was labeled with the cage number, study number and number of animals per cage.
  • mice Female, 5-6 weeks old NM RI nude mice (BomTac:NM RI-Foxn1 nu), body weight 20-22 g
  • mice 25 to 30 mm 2
  • Randomization tumor bearing mice were randomized according to the tumor area
  • Vehicle 1 (Compound A1 ) PEG400 90%, Ethanol 1 0%
  • Vehicle control 12 vehicle 1 2QD, p.o.
  • Paclitaxel 12 20 2.0 1 QW, i.v.
  • SUM-149 human breast cancer cells from Bayer-internal cell stock were cultured in DMEM/Ham ' s F12 medium containing stable glutamine (Biochrom, Germany) supplemented with 5% fetal calf serum (Biochrom, Germany), 1 ⁇ g/ml hydrocortisone (Biochrome, Germany), and 5 Mg/ml bovine insulin (Biochrome, Germany). Cells were harvested for transplantation in a subconfluent (70%) state. Animals were injected with 5 x 10 6 SUM-149 cells suspended in 100% Matrigel into the left inguinal region on day 0.
  • the oral application volumes were 10 ml/kg for mice, the intravenous application volume was 10 ml/kg for mice.
  • the time interval between two applications per day was 6-7h.
  • Tumor response was assessed by determination of the tumor area (product of the longest diameter and its perpendicular) using a caliper.
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumor area and body weight were performed three times weekly.
  • Tumor growth inhibition is presented as T/C ratio (Treatment / Control) calculated with tumor areas when the vehicle control group had to be closed.
  • Relative tumor growth inhibition based on tumor area was calculated by the formula [(tumor area of treatment group at day x) - (tumor area of treatment group at day before first treatment)] / [(tumor area of vehicle group at day x) - (tumor area of vehicle group at day before first treatment)].
  • Treatment with vehicle (control), Compound A1 , paclitaxel, or the combination of Compound A1 and paclitaxel started on day 10.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 25 mg/kg
  • paclitaxel was administered once daily i.v. 1 day on/ 6 days off (QW) at a dose of 20 mg/kg.
  • Animals were randomly assigned to experimental groups, twelve animals per group. At the initiation of the treatment, animals were tattooed and each cage was labeled with the cage number, study number and number of animals per cage.
  • NCI-H1299 human non-small cell lung cancer cells originally purchased from ATCC (Manassas, VA, USA; #CRL-5803) were cultured as described according to the supplier ' s protocols. Cells were harvested for transplantation in a subconfluent (70%) state. Animals were injected with 3 x 10 6 NCI-H1299 cells suspended in 100% Matrigel into the left inguinal region on day 0.
  • the oral application volumes were 10 ml/kg for mice, the intravenous application volume was 10 ml/kg for mice.
  • the time interval between two applications per day was 6-7h.
  • Tumor response was assessed by determination of the tumor area (product of the longest diameter and its perpendicular) using a caliper.
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumor area and body weight were performed three times weekly.
  • Tumor growth inhibition is presented as T/C ratio (Treatment / Control) calculated with tumor areas when the vehicle control group had to be closed.
  • Relative tumor growth inhibition based on tumor area was calculated by the formula [(tumor area of treatment group at day x) - (tumor area of treatment group at day before first treatment)] / [(tumor area of vehicle group at day x) - (tumor area of vehicle group at day before first treatment)].
  • the animals treated with the combination of Compound A1 and Paclitaxel showed a strongly reduced tumor growth rate and mean relative tumor area at day 54 was 70% below the mean relative tumor area of the Paclitaxel treated tumors.
  • the difference in tumor areas between the Paclitaxel single agent treatment group and the combination treatment group were statistically significant (P ⁇ 0.05).
  • Table 4 Time corse NCI-H1299 non-small cell lung cancer (NSCLC) xenograft tumor growth.
  • Treatment with vehicle (control), Compound A1 , paclitaxel, or the combination of Compound A1 10 and paclitaxel started on day 7.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 50 mg/kg in the single agent treatment group and at 25 mg/kg in combination with paclitaxel, paclitaxel was administered once daily i.v. 1 day on/ 6 days off (QW) at a dose of 20 mg/kg (days 7-39) and 15 mg/kg (days 40-54).
  • Animals were randomly assigned to experimental groups, twelve animals per group. At the initiation of the treatment, animals were tattooed and each cage was labeled with the cage number, study number and number of animals per cage.
  • 22Rv1 human castration-resistant prostate cancer cells originally purchased from ATCC (Manassas, VA, USA; #CRL-2505) were cultured as described according to the supplier ' s protocols. Cells were harvested for transplantation in a subconfluent (70%) state. Animals were injected with 3 x 10 6 22Rv1 cells suspended in 100% Matrigel into the left inguinal region on day 0.
  • the oral application volumes were 10 ml/kg for mice, the intravenous application volume was 10 ml/kg for mice.
  • the time interval between two applications per day was 6-7h.
  • Tumor response was assessed by determination of the tumor area (product of the longest diameter and its perpendicular) using a caliper.
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumor area and body weight were performed three times weekly.
  • Tumor growth inhibition is presented as T/C ratio (Treatment / Control) calculated with tumor areas when the vehicle control group had to be closed.
  • Relative tumor growth inhibition based on tumor area was calculated by the formula [(tumor area of treatment group at day x) - (tumor area of treatment group at day before first treatment)] / [(tumor area of vehicle group at day x) - (tumor area of vehicle group at day before first treatment)].
  • Tumor area in mm 2 measured at the respective days after tumor inoculation. Treatment with vehicle (control), docetaxel, or the combination of Compound A1 and docetaxel started day 12.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 50 mg/kg, docetaxel was administered once daily i.v. 1 day on/ 6 days off (QW) at a dose of 4 mg/kg.
  • Bub1 kinase inhibitor Compound A1 did not show increased toxicity over taxane monotherapy.
  • Compound A1 plus paclitaxel in vitro combination assay with SUM-149 cells SUM-149 human triple-negative breast cancer cells were grown in the presence various concentrations of Compound A1 (0.1 -10 ⁇ ) and paclitaxel (1 -100 nM) in mono and in nine different fixed-ratio combinations. IC50 values were determined and the respective Compound A1 and paclitaxel concentrations plotted in IC50 Isobolograms. The grey dashed lines indicate the results expected for additivity.
  • NCI- H1299 human non-small cell lung cancer cells were grown in the presence various concentrations of Compound A1 (0.1 -10 ⁇ ) and paclitaxel (1 -100 nM) in mono and in nine different fixed-ratio combinations.
  • IC50 values were determined and the respective Compound A1 and paclitaxel concentrations plotted in IC50 Isobolograms. The grey dashed lines indicate the results expected for additivity.
  • NCI-H1299 human non-small cell lung cancer cells were grown in the presence various concentrations of Compound A1 (0.1 -10 ⁇ ) and docetaxel (0.3-30 nM) in mono and in nine different fixed-ratio combinations.
  • IC50 values were determined and the respective Compound A1 and paclitaxel concentrations plotted in IC50 Isobolograms. The grey dashed lines indicate the results expected for additivity.
  • Compound A1 plus docetaxel in vitro combination assay with 22Rv1 cells 22Rv1 human prostate cancer cells were grown in the presence various concentrations of Compound A1 (0.1 -10 ⁇ ) and docetaxel (0.3-30 nM) in mono and in nine different fixed-ratio combinations. IC50 values were determined and the respective Compound A1 and paclitaxel concentrations plotted in IC50 Isobolograms. The grey dashed lines indicate the results expected for additivity.
  • FIG. 5 Time course of SUM-149 triple-negative (TN) breast cancer xenograft model on female nude mice and body weight change (%).
  • Treatment with Compound A1 , paclitaxel, or the combination of Compound A1 and paclitaxel started on day 10.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 25 mg/kg
  • paclitaxel was administered once daily i.v. 1 day on/ 6 days off (QW) at a dose of 20 mg/kg.
  • Treatment with Compound A1 , paclitaxel, or the combination of Compound A1 and paclitaxel started on day 7.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 50 mg/kg in the single agent treatment group and at 25 mg/kg in combination with paclitaxel
  • paclitaxel was administered once daily i.v. 1 day on/ 6 days off (QW) at a dose of 20 mg/kg (days 7 -39) and 15 mg/kg (days 40-54).

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Abstract

La présente invention concerne des combinaisons d'au moins deux constituants, un constituant A et un constituant B, le constituant A étant un inhibiteur de Bub1 de formule générale (I), ou un stéréoisomère, un tautomère, un N-oxyde, un hydrate, un solvate ou un sel de celui-ci, en particulier un sel pharmaceutiquement acceptable, ou un mélange de ceux-ci, et le constituant B étant un agent anti-hyperprolifératif, cytotoxique et/ou cytostatique sélectionné entre un taxane, tel que le docétaxel ou le paclitaxel, ou des combinaisons de ceux-ci.
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US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266548B2 (en) 2011-10-06 2019-04-23 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as Bub1 kinase inhibitors in the treatment of hyperproliferative diseases
US10604532B2 (en) 2011-10-06 2020-03-31 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as BUB1 kinase inhibitors in the treatment of hyperproliferative diseases
US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors

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