WO2018153972A1 - Combination of atr kinase inhibitors and antiandrogens - Google Patents

Combination of atr kinase inhibitors and antiandrogens Download PDF

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WO2018153972A1
WO2018153972A1 PCT/EP2018/054365 EP2018054365W WO2018153972A1 WO 2018153972 A1 WO2018153972 A1 WO 2018153972A1 EP 2018054365 W EP2018054365 W EP 2018054365W WO 2018153972 A1 WO2018153972 A1 WO 2018153972A1
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Prior art keywords
pyrazol
naphthyridine
morpholin
methylmorpholin
naphthyridin
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PCT/EP2018/054365
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French (fr)
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Antje Margret Wengner
Pascale Lejeune
Bernard Haendler
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention covers combinations of at least two components, component A and component B, comprising component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • Another aspect of the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease
  • Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation.
  • Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.
  • DDR DNA damage response
  • Proteins that directly recognize aberrant DNA structures such as the MRE11-Rad50-Nbsl complex recognizing DNA double strand breaks by binding to double-stranded DNA ends, or RPA (replication protein A) binding to single stranded DNA, recruit and activate the most upstream kinases of the DDR pathway, ATM (ataxia-telangiectasia mutated), ATR (ATM-and Rad3-related, UniProtKB/Swiss-Prot Q13535), and DNA-PKcs (DNA-dependent protein kinase).
  • ATM is primarily activated by DNA double strand breaks
  • DNA-PKcs is mainly involved in non-homologous end joining process of DNA repair
  • ATR responds to a broad spectrum of DNA damage, including double- strand breaks and lesions derived from interference with DNA replication.
  • Major components of downstream signaling of ATM include Chk2 and p53, whereas ATR signaling involves Chkl and cdc25.
  • Knockout of the ATR gene in mice is embryonically lethal and ATR knockout cells develop chromosome breaks and undergo apoptosis [E.J. Brown, D. Baltimore: ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397-402, 2000].
  • ATM is not essential for cell survival although ATM knockout cells are hypersensitive to ionizing radiation and agents which cause DNA double-strand breaks.
  • ATR which forms a complex with ATRIP (ATR-interacting protein, UniProtKB/Swiss-Prot Q8WXE1) is mainly activated by long stretches of single-stranded DNA which are generated by the continuing DNA unwinding activity of helicases upon stalled replication.
  • This replication stress with stalled replication forks may be induced by ultraviolet light, certain chemotherapeutic drugs, hydroxyurea, or aberrant oncogenic signaling resulting in increased replication initiation or origin firing.
  • Activation of ATR results in inhibition of the cell cycle in S or G2 phase via the Chkl-cdc25 pathway and in suppression of late origin firing.
  • the cell gains time to resolve the replication stress and, eventually, to restart replication after the source of stress has been removed.
  • As the ATR pathway ensures cell survival after replication stress it potentially contributes to resistance to chemotherapy. Thus inhibition of ATR kinase activity could be useful for cancer treatment.
  • oncogene-driven tumor cells e.g. Ras mutation/upregulation, Myc upregulation, CyclinE overexpression
  • ATR suppression in Ras oncogene driven cells was reported to result in substantial tumor cell killing [O. Gilad, BY Nabet, et al.: Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70, 9693-9702, 2010].
  • ATM and ATR are principally activated by different types of DNA damage their signaling includes some cross-talk thus that they can, at least partially, substitute for each other's function. This finding suggests some tumor-cell selectivity of pharmaceutical inhibition of ATR.
  • a healthy normal cell which has ATM and ATR pathways in parallel, arrests in Gl phase of the cell cycle upon induced DNA damage even in presence of an ATR inhibitor.
  • a tumor cell which most often deficient in ATM and/or p53 signaling relies on the ATR pathway and undergoes cell death in presence of an ATR inhibitor. This suggests that ATR inhibitors may be used for the treatment of tumors with deficient ATM signaling and/or p53 function.
  • Cimprich Causes and consequences of replication stress. Nat. Cell Biol. 16, 2-9, 2014. S. Llona-Minguez, A. Hoglund et al.: Chemical strategies for development of ATR inhibitors. Exp. Rev. Mol. Med. 16, elO, 2014.
  • inhibitors of ATR kinase represent valuable compounds that should complement therapeutic options not only as single agents but also in combination with other drugs, which are currently used in the treatment of hyperproliferative diseases. There is an acute medical need for additional therapeutic options for the treatment of hyper-proliferative diseases.
  • Combination treatment with the AR signaling inhibitor enzalutamide and the Chkl/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chkl signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild- type p53) cells (Karanika et al., Cell Rep. 2017 Feb 21;18(8): 1970-1981. doi: 10.1016/j.celrep.2017.01.072).
  • the state of the art does not disclose the combinations of the present invention comprising an inhibitor of ATR kinase and an antiandrogen.
  • the present invention provides combinations of at least two components, component A and component B, comprising
  • component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide
  • the present invention concerns combinations of two components, component A and component B, comprising
  • component A being an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra,
  • component B being an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • the combinations comprising at least two components A and B, particularly two components, as decribed herein, are also referred to as "combinations of the present invention".
  • kits comprising:
  • component A one or more ATR kinase inhibitor(s) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
  • component B one or more antiandrogen(s) as described herein,
  • kit optionally either or both of said components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • the present invention concerns the combinations as described herein for use in the treatment of for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper -proliferative disease as described infra, using an effective amount of the combinations as described herein.
  • halogen atom halo- or Hal-
  • halogen atom halo- or Hal-
  • Ci-C6-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.
  • said group has 1, 2, 3 or 4 carbon atoms ("Ci-C/t-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.
  • Si-C/t-alkyl 1, 2, 3 or 4 carbon atoms
  • Ci-C6-haloalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-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.
  • Said C 1 -C6- haloalkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 or -CH 2 CF 3 .
  • Ci-C t-hydroxyaikyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C t-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, l,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-mefhyl- propyl, l-hydroxy-2-methyl-propyl group.
  • a hydroxymethyl 1- hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3- dihydroxypropyl, l,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl
  • Ci-C6-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.
  • said "Ci-C6-alkoxy” can contain 1, 2, 3, 4 or 5 carbon atoms, (a "Ci-Cs-alkoxy”), preferably 1, 2, 3 or 4 carbon atoms ("d-C ⁇ alkoxy").
  • Ci-C6-haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci-C6-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-C6-haloalkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or
  • C 2 -C6-alkenyl is to be understood as meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms ("C 2 -C4-alkenyl), particularly 2 or 3 carbon atoms (“C 2 - C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but- l-enyl, pent-4-enyl, (E)-pent-
  • C3-Cio-cycloalkyl is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3-C10- cycloalkyl").
  • Said C3-Cio-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
  • said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl”), preferably cyclopropyl.
  • said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
  • said heterocycloalkyl can be benzo fused.
  • the 3- to 6-membered heterocycloalkyl is a tetrahydrofuranyl, tetrahydropyranyl or piperazinyl
  • Said heterocycloalkyl can be bicyclic, such as, without being limited thereto, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6-membered bicyclic ring, e.g. a hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring.
  • said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-lH- pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[l,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • oxygen atom e.g. a pyrrolidineoxy, tetrahydrofuraneoxy or tetrahydropyranoxy.
  • heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3,6- dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-thiopyran-4-yl, l,2,3,6-tetrahydropyridin-4-yl, 3H- diazirinyl, 2,5-dihydro-lH-pyrrolyl, [l,3]dioxolyl, 4H-[l,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, 4H- [l,4]thiazinyl or 5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl group or it may be be be
  • heteroaryl is understood as meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14- membered heteroaryl” group), 5 or 6 or 9 or 10 ring atoms (a "5- to 10-membered heteroaryl” group) or particularly 5 or 6 ring atoms ("5- to 6-membered heteroaryl” group), and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.;
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • Ci-Ce as used throughout this text, e.g. in the context of the definition of "C1-C6- alkyl", “Ci-C6-haloalkyl", “Ci-C6-alkoxy”, or “Ci-C6-haloalkoxy” 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 subrange comprised therein, e.g.
  • C1-C6 C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5, Ci-Ce; more particularly C1-C4 ; in the case of "Ci-C6-haloalkyl" or "Ci-C6-haloalkoxy" even more particularly C1-C2.
  • C2-C6 as used throughout this text, e.g. in the context of the definitions of "C 2 -C6-alkenyl” and “C 2 -C6-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl 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 -C6” is to be interpreted as any subrange comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5; particularly C2-C3.
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl 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-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6, C4-C5, C3-C5, C3-C4, C 4 -C 6 , C 5 -C 6 ; particularly C 3 -C 6 .
  • C 2 -C4-alkenyl is to be understood as meaning a alkenyl group having a finite number of carbon atoms of 2 to 4, i.e. 2, 3 or 4 carbon atoms. It is to be understood further that said term “C2-C4" is to be interpreted as any sub-range comprised therein, e.g. C2-C4, C2-C3, C3-C4.
  • 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.
  • 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.
  • 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 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".
  • the invention also includes all suitable isotopic variations of the compound of component A.
  • An isotopic variation of the compound of component A 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 that can be incorporated into the compound of component A include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), U 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 C1, 82 Br, 123 I, 124 I, 129 I and 131 I, respectively.
  • Certain isotopic variations of the compound of component A for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, 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 may be preferred in some circumstances.
  • isotopic variations of the compound of component A 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.
  • the compounds of component A may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be 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 of component A may contain sulphur atoms which are asymmetric, such as an asymmetric sul hoxide or sulphoximine group, of structure:
  • Preferred compounds of component A 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 of component A 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.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • 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 of component A 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 of component A may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of component A may exist as tautomers.
  • any compound of component A which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely :
  • the present combination includes all possible tautomers of the compounds of component A, particularly the 1 H-tautomer or the 2H-tautomer of the pyrazol-5-yl group in 8-position of the naphthyridine core of Compound A, as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of component A 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 combination includes all such possible N-oxides of component A.
  • the present combination also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present combination can exist as a hydrate, or as a solvate, wherein the compounds of the present combination 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. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, terra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present combination includes all such hydrates or solvates.
  • the compounds of the present combination 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.
  • the present invention includes all possible salts of the components of the present combination as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of components of the present combination, either as single polymorphs, or as a mixture of more than one polymorph, in any ratio.
  • radicals in the compounds of the present combination When radicals in the compounds of the present combination are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.
  • treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease or the development, the course or the progression of such states and/or the symptoms of such states.
  • disease includes but is not limited a condition, a disorder, an injury or a health problem.
  • therapy is understood here to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease or a development or advancement of such states and/or the symptoms of such states.
  • the treatment or prevention of a disease may be partial or complete.
  • Component A can be selected from inhibitors of ATR kinase specifically or generically disclosed in the following publications: J. Med. Chem. 2013, 56, 2125-2138; Exp. Rev. Mol.
  • component A is a compound selected from VX- 803, VX-970, compound of general formula (I)
  • each Ci-C6-alkyl, Ci-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C 2 -C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR 7 R 8 , Ci-C6-alkyl optionally substituted one or more times with hydroxyl or phenyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C 3 -C6-cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, -(CO)OR 7 , -(CO)NR 7 R 8 , -NR 7 (CO)R 10 , -NR 8 (CO)OR 7 , -NR 8 (CO) NR 7 R 8 , -(S0 2 )R 9
  • each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with Ci-C/t-alkyl;
  • R 3 , R 4 represent, independently from each other, hydrogen or methyl
  • R 7 , R 8 represent, independently from each other, hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R 7 and R 8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from Ci-C6-alkyl, Ci-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S;
  • R 9 represents Ci-C t-alkyl or phenyl, wherein each Ci-C/t-alkyl or phenyl is optionally
  • R 10 represents Ci-C t-alkyl
  • R 11 represents hydrogen, Ci-C 4 -alkyl, -(CO)OR 7 , -(CO)NR 7 R 8 or CN;
  • R 12 represents hydrogen or Ci-C/t-alkyl
  • R 13 represents halogen, OH, -NR 7 R 8 , CN, N0 2 , G-Ce-alkyl, Ci-Ce-haloalkyl, G-Ce-alkoxy,
  • Ci-Ce-haloalkoxy C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, -(CO)OR 7 or -(CO)NR 7 R 8 ;
  • VX-803 is understood as meaning 2-amino-6- fluoro-N- [5-fluoro-4-(4- ⁇ [4-(oxetan-3-yl)piperazin- 1 -yljcarbonyl Jpiperidin- l-yl)pyridin-3- yl]pyrazolo[l,5-a]pyrimidine-3-carboxamide. It has the following structure:
  • VX-970 is understood as meaning 3-(3- ⁇ 4- [(methylamino)methyl]phenyl ⁇ - 1 ,2-oxazol-5-yl)-5-[4-(propan-2-ylsulfonyl)phenyl]pyrazin-2- amine. It has the following structure:
  • AZD-6738 is understood as meaning 4- ⁇ 4- [(3R)-3-methylmo holin-4-yl]-6-[l-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl ⁇ -lH- pyrrolo[2,3-b]pyridine. It has the following structure:
  • component A is a compound selected from VX-803, VX-970, AZD- f general formula (lb)
  • R 1 , R 2 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined for the compound of general formula (I) supra.
  • component A is a compound selected from VX-803, VX-970, AZD-6738 and/or a compound of general formula (lb)
  • each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl;
  • R 4 represents hydrogen or methyl
  • R 7 , R 8 represent, independently from each other, hydrogen or Ci-C/t-alkyl
  • R 9 represents Ci-C/t-alkyl
  • R 10 represents Ci-C t-alkyl
  • R 11 represents hydrogen, methyl, -(CO)OR 7 ;
  • component A is a compound of general formula (lb)
  • each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl;
  • R 7 , R 8 represent, independently from each other, hydrogen or Ci-C t-alkyl
  • R 9 represents Ci-C t-alkyl
  • R 10 represents Ci-C4-alkyl
  • R 11 represents hydrogen, methyl, -(CO)OR 7 ;
  • component A is a compound selected from:
  • component A of the combination of the present invention is 2-[(3R)- 3-methylmorpholin-4-yl] -4-( 1 -methyl- 1 H-pyrazol-5-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine ("Compound A” in the following), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
  • component A of the combination of the present invention is Compound A of structur
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • an appropriate base e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed 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 of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of a component A of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially with component B and optionally component C as further described infra.
  • the components A and B and optionally C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component B of the combination of the present invention is an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • an antiandrogen particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • component B is an antiandrogen selected from bicalutamide, enzalutamide, apalutamide, ODM-201, ORM-15341 and abiraterone, particularly abiraterone acetate.
  • component B is an antiandrogen selected from enzalutamide and ODM-201.
  • Androgen receptor (AR) antagonists compete with the natural androgens such as testosterone and its more active metabolite dihydrotestosterone (DHT) for binding to the AR in the prostate gland and in other tissues:
  • Cyproterone acetate is an antiandrogen and progestogen that is used in the treatment of androgen-related conditions like acne, hirsutism, early-onset puberty, and prostate cancer, as a component of hormone therapy for transgender women, and in oral contraceptives [F. Neumann, J. Kalmus: Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience. Exp. Clin. Endocrinol. 98, 71-80, 1991].
  • Bicalutamide is a non-steroidal antiandrogen that is primarily used to treat castration-resistant prostate cancer (CRPC). It is typically used after androgen deprivation therapy by a gonadotropin-releasing hormone (GnRH) analogue or by surgical removal of the testicles to treat metastatic CRPC [Y. Fradet: Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev. Anticancer 4, 37-48, 2004].
  • GnRH gonadotropin-releasing hormone
  • Flutamide is a non-steroidal antiandrogen used primarily to treat metastatic CRPC [R.N. Brogden, P. Chrisp: Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer. Drugs Aging 1, 104-115, 1991].
  • Nilutamide is a non-steroidal antiandrogen used in the treatment of metastatic CRPC [E.J. Dole, MT Holdsworth: Nilutamide: an antiandrogen for the treatment of prostate cancer. Ann. Pharmacother. 31, 65-75, 1997].
  • Enzalutamide is a second-generation antiandrogen used to treat metastatic CRPC [R.M. Bambury, H.I. Scher: Enzalutamide: Development from bench to bedside. Urol. Oncol. 33, 280- 288, 2015].
  • Enzalutamide may also be effective in the treatment of certain types of breast cancer [A. Gucalp, T.A. Traina: Targeting the androgen receptor in triple-negative breast cancer. Curr. Probl. Cancer 40, 141-150, 2016].
  • Apalutamide (developmental code name ARN-509, also JNJ-56021927) is a second-generation antiandrogen that is under clinical development for the treatment of prostate cancer [D.E. Rathkopf, E.S. Antonarakis et al.: Safety and antitumor activity of apalutamide (ARN-509) in metastatic castration-resistant prostate cancer with and without prior abiraterone acetate and prednisone. Clin. Cancer Res. DOI: 10.1158/1078-0432.CCR-16-2509, 2017].
  • ODM-201 also known as darolutamide, BAY 1841788 or N-((S)-l-(3-(3-Chloro-4- cyanophenyl)-lH-pyrazol-l-yl-)-propan-2-yl)-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide) is a non-steroidal AR antagonist that has demonstrated significant antitumor activity in different prostate cancer models.
  • ORM 16555 also known as N- ⁇ (2S)- 1 - [3-(3-chloro-4-cy anophenyl)- 1 H-pyrazol- 1 -yl]propan-2-yl ⁇ -5- [( 1 S)- 1 -hydroxyethyl] - lH-pyrazole-3-carboxamide
  • ORM 16497 also known as N- ⁇ (2S)-l-[3-(3-chloro-4- cyanophenyl)- 1 H-pyrazol- 1 -yl]propan-2-yl ⁇ -5- [( 1R)- 1 -hydroxyethyl] - 1 H-pyrazole-3- carboxamide).
  • ORM-15341 (also known as 5-acetyl-N- ⁇ (2S)-l-[3-(3-chloro-4-cyanophenyl)- lH-pyrazol-l-yl]propan-2-yl ⁇ -lH-pyrazole-3-carboxamide) is the main metabolite of ODM-201 and possesses similar pharmacological properties [A.J. Moilanen, R Riikonen, et al.: Discovery of ODM-201, a new generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci. Rep. 5, 12007, 2005].
  • ODM-201 is of structure
  • ORM-15341 is of structure:
  • EPI-506 is a non-steroidal antiandrogen in clinical trials for prostate cancer [G. Martinez- Ariza, C. Hulme: Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharm. Pat. Anal. 4, 387-402, 2015]. It is the successor of EPI-001 and targets the N- terminal domain of the androgen receptor (AR). This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants.
  • EPI- 506 is a prodrug of EPI-002 [Y. Imamura, M.D. Sadar: Androgen receptor targeted therapies in castration-resistant prostate cancer. Int. J. Urol.
  • CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17a- hydroxy derivatives by its 17a-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity [D. Poubek: CYP17A1: a biochemistry, chemistry, and clinical review. Curr. Top. Med. Chem. 13, 1364-1384, 2013]. DHEA and androstenedione are precursors of the more potent androgens testosterone and dihydrotestosterone. Inhibition of CYP17 activity thus decreases circulating levels of active androgens.
  • Abiraterone acetate is a steroidal androgen synthesis inhibitor which blocks the CYP17A1 enzyme. It is used in combination with prednisone for treatment of metastatic CRPC, before and after chemotherapy treatment. It is a prodrug of the active metabolite abiraterone. It also has some AR antagonist activity [E. Grist, R. Attard: The development of abiraterone acetate for castration-resistant prostate cancer. Urol. Ocol. 33, 289-294, 2015].
  • Seviteronel (developmental code VT-464; also known as (lS)-l-[6,7- bis(difluoromethoxy)naphthalen-2-yl]-2-methyl-l-(2H-triazol-4-yl)propan-l-ol) is a nonsteroidal CYP17A1 inhibitor and in clinical studies for prostate cancer. It also has some AR antagonist activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
  • Galeterone (TOK-001 or VN/ 124-1, also known as (3S,8R,9S,10R,13S,14S)-17-(benzimidazol- l-yl)-10,13-dimethyl-2,3,4,7,8,9,l l,12,14,15-decahydro-lH-cyclopenta[a]phenanthren-3-ol ) is a steroidal antiandrogen under clinical development for the treatment of prostate cancer. It possesses a dual mechanism of action, acting as both an AR antagonist and a CYP17A1 inhibitor activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
  • Orteronel (TAK-700, also known as 6-(7-Hydroxy-6,7-dihydro-5/i-pyrrolo[l,2-c]imidazol-7- yl)-/V-methylnaphthalene-2-carboxamide) is a non-steroidal CYP17A1 inhibitor which completed clinical trials for metastatic CRPC treatment activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
  • Ketoconazole has antiandrogenic activity through at least two mechanisms of action [T.A. Yap, CP. Carden et al.: Targeting CYP17: established and novel approaches in prostate cancer. Curr. Opin. Pharmacol.. 8, 449-457, 2008]. It blocks both testicular and adrenal androgen biosynthesis by inhibiting the 17a-hydroxylase and 17,20-lyase, thus leading to a reduction in circulating testosterone levels. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Secondly, ketoconazole is an AR antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the AR.
  • DHT dihydrotestosterone
  • Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component B may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially with component A and optionally component C as further described infra.
  • the components A and B and optionally C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • the present invention provides combinations of at least two components, preferably two components, component A and component B,
  • component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide
  • the present invention provides combinations of at least two components, preferably two components, component A and component B, component A being an inhibitor of ATR kinase, particularly Compound A, or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen, particularly an antiandrogen selected from bicalutamide, enzalutamide, apalutamide, ODM-201, ORM-15341 and abiraterone acetate.
  • component A being an inhibitor of ATR kinase, particularly Compound A, or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof
  • component B being an antiandrogen, particularly an antiandrogen selected from bicalutamide, enzalutamide, apalutamide, ODM-201, ORM-15341 and abiraterone acetate.
  • the present invention covers a combination of any component A mentioned herein with any component B mentioned herein, optionally with any component C mentioned herein.
  • kits comprising:
  • component A one or more, preferably one, ATR kinase inhibitor(s) as described supra, particularly Compound A or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
  • component B an antiandrogen, or combinations of antiandrogens, as described supra.
  • either or both of said components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components A and B may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Preferably components A and B are administered by the oral route.
  • kits comprising:
  • component A one or more, preferably one, ATR kinase inhibitor(s) as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
  • component B an antiandrogen, or combinations of antiandrogens, as described supra; and, optionally,
  • component C one or more, preferably one, further pharmaceutical agent(s),
  • components A, B and C in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components A and B, optionally C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • 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 pharmaceutical composition comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers.
  • a list of such pharmaceutical agents of component C is being provided further below.
  • 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 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.
  • Optional pharmaceutical agents which can be added as component C to the combination of components A and B can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basilixima
  • the present invention covers a pharmaceutical composition comprising a combination of the present invention as described herein together with one or more pharmaceutically acceptable excipients.
  • the present invention covers a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of at least two components, particularly of two components, component A and component B, component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, together with one or more pharmaceutically acceptable excipients.
  • the present invention covers a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of at least two components, particularly of two components, component A and component B, component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen as described supra; optionally with any component C mentioned herein, together with one or more pharmaceutically acceptable excipients.
  • a preferred aspect of the present invention covers a pharmaceutical composition
  • components A and B, and optionally component C are present in separate formulations.
  • compositions A and B, and optionally component C are present in a joint formulation.
  • Pharmaceutically acceptable excipients are non-toxic, preferably they are non-toxic and inert.
  • Pharmaceutically acceptable excipients include, inter alia,
  • fillers and excipients for example cellulose, microcrystalline cellulose, such as, for example, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for example, Di-Cafos®),
  • ⁇ ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, Isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyle sulphate, lecithin, phospholipids, fatty alcohols such as, for example, Lanette®, sorbitan fatty acid esters such as, for example, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example,
  • Cremophor® polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such as, for example, Pluronic®),
  • buffers and also acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine),
  • binders for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • modified starch carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®),
  • capsule materials for example gelatine, hydroxypropylmethylcellulose
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • the components A, B and C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Components A, B and C are preferably administered orally.
  • compositions of this invention varies by the route of administration.
  • 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
  • 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 from 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 compound in preferably a pharmaceutically 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-l,l-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 surfact
  • 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.
  • compositions of the present invention can be in the form of sterile injectable aqueous suspensions.
  • 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
  • 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.
  • 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.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • 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.
  • 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 11, 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.
  • the present invention concerns the use of the combination of the present invention as described supra for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra and/or metastases thereof, preferably metastases in bone.
  • the present invention concerns the combination of the present invention as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
  • a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
  • CRPC castration-resistant prostate cancer
  • mHSPC metastatic hormone sensitive prostate cancer
  • the present invention concerns the kit as described supra for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention concerns the kit as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
  • a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
  • CRPC castration-resistant prostate cancer
  • mHSPC metastatic hormone sensitive prostate cancer
  • the present invention concerns the pharmaceutical composition as described supra for the treatment or prophylaxis of a disease, preferably a hyper- proliferative disease as described infra.
  • the present invention concerns the pharmaceutical composition as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
  • CRPC castration-resistant prostate cancer
  • mHSPC metastatic hormone sensitive prostate cancer
  • the present invention covers the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention covers the use of such kit as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention covers the use of such pharmaceutical composition as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
  • the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra using an effective amount of the combination of the present invention as described supra.
  • the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra using an effective amount of the kit or pharmaceutical composition as described supra.
  • the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising
  • component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
  • component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
  • the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising
  • component A being an inhibitor of ATR kinase as described supra, particularly Compound A, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
  • component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, wherein components A and B are administered simultaneously, concurrently, separately or sequentially.
  • an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, wherein components A and B are administered simultaneously, concurrently, separately or sequentially.
  • the present invention concerns a method of treating a hyper- proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
  • component B being an antiandrogen selected from enzalutamide and
  • the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
  • component B being an antiandrogen selected from enzalutamide and ODM-201, wherein Compound A and component B are administered concurrently.
  • the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
  • component B being an antiandrogen selected from enzalutamide and ODM-201, wherein Compound A is administered prior to component B.
  • the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating breast cancer or prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
  • the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising a) administering component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
  • component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel; and optionally
  • component C being a pharmaceutical agent as described supra.
  • kits or pharmaceutical compositions of the present invention thus can be used for the treatment or prophylaxis of hyper-proliferative diseases, including 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 tumors and/or metastases thereof, solid tumors, and/or metastases thereof, e.g.
  • leukemias multiple myeloma thereof and myelodysplastic syndrome, malignant lymphomas, breast tumors including and bone metastases thereof, tumors of the thorax including non-small cell and small cell lung tumors and bone metastases thereof, gastrointestinal tumors, endocrine tumors, mammary and other gynaecological tumors and bone metastases thereof, urological tumors including renal, bladder and prostate tumors, skin tumors, and sarcomas, and/or metastases thereof.
  • 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.
  • kits or pharmaceutical compositions 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 and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the hyper-proliferative disease.
  • Hyper-proliferative diseases include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia.
  • BPH benign prostate hyperplasia
  • malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g.
  • malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases").
  • Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non- Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ, particularly with bone metastases.
  • cancers of the respiratory tract include, but are not limited to small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS -related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • Combinations of the present invention might also be used for treating diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastases.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastases and the consequence spread of the cancer.
  • combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis diseases, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • prostate cancer means any histology type of prostate cancer including but not limited to acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urothelial) cancer, squamous cell cancer, carcinoid, small cell cancer, sarcomas and sarcomatoid cancers, particularly acinar adenocarcinoma, metastatic hormone sensitive prostate cancer (mHSPC), castration resistant prostate cancer (CRPC), particularly stage MO castration-resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC).
  • mHSPC metastatic hormone sensitive prostate cancer
  • CRPC castration resistant prostate cancer
  • MO CRPC stage MO castration-resistant prostate cancer
  • Ml CRPC stage Ml castration-resistant prostate cancer
  • MO and “Ml” (including Mia, Mlb, Mlc) are used in accordance with the "TNM staging system” for prostate cancer developed by the American Joint Committee on Cancer as further described in "TNM CLASSIFICATION OF MALIGNANT TUMORS", 7th edition Edited by James D. Brierley, Mary K. Gospodarowicz, Christian Wittekind, Published by UICC 2011.
  • MO CRPC means that there are no distant metastases and that the CRPC has not spread to other parts of the body.
  • Ml CRPC means that there are distant metastases and that the CRPC has spread to distant parts of the body.
  • the present invention covers the treatment of prostate cancer, particularly the treatment of metastatic hormone sensitive prostate cancer (mHSPC) or of castration-resistant prostate cancer (CRPC).
  • mHSPC metastatic hormone sensitive prostate cancer
  • CRPC castration-resistant prostate cancer
  • the combination/kit/pharmaceutical composition of the present invention are used in the treatment of prostate cancer or breast cancer, particularly in the treatment of mHSPC, MO CRPC, Ml CRPC or breast cancer.
  • the castration resistant prostate cancer is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC).
  • the castration resistant prostate cancer is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC), and the subject to be treated is chemotherapy-naive.
  • chemotherapy-naive means that the subject, prior to the treatment with the combination/ kit/pharmaceutical composition of the present invention has not received a chemotherapy.
  • the castration resistant prostate cancer is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC), and the subject to be treated is a subject, wherein the subject has received a chemotherapy prior to the treatment with the combination/kit/pharmaceutical composition of the present invention.
  • MO CRPC stage MO castration resistant prostate cancer
  • Ml CRPC stage Ml castration-resistant prostate cancer
  • chemotherapeutic agents are rather non-specific agents including but not limited to alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, nucleotide analogues, platinum-based agents, vinca alkaloids.
  • 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 component 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 50 mg/kg body weight per day.
  • 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 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.
  • Component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel can be administered to a patient at a dosage which can range from about 1 to about 2000 mg per day.
  • the agents can be administered in conventional amounts routinely used in cancer chemotherapy.
  • the following treatments are used: 100 mg two or three times a day (cyproterone acetate), 50 mg daily (bicalutamide), 250 mg three times a day (flutamide), 150 or 300 mg daily (nilutamide), 160 mg daily (enzalutamide), 240 mg daily (apalutamide), 1000 mg daily (abiraterone), 600 mg twice a day (ODM-201), 200 or 400 mg three times a day (ketoconazole), 300 mg twice daily (orteronel).
  • 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 component B 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 ATR kinase inhibitor and the antiandrogen can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection.
  • Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques.
  • the agents can be administered by any of the conventional routes of administration for these compounds.
  • the preferred route of administration for the ATR kinase inhibitor and the antiandrogen is typically orally, which is the same route of administration used for each agent alone.
  • Any of the antiandrogens described supra can be administered in combination with a compound of general formula (I) or (lb) described supra, particularly with Compound A, by any of the mentioned routes of administration.
  • the ATR kinase inhibitor, particularly Compound A can be administered simultaneously with the antiandrogen. This can be performed by administering a single formulation which contains both the ATR kinase inhibitor, particularly Compound A, and the antiandrogen. Alternatively, this can be performed by administering the ATR kinase inhibitor, particularly Compound A, and the antiandrogen in independent formulations at the same time to a patient.
  • the ATR kinase inhibitor described supra, particularly Compound A can be administered in tandem with the antiandrogen.
  • the ATR kinase inhibitor described supra, particularly Compound A can be administered prior to the antiandrogen.
  • the ATR kinase inhibitor described supra, particularly Compound A 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 antiandrogen described supra.
  • the antiandrogen as described supra can be administered first followed by adminstration of the ATR kinase inhibitor described supra, particularly Compound A.
  • the choice of sequence administration of the ATR kinase inhibitor described supra, particularly Compound A, relative to the antiandrogen may vaiy for different agents.
  • the antiandrogen described supra can be administered using any regimen which is conventionally used for these agents.
  • the ATR kinase inhibitor described supra, particularly Compound A, and the antiandrogen can be administered once or more times per day on the day of administration.
  • Component A is a compound having Component A:
  • Compound A is an example of component A.
  • Compound A is described in Example 111 of International Patent Application WO2016020320 (Al).
  • Compound A is 2-[(3R)-3-methylmorpholin-4-yl]-4-(l- methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, of structure:
  • Component B is a compound having Component B:
  • Compound C used in the Examples below is Enzalutamide.
  • Compound A monotherapy formulation: 60% PEG400/10% Ethanol/30% Water; application route: p.
  • the oral application volume was 10 ml/kg.
  • the two applications of Compound A were performed 6-7 h apart.
  • compounds B and C were given 2 hours post Compound A first treatment.
  • the tumor size was measured twice a week with an electronic caliper gauge and tumor volume was calculated using the formula: [(length (mm) x width (mm) 2 ) / 2] .
  • T/C ratio (Treatment/Control) based on the tumor volumes measured on day of termination of the control group, at day 51 after tumor inoculation.
  • T/C is calculated according to the formula: [(mean tumor volume of treatment group on day 51) - (mean tumor volume of treatment group at start of treatment)] / [(mean tumor volume of control group on day 51) - (mean tumor volume of control group at start of treatment)].
  • Compounds having a T/C below 0.5 are defined as active (effective).
  • Statistical significance was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control group were compared by a pair-wise comparison procedure (Dunn's method).
  • T/C ratio of the tumor volume of treatment versus control group [(mean tumor volume of treatment group at day 51) - (mean tumor volume of treatment group at start of treatment)] / [(mean tumor volume of control group at day 51) - (mean tumor volume of control group at start of treatment)] .
  • QD means once per day
  • 2QD means twice per day
  • p.o. means per os (orally).

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Abstract

The present invention covers combinations of at least two components, component A and component B, comprising component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (Ib) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel. Another aspect of the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment of a hyper-proliferative disease.

Description

COMBINATION of ATR KINASE INHIBITORS and ANTIANDROGENS
The present invention covers combinations of at least two components, component A and component B, comprising component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel. Another aspect of the present invention covers 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 a hyper-proliferative disease.
BACKGROUND
Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation.
Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.
The integrity of the genome of eukaryotic cells is secured by complex signaling pathways, referred to as the DNA damage response (DDR), and multiple DNA repair mechanisms. Upon recognizing DNA damage activation of the DDR pathways results in cell cycle arrest, suppression of general translation, induction of DNA repair, and, finally, in cell survival or cell death. Proteins that directly recognize aberrant DNA structures, such as the MRE11-Rad50-Nbsl complex recognizing DNA double strand breaks by binding to double-stranded DNA ends, or RPA (replication protein A) binding to single stranded DNA, recruit and activate the most upstream kinases of the DDR pathway, ATM (ataxia-telangiectasia mutated), ATR (ATM-and Rad3-related, UniProtKB/Swiss-Prot Q13535), and DNA-PKcs (DNA-dependent protein kinase). Whereas ATM is primarily activated by DNA double strand breaks, and DNA-PKcs is mainly involved in non-homologous end joining process of DNA repair, ATR responds to a broad spectrum of DNA damage, including double- strand breaks and lesions derived from interference with DNA replication. Major components of downstream signaling of ATM include Chk2 and p53, whereas ATR signaling involves Chkl and cdc25. Knockout of the ATR gene in mice is embryonically lethal and ATR knockout cells develop chromosome breaks and undergo apoptosis [E.J. Brown, D. Baltimore: ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397-402, 2000]. In contrast, ATM is not essential for cell survival although ATM knockout cells are hypersensitive to ionizing radiation and agents which cause DNA double-strand breaks.
ATR, which forms a complex with ATRIP (ATR-interacting protein, UniProtKB/Swiss-Prot Q8WXE1) is mainly activated by long stretches of single-stranded DNA which are generated by the continuing DNA unwinding activity of helicases upon stalled replication. This replication stress with stalled replication forks may be induced by ultraviolet light, certain chemotherapeutic drugs, hydroxyurea, or aberrant oncogenic signaling resulting in increased replication initiation or origin firing. Activation of ATR results in inhibition of the cell cycle in S or G2 phase via the Chkl-cdc25 pathway and in suppression of late origin firing. The cell gains time to resolve the replication stress and, eventually, to restart replication after the source of stress has been removed. As the ATR pathway ensures cell survival after replication stress it potentially contributes to resistance to chemotherapy. Thus inhibition of ATR kinase activity could be useful for cancer treatment.
In oncogene-driven tumor cells (e.g. Ras mutation/upregulation, Myc upregulation, CyclinE overexpression) increased replication stress has been observed as compared to healthy normal cells. ATR suppression in Ras oncogene driven cells was reported to result in substantial tumor cell killing [O. Gilad, BY Nabet, et al.: Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70, 9693-9702, 2010].
Although ATM and ATR are principally activated by different types of DNA damage their signaling includes some cross-talk thus that they can, at least partially, substitute for each other's function. This finding suggests some tumor-cell selectivity of pharmaceutical inhibition of ATR. A healthy normal cell, which has ATM and ATR pathways in parallel, arrests in Gl phase of the cell cycle upon induced DNA damage even in presence of an ATR inhibitor. In contrast, a tumor cell which most often deficient in ATM and/or p53 signaling relies on the ATR pathway and undergoes cell death in presence of an ATR inhibitor. This suggests that ATR inhibitors may be used for the treatment of tumors with deficient ATM signaling and/or p53 function.
Details of DDR signaling and the functional role of ATM and ATR were recently reviewed in: E. Fokas, R. Prevo et al.: Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treatment Rev 40, 109-117, 2014. J.M. Wagner & S.H. Kaufmann: Prospects for the use of ATR inhibitors to treat cancer. Pharmaceuticals 3, 1311-1334, 2010. D. Woods & J.J. Tuchi: Chemotherapy induced DNA damage response. Cancer Biol. Thera. 14, 379-389, 2013. A. Marechal & L. Zou: DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5, a012716, 2013. M.K. Zeman & K.A. Cimprich: Causes and consequences of replication stress. Nat. Cell Biol. 16, 2-9, 2014. S. Llona-Minguez, A. Hoglund et al.: Chemical strategies for development of ATR inhibitors. Exp. Rev. Mol. Med. 16, elO, 2014.
Thus inhibitors of ATR kinase represent valuable compounds that should complement therapeutic options not only as single agents but also in combination with other drugs, which are currently used in the treatment of hyperproliferative diseases. There is an acute medical need for additional therapeutic options for the treatment of hyper-proliferative diseases.
Combination treatment with the AR signaling inhibitor enzalutamide and the Chkl/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chkl signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild- type p53) cells (Karanika et al., Cell Rep. 2017 Feb 21;18(8): 1970-1981. doi: 10.1016/j.celrep.2017.01.072). The state of the art does not disclose the combinations of the present invention comprising an inhibitor of ATR kinase and an antiandrogen.
SUMMARY OF THE INVENTION
Surprising effects in an in vivo tumor model were observed when administering a ATR kinase inhibitor in combination with an antiandrogen such as enzalutamide or ODM-201
(=darolutamide). The therapeutic efficacy of the combination described in the present invention has shown superiority to the efficacy achieved by the corresponding doses of antiandrogen or ATR kinase inhibitor alone.
Therefore, in accordance with a first aspect, the present invention provides combinations of at least two components, component A and component B, comprising
component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
In accordance with a further aspect, the present invention concerns combinations of two components, component A and component B, comprising
component A being an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra,
and component B being an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel. The combinations comprising at least two components A and B, particularly two components, as decribed herein, are also referred to as "combinations of the present invention".
Further, the present invention covers a kit comprising:
component A: one or more ATR kinase inhibitor(s) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
component B: one or more antiandrogen(s) as described herein,
in which kit optionally either or both of said components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. In accordance with another aspect, the present invention concerns the combinations as described herein for use in the treatment of for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
In accordance with another aspect, the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra. In accordance with another aspect, the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper -proliferative disease as described infra, using an effective amount of the combinations as described herein.
DETAILED DESCRIPTION OF THE INVENTION
The terms as mentioned in the present text in context with compounds of general formula (I) or (lb) have the following meanings:
The term "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom. The term "Ci-C6-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-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("Ci-C/t-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.
The term "Ci-C6-haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-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. Said C1-C6- haloalkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3 or -CH2CF3.
The term "Ci-C t-hydroxyaikyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C t-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, l,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-mefhyl- propyl, l-hydroxy-2-methyl-propyl group.
The term "Ci-C6-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, said "Ci-C6-alkoxy" can contain 1, 2, 3, 4 or 5 carbon atoms, (a "Ci-Cs-alkoxy"), preferably 1, 2, 3 or 4 carbon atoms ("d-C^alkoxy").
The term "Ci-C6-haloalkoxy" is to be understood as meaning a linear or branched, saturated, monovalent Ci-C6-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-C6-haloalkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or
The term "C2-C6-alkenyl" is to be understood as meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms ("C2-C4-alkenyl), particularly 2 or 3 carbon atoms ("C2- C3-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but- l-enyl, pent-4-enyl, (E)-pent-
3- enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-pent- l-enyl, hex- 5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-
2-enyl, (E)-hex-l-enyl, (Z)-hex-l-enyl, isopropenyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl, (Z)-l-methylprop-l-enyl, 3-methylbut-3-enyl, 2- methylbut-3-enyl, l-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2- methylbut-2-enyl, (E)-l-methylbut-2-enyl, (Z)-l-methylbut-2-enyl, (E)-3-methylbut-l-enyl, (Z)- 3-methylbut-l-enyl, (E)-2-methylbut-l-enyl, (Z)-2-methylbut- l-enyl, (E)- l-methylbut-l-enyl, (Z)-l-methylbut-l-enyl, l,l-dimethylprop-2-enyl, 1-ethylprop-l-enyl, 1-propylvinyl, 1- isopropyl vinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-
4- enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2- methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-l-methylpent-3-enyl, (Z)-l-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent- 2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-l-methylpent-2-enyl, (Z)-l- methylpent-2-enyl, (E)-4-methylpent-l-enyl, (Z)-4-methylpent-l-enyl, (E)-3-methylpent-l-enyl, (Z)-3-methylpent-l-enyl, (E)-2-methylpent-l-enyl, (Z)-2-methylpent-l-enyl, (E)-l-mefhylpent- 1-enyl, (Z)-l-methylpent-l-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, l-ethylbut-3-enyl, (E)-3- ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-l- ethylbut-2-enyl, (Z)-l-ethylbut-2-enyl, (E)-3-ethylbut-l-enyl, (Z)-3-ethylbut-l-enyl, 2-efhylbut-
1- enyl, (E)-l-ethylbut-l-enyl, (Z)-l-ethylbut-l-enyl, 2-propylprop-2-enyl, l-propylprop-2-enyl,
2- isopropylprop-2-enyl, l-isopropylprop-2-enyl, (E)-2-propylprop-l-enyl, (Z)-2-propylprop-l- enyl, (E)-l-propylprop-l-enyl, (Z)-l-propylprop-l-enyl, (E)-2-isopropylprop-l-enyl, (Z)-2- isopropylprop-l-enyl, (E)-l-isopropylprop-l-enyl, (Z)-l-isopropylprop-l-enyl, (E)-3,3- dimethylprop-l-enyl, (Z)-3,3-dimethylprop-l-enyl, l-(l,l-dimethylethyl)ethenyl, buta-1,3- dienyl, penta-l,4-dienyl, hexa- 1,5 -dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.
The term "C3-Cio-cycloalkyl" is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3-C10- cycloalkyl"). Said C3-Cio-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl"), preferably cyclopropyl.
The term "3- to 10-membered heterocycloalkyl" is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom, or a Ci-C6-alkyl or Ci-C6-haloalkyl group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.
Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused. Preferably, the 3- to 6-membered heterocycloalkyl is a tetrahydrofuranyl, tetrahydropyranyl or piperazinyl.
Said heterocycloalkyl can be bicyclic, such as, without being limited thereto, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6-membered bicyclic ring, e.g. a hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring.
As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-lH- pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[l,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
The term "3- to 10-membered heterocycloalkoxy" of formula -O-heterocycloalkyl, in which the term "heterocycloalkyl" is defined supra, is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom, a Ci-C6-alkyl or Ci-C6-haloalkyl group and which is connected to the rest of the molecule via an oxygen atom, e.g. a pyrrolidineoxy, tetrahydrofuraneoxy or tetrahydropyranoxy.
The term "4- to 10-membered heterocycloalkenyl" is to be understood as meaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom, or a Ci-C6-alkyl or Ci-C6-haloalkyl group; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Examples of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3,6- dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-thiopyran-4-yl, l,2,3,6-tetrahydropyridin-4-yl, 3H- diazirinyl, 2,5-dihydro-lH-pyrrolyl, [l,3]dioxolyl, 4H-[l,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, 4H- [l,4]thiazinyl or 5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl group or it may be benzo fused.
The term "heteroaryl" is understood as meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14- membered heteroaryl" group), 5 or 6 or 9 or 10 ring atoms (a "5- to 10-membered heteroaryl" group) or particularly 5 or 6 ring atoms ("5- to 6-membered heteroaryl" group), and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl or lH-pyrrolo[2,3-b]pyridin-4-yl, etc..
In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
The term "Ci-Ce", as used throughout this text, e.g. in the context of the definition of "C1-C6- alkyl", "Ci-C6-haloalkyl", "Ci-C6-alkoxy", or "Ci-C6-haloalkoxy" 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 subrange comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5, Ci-Ce; more particularly C1-C4 ; in the case of "Ci-C6-haloalkyl" or "Ci-C6-haloalkoxy" even more particularly C1-C2.
Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g. in the context of the definitions of "C2-C6-alkenyl" and "C2-C6-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl 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 "C2-C6" is to be interpreted as any subrange comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5; particularly C2-C3.
Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl", is to be understood as meaning a cycloalkyl 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-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C6; particularly C3-C6.
Further, as used herein, the term "C2-C4", as used throughout this text, e.g. in the context of "C2- C4-alkenyl" is to be understood as meaning a alkenyl group having a finite number of carbon atoms of 2 to 4, i.e. 2, 3 or 4 carbon atoms. It is to be understood further that said term "C2-C4" is to be interpreted as any sub-range comprised therein, e.g. C2-C4, C2-C3, C3-C4.
The term "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.
The term "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. By "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.
As used herein, 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".
The invention also includes all suitable isotopic variations of the compound of component A. An isotopic variation of the compound of component A 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. Examples of isotopes that can be incorporated into the compound of component A include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), UC, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 123I, 124I, 129I and 131I, respectively. Certain isotopic variations of the compound of component A, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, 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 may be preferred in some circumstances. Isotopic variations of the compound of component A 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.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. The compounds of component A may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be 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. In certain instances, 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 of component A may contain sulphur atoms which are asymmetric, such as an asymmetric sul hoxide or sulphoximine group, of structure:
Figure imgf000012_0001
, for example, in which * indicates atoms to which the rest of the molecule can be bound.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds of component A 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 of component A 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. Examples of 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.
In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of component A 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 of component A may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of component A, particularly Compound A, may exist as tautomers. For example, any compound of component A which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely :
Figure imgf000014_0001
1 H-tautomer 2H-tautomer
Figure imgf000014_0002
1 H-tautomer 2H-tautomer 4H-tautomer
The present combination includes all possible tautomers of the compounds of component A, particularly the 1 H-tautomer or the 2H-tautomer of the pyrazol-5-yl group in 8-position of the naphthyridine core of Compound A, as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds of component A 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 combination includes all such possible N-oxides of component A.
The present combination also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates. The compounds of the present combination can exist as a hydrate, or as a solvate, wherein the compounds of the present combination 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. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, terra-, penta- etc. solvates or hydrates, respectively, are possible. The present combination includes all such hydrates or solvates.
Further, the compounds of the present combination 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.
The present invention includes all possible salts of the components of the present combination as single salts, or as any mixture of said salts, in any ratio.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of components of the present combination, either as single polymorphs, or as a mixture of more than one polymorph, in any ratio.
When radicals in the compounds of the present combination are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.
In the context of the present invention, the term "treatment" or "treating" includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease or the development, the course or the progression of such states and/or the symptoms of such states. The term "disease" includes but is not limited a condition, a disorder, an injury or a health problem. The term "therapy" is understood here to be synonymous with the term "treatment".
The terms "prevention", "prophylaxis" or "preclusion" are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease or a development or advancement of such states and/or the symptoms of such states.
The treatment or prevention of a disease may be partial or complete.
COMPONENT A OF THE COMBINATION
Component A can be selected from inhibitors of ATR kinase specifically or generically disclosed in the following publications: J. Med. Chem. 2013, 56, 2125-2138; Exp. Rev. Mol.
Med. 16, elO, 2014; WO2010054398A1; WO2010071837A1; WO2010073034A1;
WO2011143399A1; WO2011143419A1; WO2011143422A1; WO2011143423 A2;
WO2011143425 A2; WO2011143426A1; WO2011154737A1; WO2011163527 Al;
WO2012138938A1; WO2012178123A1; WO2012178124A1; WO2012178125A1;
WO2013049719A1; WO2013049720A1; WO2013049722A1; WO2013049859A1;
WO2013071085A1; WO2013071088A1; WO2013071090A1; WO2013071093A1; WO2013071094A1; WO2013152298 Al; WO2014062604A1; WO2014089379A1;
WO2014143240; WO 2014143241; WO 2014143242; ACS Med. Chem. Lett. 2015. 6, 37-41; ACS Med. Chem. Lett. 2015. 6, 42-46, WO 2015085132, WO 2015187451. In another embodiment of the present invention component A is a compound selected from VX- 803, VX-970, compound of general formula (I)
Figure imgf000016_0001
(I)
in which:
R1 represents a group selected from:
Figure imgf000016_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen, halogen, -NR7R8, CN, Ci-C6-alkyl, Ci-C6-alkoxy, 3- to 10- membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(S02)R9, -(SO)R9, -SR9, -(S02)NR7R8, -NR7(S02)R9, -((SO)=NRu)R10, -N=(SO)R9R10, -SiR10RuR12, -(PO)(OR7)2, -(PO)(OR7)R10 or -(PO)(R10)2,
wherein each Ci-C6-alkyl, Ci-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, Ci-C6-alkyl optionally substituted one or more times with hydroxyl or phenyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, -(CO)OR7, -(CO)NR7R8, -NR7(CO)R10, -NR8(CO)OR7, -NR8(CO) NR7R8, -(S02)R9, -(SO)R9, -SR9, -(S02)NR7R8,
-NR7(S02)R9, -((SO)=NRu)R10, -N=(SO)R9R10, -(PO)(OR7)2, -(PO)(OR7)R10, -(PO)(R10)2 or with a heteroaryl group which is optionally substituted, one or more times, with Ci-C t-aikyl;
wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with Ci-C/t-alkyl;
R3, R4 represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from Ci-C6-alkyl, Ci-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S;
R9 represents Ci-C t-alkyl or phenyl, wherein each Ci-C/t-alkyl or phenyl is optionally
substituted, one or more times, independently from each other, with R13;
R10 represents Ci-C t-alkyl; or
R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered
heterocycloalkyl group;
R11 represents hydrogen, Ci-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN;
R12 represents hydrogen or Ci-C/t-alkyl;
R13 represents halogen, OH, -NR7R8, CN, N02, G-Ce-alkyl, Ci-Ce-haloalkyl, G-Ce-alkoxy,
Ci-Ce-haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
In context with the present invention the term "VX-803" is understood as meaning 2-amino-6- fluoro-N- [5-fluoro-4-(4- { [4-(oxetan-3-yl)piperazin- 1 -yljcarbonyl Jpiperidin- l-yl)pyridin-3- yl]pyrazolo[l,5-a]pyrimidine-3-carboxamide. It has the following structure:
Figure imgf000017_0001
In context with the present invention the term "VX-970" is understood as meaning 3-(3-{4- [(methylamino)methyl]phenyl } - 1 ,2-oxazol-5-yl)-5-[4-(propan-2-ylsulfonyl)phenyl]pyrazin-2- amine. It has the following structure:
Figure imgf000018_0001
In context with the present invention the term "AZD-6738" is understood as meaning 4-{4- [(3R)-3-methylmo holin-4-yl]-6-[l-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl }-lH- pyrrolo[2,3-b]pyridine. It has the following structure:
Figure imgf000018_0002
In another embodiment of the invention, component A is a compound selected from VX-803, VX-970, AZD- f general formula (lb)
Figure imgf000018_0003
(lb)
in which R1, R2, R4, R7, R8, R9, R10, R11, R12 and R13 are as defined for the compound of general formula (I) supra.
In another embodiment of the invention, component A is a compound selected from VX-803, VX-970, AZD-6738 and/or a compound of general formula (lb)
Figure imgf000019_0001
R :
Figure imgf000019_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen, fluoro, chloro, CN, methyl, Ci-C t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl, -(S02)R9, -SR9, -((SO)=NRu)R10, -N=(SO)R9R10, wherein each methyl, Ci-C/t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally substituted, one or more times, independently from each other, with fluoro, chloro, OH, -NR7R8, methyl, 5-membered heterocycloalkyl, -NR8(CO)OR7,
-(S02)R9, -((SO)=NRU)R10,-(PO)(OR7)2, or with a group selected from:
Figure imgf000019_0003
wherein * indicates the point of attachment of said group with the rest of the molecule;
wherein each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl;
R4 represents hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen or Ci-C/t-alkyl;
R9 represents Ci-C/t-alkyl;
R10 represents Ci-C t-alkyl; or
R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 6-membered heterocycloalkyl group;
R11 represents hydrogen, methyl, -(CO)OR7;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
In another embodiment of the invention, component A is a compound of general formula (lb)
Figure imgf000020_0001
(lb) , in which
R :
Figure imgf000020_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen, fluoro, chloro, CN, methyl, Ci-C t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl, -(S02)R9, -SR9, -((SO)=NRu)R10, -N=(SO)R9R10, wherein each methyl, Ci-C t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally substituted, one or more times, independently from each other, with fluoro, chloro, OH, -NR7R8, methyl, 5-membered heterocycloalkyl, -NR8(CO)OR7,
-(S02)R9, -((SO)=NRU)R10,-(PO)(OR7)2, or with a group selected from:
Figure imgf000020_0003
wherein * indicates the point of attachment of said group with the rest of the molecule;
wherein each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl;
represents hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen or Ci-C t-alkyl;
R9 represents Ci-C t-alkyl;
R10 represents Ci-C4-alkyl; or
R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 6-membered heterocycloalkyl group;
R11 represents hydrogen, methyl, -(CO)OR7;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. In another embodiment, component A is a compound selected from:
4- [(2-(morpholin-4-yl)- 8- [2H-pyrazol-3-yl] - [ 1 ,7]--naphthyridine-4-yl]phenyl-N- ethoxycarbonyl-S-methylsulphoximide
4- [(2-(morpholin-4-yl)- 8-(2H-pyrazol-3-yl)- [ 1 ,7]naphthyridine-4-yl]phenyl-S - methylsulphoximide
4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[4-(N,S-dimethylsulfonimidoyl)phenyl]-2-[morpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]-naphthyridine
4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride
dimethyl {4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl Jphosphonate
4-isopropenyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2- (morpholin-4-yl)-4-phenyl-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
3- [(2-(morpholin-4-yl)- 8- [2H-pyrazol-3-yl] - [ 1 ,7]naphthyridine-4-yl]phenyl-N- ethoxycarbonyl-S-methylsulphoximide 4-(l -methyl- l,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)- 1,7- naphthyridine
4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- (morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-l,7-naphthyridine 4-cyclopropyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
3- [(2-(morpholin-4-yl)- 8-(2H-pyrazol-3-yl)- [ 1 ,7]naphthyridine-4-yl]phenyl-S - methylsulphoximide
4-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride
4- [2-(methylsulfonyl)- 1 ,3-thiazol-4-yl] -2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
4- [2-(mo holirl-4-yl)-8-(lH-pyrazol-5-yl)-l,7-rlaphthyridirl-4-yl]pyridirl-2(lH)-orle
5- [2-(mo holirl-4-yl)-8-(lH-pyrazol-5-yl)-l,7-rlaphthyridirl-4-yl]pyridirl-2(lH)-orle 4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-4- { 4-[S-(propan-2-yl)sulfonimidoyl]phenyl }-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)- [l,7]naphthyridine
2- ((R)-3-methylmorpholin-4-yl)-4-phenyl-8-(2H-pyrazol-3-yl)- [1,7] naphthyridine
4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)- [ 1 ,7] naphthyridine
4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[ 1,7] -naphthyridine 4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
3- [2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
4- methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]- [l,7]naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine-4-carbonitrile
2-((R)-3-methylmorpholin-4-yl)-8-(-2H-pyrazol-3-yl]-[l ,7]naphthyridine-4-carbonitrile
2-morpholin-4-yl-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine-4-carboxamide
4-methanesulphonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine
[2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]methanol
4-(l-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)- [ 1 ,7] naphthyridine
4-isopropoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(lH-pyrrol-2-yl)-l,7-naphthyridine
4-[3-(S-methylsulfonimidoyl)propoxy]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-ethoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-methoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-methyl-l-{ [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]oxy }propan-2-ol
2- (morpholin-4-yl)-8-(lH^yrazol-5-yl)-4-(tetrahydroi iran-2-ylmethoxy)-l,7-naphthyridine
3- { [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]oxy}dihydrofuran-2(3H)- one
4- [(3-methyl- 1 ,2-oxazol-5-yl)methoxy] -2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)- 1 ,7- naphthyridine
4-[(5-methyl- 1 ,2-oxazol-3-yl)methoxy] -2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)- 1 ,7- naphthyridine
4-benzyloxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l, 7] naphthyridine
4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l, 7] naphthyridine tert-butyl [4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl }oxy)butyl] carbamate
4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine tert-butyl [3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)propy 1] carbamate 2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)eth an amine
tert-butyl [2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)ethyl] carbamate
4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}oxy)butan-
1 - amine
2- [(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride
4-chloro-2-morpholin-4-yl- 8-( 1 H-pyrazol-3-yl)- [ 1 ,7] naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfanyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-l,4 4- oxathian-4-imine 4-oxide
4-{ [dimethyl(oxido)- λ 6-sulfanylidene] amino }-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)- 1,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(piperazin-l-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(lH-pyrrol-3-yl)-l,7-naphthyridine
4-(l-ethyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-methyl-lH-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- { 2- [(3R)-3-methylmorpholin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl] aniline
4-(2,3-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine 4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl) - 1 ,7 -naphthyridine
4-fluoro-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl] aniline
4-(l-benzyl-lH-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-l,3-thiazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine
4-(l-cyclopropyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[2-fluoro-4-(piperazin-l-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-l-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
N-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
(l-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}piperidin-4- yl)methanol
N-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
4-(5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine
N-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(2-fluoro-4-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrrol-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoro-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-methoxy-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-(6-fluoro-2-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- [(3R)-3-methylmorpholin-4-yl] -4- [ 1 -methyl-3-(trifluoromethyl)- 1 H-pyrazol-5-yl] -8-( 1 H- pyrazol-5-yl)- 1,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-2-thienyl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-2-thienyl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-3-thienyl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-chloro-2-thienyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-3-thienyl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,7- naphthyridine
4-(3,5-dimethyl-l,2-oxazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(3-chloro-2-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-l,7- naphthyridine
4-(3,6-dihydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylpiperidin-l-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-tert-butyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-l,2-oxazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-(l,4-dimethyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine
4-[2-methyl-6-(S-methylsulfonimidoyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8- (lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-propyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine
4-[l-ethyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7 -naphthyridine
methyl 5-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH- pyrrole-2-carboxylate
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2-thiazol-5-yl)-l,7-naphthyridine N,N-dimethyl-2-{2 (3R)-3-methylmoφholin -yl]-8 m yrazol-5-yl) J-naphthyridin-4- yl} aniline
4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-isopropyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
ethyl methyl { 2- [(3R)-3-methylmc^holin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yljphosphinate
4- { [diethyl(oxido)- λ 6-sulfanylidene] amino } -2-[(3R)-3-methylmoφholin-4-yl]-8-( 1H- pyrazol-5-yl)- 1,7-naphthyridine
isobutyl methyl} 2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yljphosphinate
2- {2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}propan-2-ol
3- {2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pentan-3-ol 4-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
5- fluoro-2- { 2-[(3R)-3-methylmoφholin-4-yl] -8-( lH-pyrazol-5-yl)- l,7-naphthyridin-4- yl} aniline
4- [2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7-naphthyridine
2- [(3R)-3-methylm(^holin-4-yl] -4- [ 1 -(oxetan-3-yl)- 1 H-pyrazol-5 -yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[2-fluoro-4-(pyrrolidin-l-yl)phenyl]-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7 -naphthyridine
4-[3-(methoxymethyl)-5-methyl-l,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7-naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(5-methyl-l,3,4-oxadiazol-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N- { 2- [(3R)-3-methylmorpholin-4-yl] - 8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl } tetrahydro- lH-l 4-thiophen-l-imine 1 -oxide
4- { [(4-fluorophenyl)(methyl)oxido- λ 6-sulf anylidene] amino } -2- [(3R)-3-methylmorpholin-4- yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, mixture of 2 diastereoisomers
4- { [(2-fluorophenyl)(methyl)oxido- λ 6-sulf anylidene] amino } -2- [(3R)-3-methylmorpholin-4- yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, mixture of 2 diastereoisomers
4-{ [(R)(2-fluorophenyl)(methyl)oxido- λ6-sulfanylidene]amino}-2-[(3R)-3- methylmorpholin-4-yl] -8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridine, diastereoisomer
4-{ [(S)(2-fluorophenyl)(methyl)oxido- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin- 4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, diastereoisomer
4-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(diethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
ethyl isobutyl{2-[(3R)-3-methylmo holirl-4-yl]-8-(lH-pyrazol-5-yl)-l,7-rlaphthyridirl-4- yljphosphinate
2- [(3R)-3-methylmo holin-4-yl]-4-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-rlaphthyridirle 4-(l-isobutyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4- [5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholiri-4-yl]-8-(lH-pyrazol-
5- yl) - 1 ,7 -naphthyridine
4-[(3R)-3-methylmoφholin-4-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-rlaphthyridirle 2-[(3R)-3-methylmoφholin-4-yl]-4-(4-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7-naphthyridine
4-[4-(isopropylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-ethyl-lH-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
1 - { 2- [(3R)-3-methylmorpholin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl Jprolinamide
3- {2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pyridin-2- amine
2 (3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[l-(2,2,2-trifluoroethyl)-lH-pyrazol- 5-yl] - 1 ,7-naphthyridine
1- methyl -{2 (3R)-3-methylmorpholin-4-yl]-8^m^yrazol-5-yl)-l,7-naphthyridin-4- yl}piperazin-2-one
4-[l-(2-fluoroethyl)-lH-pyrazol-3-yl]-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[l-(2-fluoroethyl)-lH-pyrazol-5-yl]-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-(3-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH- pyrazol- 1 -yl)ethanol
2- methyl-l-(3-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } - 1 H-pyrazol- 1 -yl)propan-2-ol
4-[(2R)-2-methylmoφholin-4-yl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(6-methylpyridin-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- [(3R)-3-methylmoφholin-4-yl]-4-(3-methylpyridin-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl }phenyl)acetamide
3- {2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pyridin-2-ol
2-(3-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}phenyl)propan-2-ol
4- (5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[(2S)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(difluoromethoxy)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]propan-2-ol
2-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-4-(pyrrolidin-l-yl)-l,7-naphthyridine
4-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperazin-2-one
4-(dimethylphosphoryl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[(trans)-2,5-dimethylpiperazin-l-yl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[(cis)-3,5-dimethylpiperazin-l-yl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
1- [2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-3- (trifluoromethyl)azetidin-3-ol
methyl hydrogen {4-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl}phosphonate
4-(4-methylpiperazin- 1 -yl)-2-(mc^holin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine
2- (morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[(3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol- 5(3H)-yl]- 1,7 -naphthyridine
4-(3-methoxy-3-methylazetidin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N,N-dimethyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2- amine
4-(2-methylpyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
1 - { 2- [(3R)-3-methylmorpholin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yljcyclohexanol
2-fluoro-6- { 2-[(3R)-3-methylmoφholin-4-yl] -8-( lH-pyrazol-5-yl)- l,7-naphthyridin-4- yl} aniline (methyl} 4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}oxido- λ6- sulfanylidene)cyan amide
1 -ethyl-3-(methyl { 4- [2-(morpholin-4-yl)- 8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl]phenyl } oxido- λ 6-sulf anylidene)urea
3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl }oxy)propan- 1 -amine
4-(4-cyclopropyl-lH-l,2,3-triazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7-naphthyridine
4-ethylsulfinyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-[propan-2-ylsulfinyl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[3-(methylsulfonyl)propoxy]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-4-(phenylsulfonyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-(propan-2-ylsulfonyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(ethylsulfonyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-(phenylsulfinyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(methylsulfinyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-oxidotetrahydro-2H-thiopyran-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7-naphthyridine
4-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4,8-di(lH-pyrazol-5-yl)-l,7-naphthyridine
N,N-dimethyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
2-(morpholin-4-yl)-4-(phenylsulfanyl)-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine
2-(morpholin-4-yl)-N-(propan-2-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine 4-(ethylsulfanyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine
2-(morpholin-4-yl)-4-(propan-2-ylsulfanyl)-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrol-2-yl)- 1,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrol-3-yl)- 1,7-naphthyridine 4-[(4-methoxyphenyl)sulfanyl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-methyl-lH-pyrazol-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine l-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyrrolidin-2-one
4-(l , 1-dioxido- l,2-thiazolidin-2-yl)-2-(morpholiii-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
1- [2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-2-one
2- [(3R)-3-methylmoφholin-4-yl]-4-(2-methylpyridin-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(lH-pyrazol-5-yl)- 1,7 -naphthyridine
4-(2-methoxypyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- (mo holin-4-yl)-8-(lH-pyrazol-5-yl)-4-(pyridin-4-yl)-l,7-naphthyridine
4-[(4-methoxyphenyl)sulfanyl]-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4- [3-fluoro-2-(morpholin-4-yl)pyridin-4-yl] -2- [(3R) -3-methylmorpholin-4-yl] - 8-( 1 H- pyrazol-5-yl)- 1,7 -naphthyridine
4-(6-fluoro-5-methylpyridin-3-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
3- [2-(moφholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl]- 1 ,3-oxazinan-2-one 3-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-l,3-oxazolidin-2-one
4- (3-methoxypyridin-4-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2,6-dirluoropyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(5-chloro-2-fluoropyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-fluoropyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-chloro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(5,6-dimethylpyridin-3-yl)-2 (3R)-3-methylmorpholin-4-yl]-8-(m-pyrazol-5-yl)-l,7- naphthyridine
4-(5-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methylthiophen-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-methoxythiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-chlorothiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(isoquinolin-4-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-chlorothiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(4-methylthiophen-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4- (2,5-dimethylthiophen-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-thiopyran-4-yl)-l,7- naphthyridine
2 (3R)-3-methylmoφholin-4-yl]-4-(l-methyl-l,2,5,6-tetrahydropyridin-3-yl)-8-(lH-pyrazol-
5- yl) - 1 ,7 -naphthyridine
2-[(3R)-3-methylmc^holin-4-yl]-4-(l -methyl- 1,2, 3,6-tetrahydropyridin-4-yl)-8-(lH-pyrazol- 5-yl) - 1 ,7 -naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-[l-methylpiperidin-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[l-(tetrahydro-2H-pyran-4-yl)-lH- pyrazol-3-yl]- 1,7 -naphthyridine
4-(4,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l,3-dimethyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l,5-dimethyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmo holin-4-yl]-4-(piperidin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2 (3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[3-(trifluoromethyl)-lH-pyrazol-4- yl] - 1 ,7 -naphthyridine
4-(l-cyclobutyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-cyclopropyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-[l-(propan-2-yl)-lH-pyrazol-4-yl]-8-(lH-pyrazol-5-yl)- 1,7 -naphthyridine
4-[l-(difluoromethyl)-lH-pyrazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7 -naphthyridine
4-(l-tert-butyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)- 1 ,7 -naphthyridine
2- [(3R)-3-methylm(^holin-4-yl] -4- [ 1 -methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl] -8-( 1 H- pyrazol-5-yl)- 1,7 -naphthyridine
2-(4-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH- pyrazol-l-yl)ethanol
4-(l-ethyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(l-methyl-lH-pyrrol-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-[l-(propan-2-yl)-lH-pyrazol-3-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2,5-trimethyl-lH-pyrrol-3-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-phenyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
2-[(3R)-3-methylmoφholin-4-yl]-4-[l-(2-methylpropyl)-lH-pyrazol-4-yl]-8-(lH-pyrazol-5- yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmoφholin-4-yl]-4-(l,3-oxazol-2-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(1 -dimethyl-lH-pyrazol-4-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(l,5-dimethyl-lH-pyrazol-4-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)-l,7- naphthyridine
4-{ [(2-methoxyethyl)(methyl)oxido- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmoφholin-4- yl] - 8 -( 1 H-pyrazol-5 -yl) - 1 ,7 -naphthyridine
4-{ [(4-bromophenyl)(oxido)propan-2-yl- λ 6-sulfanylidene] amino }-2-[(3R)-3- methylmorpholin-4-yl] -8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridine
2-(methyl-N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } sulf onimidoyl)phenol
4-{ [(4-bromophenyl)(methyl)oxido- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmoφholin-4- yl] - 8 -( 1 H-pyrazol-5 -yl) - 1 ,7 -naphthyridine
4-{ [tert-butyl(methyl)oxido- λ 6-sulfanylidene]amino}-2-[(3R)-3-methylmoφholin-4-yl]-8- (1 H-pyrazol-5-yl) - 1 ,7 -naphthyridine
formic acid - N-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-l,4 4- oxathian-4-imine 4-oxide (1 : 1)
N-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]hexahydro-l 4-thiopyran- 1-imine 1 -oxide
3-methyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}butan-2-ol 1 - { 2- [(3R)-3-methylmorpholin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl } - 1 - (tetrahydro-2H-pyran-4-yl)ethanol
3,3-dimethyl-2- { 2- [(3R)-3-methylmorpholin-4-yl] -8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl}butan-2-ol
2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}hexan-2-ol
2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-3-yl)-l,7-naphthyridine-4-carboxamide
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-(methylsulfonyl)cyclopropyl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2- (morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)-l,7- naphthyridine
N,N-dimethyl-3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
{4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}(piperidin-l- yl)methanone
N,N-dimethyl-2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide N-cyclopropyl-4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide 4-(4-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(lH-indol-6-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(lH-indol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
3- [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benz amide
4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
N-methyl-3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
4- (3-fluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-chlorothiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[2-(trifluoromethyl)phenyl]-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[4-(trifluoromethyl)phenyl]-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[3-(trifluoromethyl)phenyl]-l,7-naphthyridine 4-(3-chlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N- { 3- [2-(morpholin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl]phenyl } acetamide 4-(3-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,5-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(3-methylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(furan-2-ylmethyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2,6-dimethyl-4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenol 4-(23-dimethylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine {3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}methanol 4-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-fluoro-3-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2-methylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,3-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N,N-dimethyl-3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl] aniline
N,N-dimethyl-2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl] aniline
N- { 2- [2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl]phenyl } methanesulfonamide
N- { 4- [2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl]phenyl} methanesulfonamide
N,N-dimethyl-4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
2-(morpholin-4-yl)-4- [( 1 E)-prop- 1 -en- 1 -yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine
4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenol
4-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
{3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}(piperidin-l- yl)methanone
2-(morpholin-4-yl)-4-[4-(propan-2-yl)phenyl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N-cyclopropyl-3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benz amide 4-(biphenyl-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2,4-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2-chlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,5-dimethylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]aniline
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[3-(lH-pyrazol-l-yl)phenyl]-l,7-naphthyridine
3- [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenol
4- (2-fluoro-5-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(5-fluoro-2-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2,4-difluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2,3-difluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,6-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]aniline
4-(3,5-dichlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(biphenyl-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-chloropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(l-benzothiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(l -methyl- lH-pyrazol-5-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(pyridin-3-yl)-l,7-naphthyridine
4-(2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-3-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-[l-(phenylsulfonyl)-lH-indol-2-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
{5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]thiophen-2-yl}methanol 4-(2-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-chloro-6-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(isoquinolin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-chloropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-fluoropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,6-difluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(l -methyl- lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine tert-butyl 5-methoxy-2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-lH- indole- 1 -carboxylate
2-(morpholin-4-yl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(4-methylthiophen-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(thiophen-2-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(thiophen-3-yl)-l,7-naphthyridine
4-(3-methylthiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-chloro-5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(5-chloro-2-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
tert-butyl 5-methyl-2- [2-(morpholin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl] - 1 H- indole- 1 -carboxylate
4-(5-chloro-2-fluoropyridin-3-yl)-2-(morpholiri-4-yl)-8-(lH-pyrazol-5-yl)-l,7-riaphthyridirie 4-(3,5-dimethyl-l,2-oxazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-riaphthyridirie 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-8-yl)-l,7-naphthyridine
4-(5-methylthiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-riaphthyridirie 4-(6-ethoxypyridin-3-yl)-2-(morpholiri-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2-ethoxypyridin-3-yl)-2-(morpholiri-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-6-yl)-l,7-naphthyridine
4- (2-chlorothiophen-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
5- [2-(mo holin-4-yl)-8-(lH yrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-amine
2-(morpholin-4-yl)-4-(lH-pyrazol-3-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- (l -methyl- lH-pyrrol-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
5- [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-ol
4-(5-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-chloro-2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-chlorothiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[2-(methylsulfanyl)pyrimidin-5-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N-cyclopropyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]pyrimidin-
2-amine
4-(isoquinolin-5-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-methyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridine-2- carboxamide
N-tert-butyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridine-3- carboxamide
4-[5-(methylsulfanyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2- (morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,7-naphthyridine
3- [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-amine methyl 4-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]thiophene-2- carboxylate
4- [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(mo holin-4-yl)-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(5-chloro-6-ethoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine 4-(l-tert-butyl-lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-4-(piperidin-l-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-4-ol
N-methyl-2-(morpholin-4-yl)-N-phenyl-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
{ l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyrrolidin-2-yl}methanol N-methyl-2-(morpholin-4-yl)-N-propyl-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-amine 4-(azepan-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-methylpiperidin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(4-methylpiperidin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
1- [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]piperidine-3-carboxamide
4-(2,5-dihydro-lH-pyrrol-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,4-dihydroquinolin-l(2H)-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(13-dihydro-2H-isoindol-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2- (morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[l,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl]-l,7- naphthyridine
tert-butyl l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-prolinate N-methyl-N-(2-methylpropyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- amine
N-(3-fluorophenyl)-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- amine
4-(l,l-dioxido-l-thia-6-azaspiro[3.3]hept-6-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-fluoropiperidin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-(2-fluorophenyl)-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- amine
l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-prolinamide { l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-4-yl}m
4-(4-memoxypiperidin- 1 -yl)-2-(morphoK^
N-(4-fluorophenyl)-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin amine
N-methyl-l-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-prolinamide
4-[4-(ethylsulfonyl)piperazin-l-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[4-(methylsulfonyl)piperazin- 1 -yl] -2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
N-cyclopropyl-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
N-(2,2-dimethylpropyl)-N-methyl-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin- 4-amine
{ l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-3-yl}methanol or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
The synthesis of the compounds of general formula (I) or (lb) of component A listed above is described in International Patent Publication WO2016020320 (Al). In a preferred embodiment, component A of the combination of the present invention is 2-[(3R)- 3-methylmorpholin-4-yl] -4-( 1 -methyl- 1 H-pyrazol-5-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine ("Compound A" in the following), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. In another preferred embodiment, component A of the combination of the present invention is Compound A of structur
Figure imgf000043_0001
The synthesis of Compound A is described in Example 111 of WO2016020320 (Al).
The term "pharmaceutically acceptable salt" of component A 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," /. Pharm. Sci. 1911 , 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Representative salts of a component A of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially with component B and optionally component C as further described infra. The components A and B and optionally C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
COMPONENT B OF THE COMBINATION
Component B of the combination of the present invention is an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
According to another embodiment of the aspects of the present invention, component B is an antiandrogen selected from bicalutamide, enzalutamide, apalutamide, ODM-201, ORM-15341 and abiraterone, particularly abiraterone acetate.
According to a preferred embodiment of the aspects of the present invention, component B is an antiandrogen selected from enzalutamide and ODM-201. Androgen receptor (AR) antagonists compete with the natural androgens such as testosterone and its more active metabolite dihydrotestosterone (DHT) for binding to the AR in the prostate gland and in other tissues:
Cyproterone acetate (abbreviated as CPA) is an antiandrogen and progestogen that is used in the treatment of androgen-related conditions like acne, hirsutism, early-onset puberty, and prostate cancer, as a component of hormone therapy for transgender women, and in oral contraceptives [F. Neumann, J. Kalmus: Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience. Exp. Clin. Endocrinol. 98, 71-80, 1991].
Bicalutamide is a non-steroidal antiandrogen that is primarily used to treat castration-resistant prostate cancer (CRPC). It is typically used after androgen deprivation therapy by a gonadotropin-releasing hormone (GnRH) analogue or by surgical removal of the testicles to treat metastatic CRPC [Y. Fradet: Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev. Anticancer 4, 37-48, 2004].
Flutamide is a non-steroidal antiandrogen used primarily to treat metastatic CRPC [R.N. Brogden, P. Chrisp: Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer. Drugs Aging 1, 104-115, 1991].
Nilutamide is a non-steroidal antiandrogen used in the treatment of metastatic CRPC [E.J. Dole, MT Holdsworth: Nilutamide: an antiandrogen for the treatment of prostate cancer. Ann. Pharmacother. 31, 65-75, 1997]. Enzalutamide is a second-generation antiandrogen used to treat metastatic CRPC [R.M. Bambury, H.I. Scher: Enzalutamide: Development from bench to bedside. Urol. Oncol. 33, 280- 288, 2015]. Enzalutamide may also be effective in the treatment of certain types of breast cancer [A. Gucalp, T.A. Traina: Targeting the androgen receptor in triple-negative breast cancer. Curr. Probl. Cancer 40, 141-150, 2016].
Apalutamide (developmental code name ARN-509, also JNJ-56021927) is a second-generation antiandrogen that is under clinical development for the treatment of prostate cancer [D.E. Rathkopf, E.S. Antonarakis et al.: Safety and antitumor activity of apalutamide (ARN-509) in metastatic castration-resistant prostate cancer with and without prior abiraterone acetate and prednisone. Clin. Cancer Res. DOI: 10.1158/1078-0432.CCR-16-2509, 2017].
ODM-201 (also known as darolutamide, BAY 1841788 or N-((S)-l-(3-(3-Chloro-4- cyanophenyl)-lH-pyrazol-l-yl-)-propan-2-yl)-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide) is a non-steroidal AR antagonist that has demonstrated significant antitumor activity in different prostate cancer models. It is a mixture of two diastereomers ORM 16555 (also known as N- { (2S)- 1 - [3-(3-chloro-4-cy anophenyl)- 1 H-pyrazol- 1 -yl]propan-2-yl } -5- [( 1 S)- 1 -hydroxyethyl] - lH-pyrazole-3-carboxamide) and ORM 16497 (also known as N-{(2S)-l-[3-(3-chloro-4- cyanophenyl)- 1 H-pyrazol- 1 -yl]propan-2-yl } -5- [( 1R)- 1 -hydroxyethyl] - 1 H-pyrazole-3- carboxamide). ORM-15341 (also known as 5-acetyl-N-{ (2S)-l-[3-(3-chloro-4-cyanophenyl)- lH-pyrazol-l-yl]propan-2-yl}-lH-pyrazole-3-carboxamide) is the main metabolite of ODM-201 and possesses similar pharmacological properties [A.J. Moilanen, R Riikonen, et al.: Discovery of ODM-201, a new generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci. Rep. 5, 12007, 2005]. ODM-201 is of structure
Figure imgf000047_0001
ORM-15341 is of structure:
Figure imgf000047_0002
EPI-506 is a non-steroidal antiandrogen in clinical trials for prostate cancer [G. Martinez- Ariza, C. Hulme: Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharm. Pat. Anal. 4, 387-402, 2015]. It is the successor of EPI-001 and targets the N- terminal domain of the androgen receptor (AR). This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants. EPI- 506 is a prodrug of EPI-002 [Y. Imamura, M.D. Sadar: Androgen receptor targeted therapies in castration-resistant prostate cancer. Int. J. Urol. 23, 654-665, 2016], one of the four stereoisomers of EPI-001 [J.K. Myung, C. Banuelos et al.: An androgen receptor N-terminal domain antagonist for treating prostate cancer. J. Clin. Invest., 123, 2948-2960, 2013]. Different blockers of androgen synthesis have been described. They inhibit the enzyme CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17a- hydroxy derivatives by its 17a-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity [D. Poubek: CYP17A1: a biochemistry, chemistry, and clinical review. Curr. Top. Med. Chem. 13, 1364-1384, 2013]. DHEA and androstenedione are precursors of the more potent androgens testosterone and dihydrotestosterone. Inhibition of CYP17 activity thus decreases circulating levels of active androgens. Abiraterone acetate is a steroidal androgen synthesis inhibitor which blocks the CYP17A1 enzyme. It is used in combination with prednisone for treatment of metastatic CRPC, before and after chemotherapy treatment. It is a prodrug of the active metabolite abiraterone. It also has some AR antagonist activity [E. Grist, R. Attard: The development of abiraterone acetate for castration-resistant prostate cancer. Urol. Ocol. 33, 289-294, 2015].
Seviteronel (developmental code VT-464; also known as (lS)-l-[6,7- bis(difluoromethoxy)naphthalen-2-yl]-2-methyl-l-(2H-triazol-4-yl)propan-l-ol) is a nonsteroidal CYP17A1 inhibitor and in clinical studies for prostate cancer. It also has some AR antagonist activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
Galeterone (TOK-001 or VN/ 124-1, also known as (3S,8R,9S,10R,13S,14S)-17-(benzimidazol- l-yl)-10,13-dimethyl-2,3,4,7,8,9,l l,12,14,15-decahydro-lH-cyclopenta[a]phenanthren-3-ol ) is a steroidal antiandrogen under clinical development for the treatment of prostate cancer. It possesses a dual mechanism of action, acting as both an AR antagonist and a CYP17A1 inhibitor activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
Orteronel (TAK-700, also known as 6-(7-Hydroxy-6,7-dihydro-5/i-pyrrolo[l,2-c]imidazol-7- yl)-/V-methylnaphthalene-2-carboxamide) is a non-steroidal CYP17A1 inhibitor which completed clinical trials for metastatic CRPC treatment activity [I.M. Bird, D.H. Abbott: The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136-146, 2016].
Ketoconazole has antiandrogenic activity through at least two mechanisms of action [T.A. Yap, CP. Carden et al.: Targeting CYP17: established and novel approaches in prostate cancer. Curr. Opin. Pharmacol.. 8, 449-457, 2008]. It blocks both testicular and adrenal androgen biosynthesis by inhibiting the 17a-hydroxylase and 17,20-lyase, thus leading to a reduction in circulating testosterone levels. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Secondly, ketoconazole is an AR antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the AR.
Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component B may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially with component A and optionally component C as further described infra. The components A and B and optionally C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
COMBINATION In accordance with another aspect, the present invention provides combinations of at least two components, preferably two components, component A and component B,
component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described infra, a compound of general formula (lb) described infra and Compound A described infra, and component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel. In accordance with another aspect, the present invention provides combinations of at least two components, preferably two components, component A and component B, component A being an inhibitor of ATR kinase, particularly Compound A, or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen, particularly an antiandrogen selected from bicalutamide, enzalutamide, apalutamide, ODM-201, ORM-15341 and abiraterone acetate.
In accordance with another aspect, the present invention covers a combination of any component A mentioned herein with any component B mentioned herein, optionally with any component C mentioned herein.
The combinations comprising at least two components A and B, preferably two components, as described and defined herein, are also referred to as "combinations of the present invention".
The surprising behavior of a combination of the present invention is demonstrated herein with one of the ATR kinase inhibitors ("Compound A") specifically disclosed in the Examples section. In addition, a combination of the present invention comprising Compound A and enzalutamide is a preferred aspect of the invention. Further, a combination of the present invention comprising Compound A and ODM-201 is another preferred aspect of the invention.
Further, the present invention covers a kit comprising:
component A: one or more, preferably one, ATR kinase inhibitor(s) as described supra, particularly Compound A or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
component B: an antiandrogen, or combinations of antiandrogens, as described supra.
In the kit optionally either or both of said components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components A and B may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Preferably components A and B are administered by the oral route.
Further, the present invention covers a kit comprising:
component A: one or more, preferably one, ATR kinase inhibitor(s) as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
component B: an antiandrogen, or combinations of antiandrogens, as described supra; and, optionally,
component C: one or more, preferably one, further pharmaceutical agent(s),
in which optionally either or all of said components A, B and C in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components A and B, optionally C, may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
The term "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 pharmaceutical composition comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers. A list of such pharmaceutical agents of component C is being provided further below.
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 where the resulting combination of components A, B and C causes no unacceptable adverse effects. For example, 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.
Optional pharmaceutical agents which can be added as component C to the combination of components A and B can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydro xycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-221, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3] -octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin or combinations thereof.
Generally, the use of pharmaceutical 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,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Further, the present invention covers a pharmaceutical composition comprising a combination of the present invention as described herein together with one or more pharmaceutically acceptable excipients.
Further, the present invention covers a pharmaceutical composition comprising a combination of at least two components, particularly of two components, component A and component B, component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, together with one or more pharmaceutically acceptable excipients.
Further, the present invention covers a pharmaceutical composition comprising a combination of at least two components, particularly of two components, component A and component B, component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being an antiandrogen as described supra; optionally with any component C mentioned herein, together with one or more pharmaceutically acceptable excipients.
A preferred aspect of the present invention covers a pharmaceutical composition comprising a combination of at least two components, particularly of two components, component A and component B, component A being Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and component B being ODM- 201 (=darolutamide) or enzalutamide, together with one or more pharmaceutically acceptable excipients.
In another embodiment the components A and B, and optionally component C, are present in separate formulations.
In another embodiment the components A and B, and optionally component C, are present in a joint formulation. Pharmaceutically acceptable excipients are non-toxic, preferably they are non-toxic and inert. Pharmaceutically acceptable excipients include, inter alia,
• fillers and excipients (for example cellulose, microcrystalline cellulose, such as, for example, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for example, Di-Cafos®),
· ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat)
• solvents (for example water, ethanol, Isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
· surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyle sulphate, lecithin, phospholipids, fatty alcohols such as, for example, Lanette®, sorbitan fatty acid esters such as, for example, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example,
Cremophor®, polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such as, for example, Pluronic®),
buffers and also acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine)
isotonicity agents (for example glucose, sodium chloride),
adsorbents (for example highly-disperse silicas)
viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine),
disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®),
flow regulators, lubricants, glidant and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®),
capsule materials (for example gelatine, hydroxypropylmethylcellulose),
synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
penetration enhancers,
stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
flavourings, sweeteners, flavour- and/or odour-masking agents. Further excipients and procedures are 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), 238-311 ; 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.
The components A, B and C may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Components A, B and C are preferably administered orally.
The pharmaceutical composition (formulation) varies by the route of administration. 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. 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 from 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.
Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a pharmaceutically 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-l,l-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 surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. 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.
The parenteral 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.
Illustrative of 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 of the present invention 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 sorbitan monooleate.
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. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, 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. Such materials are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). 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 11, 1991, incorporated herein by reference). Such 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.
It 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. 5,011,472, issued April 30, 1991. In accordance with another aspect, the present invention concerns the use of the combination of the present invention as described supra for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra and/or metastases thereof, preferably metastases in bone.
In accordance with another aspect, the present invention concerns the combination of the present invention as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
In accordance with another aspect, the present invention concerns the kit as described supra for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
In accordance with another aspect, the present invention concerns the kit as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
In accordance with another aspect, the present invention concerns the pharmaceutical composition as described supra for the treatment or prophylaxis of a disease, preferably a hyper- proliferative disease as described infra. In accordance with another aspect, the present invention concerns the pharmaceutical composition as described supra for use in the treatment or prophylaxis of a hyper-proliferative disease as described infra, particularly of prostate cancer, preferably in the treatment of castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC).
In accordance with another aspect, the present invention covers the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
In accordance with another aspect, the present invention covers the use of such kit as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra. In accordance with another aspect, the present invention covers the use of such pharmaceutical composition as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra.
In accordance with another aspect, the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra using an effective amount of the combination of the present invention as described supra. In accordance with another aspect, the present invention concerns methods for the treatment and/or prophylaxis of a disease, preferably a hyper-proliferative disease as described infra using an effective amount of the kit or pharmaceutical composition as described supra.
In accordance with another aspect, the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising
a) administering component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
In accordance with another aspect, the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising
a) administering component A being an inhibitor of ATR kinase as described supra, particularly Compound A, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, wherein components A and B are administered simultaneously, concurrently, separately or sequentially.
In accordance with another aspect, the present invention concerns a method of treating a hyper- proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
a) administering Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen selected from enzalutamide and
ODM-201.
In accordance with another aspect, the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
a) administering Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen selected from enzalutamide and ODM-201, wherein Compound A and component B are administered concurrently.
In accordance with another aspect, the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
a) administering Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen selected from enzalutamide and ODM-201, wherein Compound A is administered prior to component B.
In accordance with another aspect, the present invention concerns a method of treating a hyper - proliferative disease as described infra, particularly of treating breast cancer or prostate cancer, preferably of treating castration-resistant prostate cancer (CRPC) or of metastatic hormone sensitive prostate cancer (mHSPC), comprising
a) administering Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen selected from enzalutamide and ODM-201, wherein component B is administered prior to Compound A. In accordance with another aspect, the present invention concerns a method of treating a disease in a patient, preferably a hyper-proliferative disease as described infra comprising a) administering component A being an inhibitor of ATR kinase as described supra, particularly Compound A or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and
b) administering component B being an antiandrogen as described supra, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel; and optionally
c) administering component C being a pharmaceutical agent as described supra.
The combinations, kits or pharmaceutical compositions of the present invention thus can be used for the treatment or prophylaxis of hyper-proliferative diseases, including 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 tumors and/or metastases thereof, solid tumors, and/or metastases thereof, e.g. leukemias, multiple myeloma thereof and myelodysplastic syndrome, malignant lymphomas, breast tumors including and bone metastases thereof, tumors of the thorax including non-small cell and small cell lung tumors and bone metastases thereof, gastrointestinal tumors, endocrine tumors, mammary and other gynaecological tumors and bone metastases thereof, urological tumors including renal, bladder and prostate tumors, skin tumors, and sarcomas, and/or metastases thereof.
The term "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, kits or pharmaceutical compositions 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 and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the hyper-proliferative disease.
Hyper-proliferative diseases include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non- Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ, particularly with bone metastases.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS -related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These diseases have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
Combinations of the present invention might also be used for treating diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastases. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastases and the consequence spread of the cancer. Thus, combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis diseases, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
The term "prostate cancer" as used herein means any histology type of prostate cancer including but not limited to acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urothelial) cancer, squamous cell cancer, carcinoid, small cell cancer, sarcomas and sarcomatoid cancers, particularly acinar adenocarcinoma, metastatic hormone sensitive prostate cancer (mHSPC), castration resistant prostate cancer (CRPC), particularly stage MO castration-resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC).
The terms "MO" and "Ml" (including Mia, Mlb, Mlc) are used in accordance with the "TNM staging system" for prostate cancer developed by the American Joint Committee on Cancer as further described in "TNM CLASSIFICATION OF MALIGNANT TUMORS", 7th edition Edited by James D. Brierley, Mary K. Gospodarowicz, Christian Wittekind, Published by UICC 2011.
According to said TNM classification and as used herein the term "MO CRPC" means that there are no distant metastases and that the CRPC has not spread to other parts of the body. The term "Ml CRPC" as used herein means that there are distant metastases and that the CRPC has spread to distant parts of the body.
In particular, the present invention covers the treatment of prostate cancer, particularly the treatment of metastatic hormone sensitive prostate cancer (mHSPC) or of castration-resistant prostate cancer (CRPC).
In another embodiment the combination/kit/pharmaceutical composition of the present invention are used in the treatment of prostate cancer or breast cancer, particularly in the treatment of mHSPC, MO CRPC, Ml CRPC or breast cancer.
In another embodiment of the use of the combination/kit/pharmaceutical composition of the present invention, the castration resistant prostate cancer (CRPC) is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC). In another embodiment of the use of the combination/kit/pharmaceutical composition of the present invention the castration resistant prostate cancer (CRPC) is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC), and the subject to be treated is chemotherapy-naive.
The term "chemotherapy-naive" as used herein means that the subject, prior to the treatment with the combination/ kit/pharmaceutical composition of the present invention has not received a chemotherapy.
In another embodiment of the use of the combination/kit/pharmaceutical composition of the present invention the castration resistant prostate cancer (CRPC) is stage MO castration resistant prostate cancer (MO CRPC) or stage Ml castration-resistant prostate cancer (Ml CRPC), and the subject to be treated is a subject, wherein the subject has received a chemotherapy prior to the treatment with the combination/kit/pharmaceutical composition of the present invention.
The term "chemotherapy" as used herein means a category of cancer treatment that uses one or more chemotherapeutic agents as part of a standardized chemotherapy regimen. Chemotherapeutic agents are rather non-specific agents including but not limited to alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, nucleotide analogues, platinum-based agents, vinca alkaloids.
DOSE AND ADMINISTRATION
Component A
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative diseases and angiogenic diseases, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, 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 component 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 50 mg/kg body weight per day. Clinically useful dosing schedules of a compound will range from one to three times a day dosing to once every four weeks dosing. In addition, "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.
Component B
Component B being an antiandrogen, particularly an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM-15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel can be administered to a patient at a dosage which can range from about 1 to about 2000 mg per day.
Also, the agents can be administered in conventional amounts routinely used in cancer chemotherapy. Typically, the following treatments are used: 100 mg two or three times a day (cyproterone acetate), 50 mg daily (bicalutamide), 250 mg three times a day (flutamide), 150 or 300 mg daily (nilutamide), 160 mg daily (enzalutamide), 240 mg daily (apalutamide), 1000 mg daily (abiraterone), 600 mg twice a day (ODM-201), 200 or 400 mg three times a day (ketoconazole), 300 mg twice daily (orteronel). Of course 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 component B being an antiandrogen selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel, preferably for component B being enzalutamide or ODM-201, include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines in Oncology, Version 1.2014.
Further, suitable dose(s), administration regime(s) and administration route(s) for component B 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. For both, for the ATR kinase inhibitors, particularly Compound A, and for the antiandrogen 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 ATR kinase inhibitor and the antiandrogen can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection. Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques. The agents can be administered by any of the conventional routes of administration for these compounds. The preferred route of administration for the ATR kinase inhibitor and the antiandrogen is typically orally, which is the same route of administration used for each agent alone. Any of the antiandrogens described supra can be administered in combination with a compound of general formula (I) or (lb) described supra, particularly with Compound A, by any of the mentioned routes of administration.
For administering the ATR kinase inhibitor, particularly Compound A, and the antiandrogen by any of the routes of administration herein discussed, the ATR kinase inhibitor, particularly Compound A, can be administered simultaneously with the antiandrogen. This can be performed by administering a single formulation which contains both the ATR kinase inhibitor, particularly Compound A, and the antiandrogen. Alternatively, this can be performed by administering the ATR kinase inhibitor, particularly Compound A, and the antiandrogen in independent formulations at the same time to a patient.
Alternatively, the ATR kinase inhibitor described supra, particularly Compound A, can be administered in tandem with the antiandrogen. The ATR kinase inhibitor described supra, particularly Compound A, can be administered prior to the antiandrogen. For example, the ATR kinase inhibitor described supra, particularly Compound A, 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 antiandrogen described supra. Also, the antiandrogen as described supra can be administered first followed by adminstration of the ATR kinase inhibitor described supra, particularly Compound A. The choice of sequence administration of the ATR kinase inhibitor described supra, particularly Compound A, relative to the antiandrogen may vaiy for different agents. Also, the antiandrogen described supra can be administered using any regimen which is conventionally used for these agents.
In another regimen of administration, the ATR kinase inhibitor described supra, particularly Compound A, and the antiandrogen can be administered once or more times per day on the day of administration.
Any of the routes and regimens of administration may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
DESCRIPTION OF FIGURES
Figur 1 shows the tumor growth of human LAPC-4 prostate cancer xenografts in male C.B-17 scid mice after treatment with Compound A in combination with Compound B (A) or Compound C (B) in comparison to the respective monotherapies and control.
Legend for Figures 1 A and B: The abbreviation QD means once per day, 2QD means twice per day, p.o. means per os (orally). * P < 0.05, combination treatment compared to Compound B (A) or Compound C (B) monotherapy, one way ANOVA, Dunn's method, on tumor volumes. EXPERIMENTAL SECTION
Component A:
In this Experimental Section, the term "Compound A" is an example of component A. Compound A is described in Example 111 of International Patent Application WO2016020320 (Al). As shown herein Compound A is 2-[(3R)-3-methylmorpholin-4-yl]-4-(l- methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, of structure:
Figure imgf000071_0001
Compound A
Component B:
Compound B used in the Examples below is ODM-201(= Darolutamide)
Component C:
Compound C used in the Examples below is Enzalutamide.
Test system (Table 1)
Figure imgf000072_0001
VTT = Technical Research Centre of Finland Ltd.
fs: frame shift; del: deletion; *: stop codon; amp: gene amplification;
Example 1
In vivo xenotransplantation of human tumor
The anti-tumor activity of combination treatment of Compound A and Compound B (= ODM- 201) or Compound A and Compound C (= Enzalutamide) was evaluated in the human androgen - dependent prostate carcinoma model LAPC-4, xenografted into male CB-17 SCID mice (Janvier Labs, France). Animals were implanted with testosterone pellets (12.5 mg) and, three days later, inoculated subcutaneously with LAPC-4 tumor cells. At a mean tumor volume of 100 mm3 (day 25 after tumor inoculation) animals were randomized into treatment and control groups (n=l l animals/group) and treatment started with Compound A monotherapy (formulation: 60% PEG400/10% Ethanol/30% Water; application route: p.o./per os , orally; dose/schedule: 40 mg/kg twice daily for 3 days on/ 4 days off), Compound B monotherapy (formulation: 50% PEG400/30% Propylenglycol/20% Glucose (5%); application route: p.o.; dose/schedule: 100 mg/kg once daily every day), Compound C monotherapy (formulation: 10% NMP/90% PEG400; application route: p.o.; dose/schedule: 10 mg/kg once daily every day) and combination of Compound A and Compound B as well as combination of Compound A and Compound C at the same doses/schedules as in the respective monotherapies. The oral application volume was 10 ml/kg. The two applications of Compound A were performed 6-7 h apart. In the combinations groups, on the days where Compound A was applied, compounds B and C were given 2 hours post Compound A first treatment. Tumor size and body weight were determined at least twice weekly. Changes in the body weight were a measure of treatment- related toxicity (> 10% = critical, stop of treatment until recovery, > 20% = toxic, termination). The tumor size was measured twice a week with an electronic caliper gauge and tumor volume was calculated using the formula: [(length (mm) x width (mm) 2) / 2] . In vivo anti-tumor efficacy is presented as T/C ratio (Treatment/Control) based on the tumor volumes measured on day of termination of the control group, at day 51 after tumor inoculation. T/C is calculated according to the formula: [(mean tumor volume of treatment group on day 51) - (mean tumor volume of treatment group at start of treatment)] / [(mean tumor volume of control group on day 51) - (mean tumor volume of control group at start of treatment)]. Compounds having a T/C below 0.5 are defined as active (effective). Statistical significance was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control group were compared by a pair-wise comparison procedure (Dunn's method).
Treatment of monotherapy and combination groups was continued for another 52 days after termination of the control group and stopped on day 103 after tumor inoculation. Final tumor volumes of combination treatment groups were compared to the respective monotherapy values. Statistical analysis was assessed again using SigmaStat software. A one-way analysis of variance was performed and differences of combination to respective monotherapy groups were compared by a pair- wise comparison procedure (Dunn's method).
Results:
In the LAPC-4 prostate cancer model, monotherapy of Compound A showed weak anti-tumor efficacy upon the used dose. Monotherapy of Compound B showed good anti-tumor efficacy (T/C = 0.19), and statistically significance compared to the control group on day 51. Monotherapy of Compound C showed good anti-tumor efficacy also reaching statistical significance compared to the control group (T/C = 0.12). At the end of the study (day 103 after tumor inoculation), both combination treatments, Compound A with Compound B or Compound A with Compound C, showed improved anti-tumor efficacy compared to the respective monotherapies with statistical significance (P < 0.05) (Figures 1A and IB). All treatments were well tolerated with maximal mean body weight losses of 2-7% (Table 2). Table 2:
Anti-tumor activity of Compound A, Compound B or Compound C in monotherapy as well as combination of Compound A and Compound B or Compound A and Compound C based on tumor volumes in the human LAPC-4 prostate cancer xenograft model in male C.B-17 scid mice.
Figure imgf000074_0001
P < 0.05 (compared to control), one way ANOVA, Dunn's method, on tumor volumes * P < 0.05 (comparison of combination treatment vs respective monotherapy), one way ANOVA, Dunn's method, on tumor volumes
a) T/C = ratio of the tumor volume of treatment versus control group [(mean tumor volume of treatment group at day 51) - (mean tumor volume of treatment group at start of treatment)] / [(mean tumor volume of control group at day 51) - (mean tumor volume of control group at start of treatment)] .
b) Comparison of mean tumor volume of combination treatment group with respective
monotherapy group at study end (day 103).
c) Loss of body weight: mean percent change in body weight compared to the mean body weight at start of treatment (> 10% = critical, stop of treatment until recovery, > 20% = toxic, termination).
The abbreviation QD means once per day, 2QD means twice per day, p.o. means per os (orally).

Claims

1. A combination of at least two components, component A and component B, comprising a component A being an inhibitor of ATR kinase and component B being an antiandrogen.
2. The combination according to claim 1, in which said component B is selected from cyproterone acetate, bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, abiraterone, particularly abiraterone acetate, ODM-201, ORM- 15341, EPI-506, ketoconazole, seviteronel, galeterone and orteronel.
3. The combination according to claim 1, in which said component B is selected from bicalutamide, enzalutamide, apalutamide, abiraterone acetate and ODM-201.
The combination according to claim 1, in which said component B is selected from enzalutamide and ODM-201.
The combination according to any one of claims 1 to 4, in which said component A is selected fr AZD-6738 and a compound of general formula I:
Figure imgf000075_0001
(') , in which:
R1 represents a group selected from:
Figure imgf000075_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, Ci-Ce-alkyl, Ci-Ce-alkoxy, 3- to 10- membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl,
4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(S02)R9, -(SO)R9, -SR9, -(S02)NR7R8, -NR7(S02)R9, -((SO)=NRu)R10, - N=(SO)R9R10, -SiR10RuR12, -(PO)(OR7)2, -(PO)(OR7)R10 or -(PO)(R10)2, wherein each Ci-C6-alkyl, Ci-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, Ci-C6-alkyl optionally substituted one or more times with hydroxyl or phenyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, -(CO)OR7,
-(CO)NR7R8, -NR7(CO)R10, -NR8(CO)OR7, -NR8(CO) NR7R8, -(S02)R9, -(SO)R9, - SR9, -(S02)NR7R8, -NR7(S02)R9, -((SO)=NRu)R10, -N=(SO)R9R10, -(PO)(OR7)2, -(PO)(OR7)R10, -(PO)(R10)2 or with a heteroaryl group which is optionally substituted, one or more times, with G-C/t-alkyl;
wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with Ci-C t-alkyl;
R3, R4 represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or
R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from Ci-C6-alkyl, Ci-C6-haloalkyl, said 4-,
5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S;
R9 represents Ci-C t-alkyl or phenyl, wherein each Ci-C/t-alkyl or phenyl is optionally
substituted, one or more times, independently from each other, with R13;
R10 represents Ci-C/t-alkyl; or
R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered
heterocycloalkyl group;
R11 represents hydrogen, Ci-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN;
R12 represents hydrogen or Ci-C/t-alkyl;
R13 represents halogen, OH, -NR7R8, CN, N02, G-Ce-alkyl, G-Ce-haloalkyl, G-Ce-alkoxy, Ci-Ce-haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same.
6. The combination according to any one of claims 1 to 4, in which said component A is selected from VX-803, VX-970, AZD-6738 and a compound of formula (lb)
Figure imgf000077_0001
(lb) , in which
:
Figure imgf000077_0002
, wherein * indicates the point of attachment of said group with the rest of the molecule;
represents hydrogen, fluoro, chloro, CN, methyl, Ci-C/t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl, -(S02)R9, -SR9, -((SO)=NRu)R10, -N=(SO)R9R10, wherein each methyl, Ci-C t-alkoxy, C2-C3-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally substituted, one or more times, independently from each other, with fluoro, chloro, OH, -NR7R8, methyl, 5-membered heterocycloalkyl, -NR8(CO)OR7,
-(S02)R9, -((SO)=NRU)R10,-(PO)(OR7)2, or with a group selected from:
Figure imgf000077_0003
wherein * indicates the point of attachment of said group with the rest of the molecule;
wherein each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl;
R4 represents hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen or Ci-C/t-aikyl;
R9 represents Ci-C t-aikyl;
R10 represents Ci-C/t-aikyl; or
R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 6-membered heterocycloalkyl group;
R11 represents hydrogen, methyl, -(CO)OR7; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same.
7. The combination according to any one of claims 1 to 4, in which said component A is a compound selected from:
4-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[l,7]-inaphthyridine-4-yl]phenyl-N-ethoxycarbonyl- S-methylsulphoximide
4-[(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[4-(N,S-dimethylsulfonimidoyl)phenyl]-2-[morpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]-naphthyridine
4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride
dimethyl {4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl Jphosphonate
4-isopropenyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2- (morpholin-4-yl)-4-phenyl-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
3- [(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[l,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl- S-methylsulphoximide
4- (l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-l,7-naphthyridine 4-cyclopropyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
3- [(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
4- methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride 4-[2-(methylsulfonyl)-l,3-thiazol-4-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-(morpholiri-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridiri-4-yl]pyridiri-2(lH)-orie
5 - [2- (morpholin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] pyridin-2( 1 H) -one
4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- (mo holin-4-yl)-4-{4-[S-(propan-2-yl)sulforlimidoyl]pherlyl}-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)- [1,7] naphthyridine
2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine
4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)- [1,7] naphthyridine
4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]-naphthyridine
4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
3- [2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]phenyl-S- methylsulphoximide
4- methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]- [1,7] naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine-4-carbonitrile
2-((R)-3-methylmorpholin-4-yl)-8-(-2H-pyrazol-3-yl]-[l,7]naphthyridine-4-carbonitrile 2-morpholin-4-yl-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine-4-carboxamide
4-methanesulphonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[l, 7] naphthyridine [2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l,7]naphthyridine-4-yl]methanol 4-(l-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[l ,7]naphthyridine
4-isopropoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(lH-pyrrol-2-yl)-l,7-naphthyridine
4-[3-(S-methylsulfonimidoyl)propoxy]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-ethoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-methoxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-methyl-l-{ [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]oxy}propan-2-ol
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(tetrahydrofuran-2-ylmethoxy)-l,7-naphthyridine 3-{ [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]oxy}dihydrofuran-2(3H)-one
4-[(3-methyl-l,2-oxazol-5-yl)methoxy]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[(5-methyl-l,2-oxazol-3-yl)methoxy]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-benzyloxy-2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine tert-butyl [4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)butyl] carbamate
4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine tert-butyl [3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)propyl] carbamate
2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } oxy)ethan amine
tert-butyl [2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}oxy)ethyl]carbamate
4-( { 2-[(3R)-3-methylmorpholin-4-yl]-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl }oxy)butan- 1- amine
2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine hydrochloride
4-chloro-2-morpholin-4-yl-8-(lH-pyrazol-3-yl)-[l,7]naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfanyl)-8-(lH-pyrazol-5-yl)-l,7-riaphthyridirie
N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-l,4 4- oxathian-4-imine 4-oxide
4-{ [dimethyl(oxido)- λ 6-sulfanylidene] amino } -2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
2- [(3R)-3-methylmorpholin-4-yl] -4-(piperazin- 1 -yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine
4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-(lH-pyrazol-3-yl)-[l,7]riaphthyridirie
2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(lH-pyrrol-3-yl)-l,7-naphthyridine
4-(l-ethyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-methyl H midazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-riaphthyridiri-4-yl] aniline
4-(23-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7-naphthyridine
4 2-fluoro -(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-fluoro-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]aniline
4-(l-benzyl-lH-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-l,3-thiazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7-naphthyridine
4-(l-cyclopropyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-[2-fluoro-4-(piperazin- 1 -yl)phenyl] -2-[(3R)-3-methylmorpholin-4-yl] -8-( lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-l-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
(1 - { 2-[(3R)-3-methylmorpholin-4-yl]-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl }piperidin-4- yl)methanol
N-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
4-(5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
N-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridin-4-amine
2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluoro-4-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrrol-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoro-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-methoxy-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(6-fluoro-2-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-2-thienyl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-2-thienyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-3-thienyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-chloro-2-thienyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-3-thienyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,7- naphthyridine
4-(3,5-dimethyl-l,2-oxazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-chloro-2-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-l,7- naphthyridine
4-(3,6-dihydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylpiperidin-l-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-tert-butyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-l,2-oxazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-(l,4-dimethyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R^
yl)- 1,7-naphthyridine
4-[2-methyl-6-(S-methylsulfonimidoyl)pyr^
pyrazol-5-yl)- 1 ,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-propyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
4-[l-ethyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
methyl 5-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH- pyrrole-2-carboxylate
2- [(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2-thiazol-5-yl)-l,7-naphthyridine
N,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl} aniline
4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine
4-(l-isopropyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
ethyl methyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } phosphinate
4-{ [diethyl(oxido)- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7-naphthyridine
isobutyl methyl} 2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yljphosphinate
2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}propan-2-ol
3- {2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pentan-3-ol
4- (5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1,7- naphthyridine
5-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}aniline 4-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-(oxetan-3-yl)-lH-pyrazol-5-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-fluoro-4-(pyrrolidin-l-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[3-(methoxymethyl)-5-methyl-l,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-l,3,4-oxadiazol-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N-{2 (3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}tetrahydro-lH- l 4-thiophen-l -imine 1 -oxide
4-{ [(4-fluorophenyl)(methyl)oxido- λ6-sulfanylidene] amino }-2-[(3R)-3-methylmo holin-4-yl]- 8-(lH-pyrazol-5-yl)-l,7-naphthyridine, mixture of 2 diastereoisomers
4-{ [(2-fluorophenyl)(methyl)oxido- λ6-sulfanylidene] amino }-2-[(3R)-3-methylmoφholin-4-yl]- 8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridine, mixture of 2 diastereoisomers
4-{ [(R)(2-fluorophenyl)(methyl)oxido- λ6-sulfanylidene] amino }-2-[(3R)-3-methylmoφholin-4- yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, diastereoisomer
4-{ [(S)(2-fluorophenyl)(methyl)oxido- λ6-sulfanylidene] amino } -2-[(3R)-3-methylmoφholin-4- yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine, diastereoisomer
4-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(diethylphosphoryl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine ethyl isobutyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yljphosphinate
2-[(3R)-3-methylmorpholin-4-yl]-4-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(l-isobutyl-lH-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7 -naphthyridine
4-[(3R)-3-methylmorpholin-4-yl]-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[4-(isopropylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-ethyl-lH-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
l-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}prolinamide
3- {2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pyridin-2- amine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[l-(2,2,2-trifluoroethyl)-lH-pyrazol-5- yl] - 1 ,7 -naphthyridine
1 -methyl-4- { 2-[(3R)-3-methylmorpholin-4-yl] -8-(lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl }piperazin-2-one
4- [l-(2-fluoroethyl)-lH-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-[l-(2-fluoroethyl)-lH-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH-pyrazol-
1- yl)ethanol
2- methyl- 1 -(3- { 2-[(3R)-3-methylmorpholin-4-yl] -8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl } - 1 H-pyrazol- 1 -yl)propan-2-ol
4-[(2R)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine N-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl }phenyl)acetamide
3- {2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}pyridin-2-ol
2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}phenyl)propan-2-ol
4- (5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[(2S)-2-methylmo holin-4-yl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(difluoromethoxy)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]propan-2-ol
2-(moφholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2. l]oct-8-yl)-8-(lH-pyrazol-5-yl)- 1,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(pyrrolidin-l-yl)-l,7-naphthyridine 4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperazin-2-one
4-(dimethylphosphoryl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[(trans)-2,5-dimethylpiperazin-l-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[(cis)-3,5-dimethylpiperazin-l-yl]-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine l-[2-(morpholin-4-yl)-8-(lH^yrazol-5-yl)-l,7-naphthyridin-4-yl]-3-(trifluoromethyl)azetidin-3- ol
methyl hydrogen { 4- [2-(mc^holin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4- yl]phenyl Jphosphonate
4-(4-methylpiperazin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[(3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl] - 1 ,7 -naphthyridine
4-(3-methoxy-3-methylazetidin-l-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(moφholin-4-yl)-4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
N,N-dimethyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]pyridin-2-amine
4-(2-methylpyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine l-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}cyclohexanol 2-fluoro-6-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl} aniline
(methyl} 4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}oxido- λ6- sulfanylidene)cyanamide
1- ethyl-3-(methyl{4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl }oxido- λ 6-sulfanylidene)urea
3-( { 2-[(3R)-3-methylmorpholin-4-yl]-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl }oxy)propan- 1- amine
4-(4-cyclopropyl-lH-l,2,3-triazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-ethylsulfinyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-[propan-2-ylsulfinyl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2- [(3R)-3-methylmorpholin-4-yl]-4-[3-(methylsulfonyl)propoxy]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(morpholin-4-yl)-4-(phenylsulfonyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-(propan-2-ylsulfonyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(ethylsulfonyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-4-(phenylsulfinyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(methylsulfinyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-oxidotetrahydro-2H-thiopyran-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-(1 -dioxidotetrahydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4,8-di(lH-pyrazol-5-yl)-l,7-naphthyridine
N,N-dimethyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
2-(morpholin-4-yl)-4-(phenylsulfanyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(mo holin-4-yl)-N-(propan-2-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
4-(ethylsulfanyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(mo holin-4-yl)-4-(propan-2-ylsulfanyl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrol-2-yl)-l,7-naphthyridine
2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrol-3-yl)-l,7-naphthyridine
4-[(4-methoxyphenyl)sulfanyl]-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(5-methyl-lH-pyrazol-3-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
1- [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyrrolidin-2-one
4-(1 -dioxido-l,2-thiazolidin-2-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine l-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-2-one
2- [(3R)-3-methylmo holin-4-yl]-4-(2-methylpyridin-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmo holin-4-yl]-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-methoxypyridin-3-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2- (moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(pyridin-4-yl)-l,7-naphthyridine
4-[(4-methoxyphenyl)sulfanyl]-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4 3-fluoro-2-(moφholin-4-yl)pyridin-4-yl]-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5- yl)- 1,7-naphthyridine
4-(6-fluoro-5-methylpyridin-3-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
3- [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-l,3-oxazinan-2-one
3- [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-l,3-oxazolidin-2-one 4-(3-methoxypyridin-4-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4- (2,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(5-chloro-2-fluoropyridin-3-yl)-2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 4-(3-fluoropyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-chloro-6-methylpyridin-3-yl)-2 (3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(5,6-dimethylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(5-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methylthiophen-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(3-methoxythiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2-chlorothiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(isoquinolin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-chlorothiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylthiophen-2-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(2,5-dimethylthiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2 (3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-thiopyran-4-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-l,2,5,6 etrahydropyridin-3-yl)-8-(lH-pyrazol-5- yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-l,23,6-tetrahydropyridin-4-yl)-8-(lH-pyrazol-5- yl)- 1,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-methylpiperidin-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-l,7- naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[l-(tetrahydro-2H-pyran-4-yl)-lH- pyrazol-3-yl] - 1 ,7-naphthyridine
4-(4,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l,3-dimethyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l,5-dimethyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(piperidin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-[3-(trifluoromethyl)-lH-pyrazol-4-yl]- 1 ,7 -naphthyridine
4-(l-cyclobutyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-(l-cyclopropyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-(propan-2-yl)-lH-pyrazol-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
4-[l-(difluoromethyl)-lH-pyrazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-(l-tert-butyl-lH-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
2-(4-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-lH-pyrazol- l-yl)ethanol
4-( 1 -ethyl- lH-pyrazol-4-yl)-2- [(3R)-3-methylmorpholin-4-yl] -8-( 1 H-pyrazol-5-yl)- 1 ,7- naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrrol-3-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-(propan-2-yl)-lH-pyrazol-3-yl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2 (3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-4-(l,2,5-trimethyl-lH-pyrrol-3-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(l-phenyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
2-[(3R)-3-methylmorpholin-4-yl]-4-[l-(2-methylpropyl)-lH-pyrazol-4-yl]-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
2-[(3R)-3-methylmorpholin-4-yl]-4-(lH-pyrazol-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(l,3-oxazol-2-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(13-dimethyl-lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(l,5-dimethyl-lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-4-(l,3, -trimethyl-lH-pyrazol-4-yl)-l,7-naphthyridine
4-{ [(2-methoxyethyl)(methyl)oxido- λ 6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4- yl]-8-( lH-pyrazol-5-yl)- 1 ,7 -naphthyridine
4-{ [(4-bromophenyl)(oxido)propan-2-yl- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin- 4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(methyl-N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl } sulfonimidoyl)phenol
4-{ [(4-bromophenyl)(methyl)oxido- λ 6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]- 8 -( 1 H-pyrazol-5 -yl) - 1 ,7-naphthyridine
4-{ [tert-butyl(methyl)oxido- λ6-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(lH- pyrazol-5-yl)- 1 ,7-naphthyridine
formic acid - N-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-l,4 4-oxathian- 4-imine 4-oxide (1: 1) N-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]hexahydro-l 4-thiopyran-l- imine 1 -oxide
3- methyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}butan-2-ol
l-{2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}-l-(tetrahydro- 2H-pyran-4-yl)ethanol
3,3-dimethyl-2-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl}butan-2-ol
2-{2-[(3R)-3-methylmoφholin-4-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl}hexan-2-ol 2-[(3R)-3-methylmo holin-4-yl]-8-(lH-pyrazol-3-yl)-l ,7-naphthyridine-4-carboxamide
2-[(3R)-3-methylmo holin-4-yl]-4-[l-(methylsulfonyl)cyclopropyl]-8-(lH-pyrazol-5-yl)-l,7- naphthyridine
2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)-l,7- naphthyridine
N,N-dimethyl-3-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
{4-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}(piperidin-l- yl)methanone
N,N-dimethyl-2-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benz amide N-cyclopropyl-4-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide 4-(4-methylpyridin-3-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- (lH-indol-6-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(lH-indol-4-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
3 - [2- (mo holin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] benzamide
4-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
N-methyl-3-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide 4-(3-fluorophenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-chlorothiophen-2-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-methoxyphenyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[2-(trifluoromethyl)phenyl]-l,7-naphthyridine 2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[4-(trifluoromethyl)phenyl]-l ,7-naphthyridine 2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-4-[3-(trifluoromethyl)phenyl]-l,7-naphthyridine 4-(3-chlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-{3-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}acetamide 4-(3-methoxyphenyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,5-dimethoxyphenyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(3-methylphenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methoxyphenyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(furan-2-ylmethyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2,6-dimethyl-4-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenol 4-(2,3-dimethylphenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine {3-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenyl}methanol 4-(4-fluorophenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methylphenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-chlorophenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-fluoro-3-methoxyphenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(2-methylphenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,3-dimethoxyphenyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N,N-dimethyl-3-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl] aniline N,N-dimethyl-2-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]aniline
N-{2-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl Jmethanesulfonamide
N-{4-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- yl]phenyl Jmethanesulfonamide
N,N-dimethyl-4-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide
2-(moφholin-4-yl)-4-[(lE)-prop-l-en-l-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]phenol
4-(2-fluorophenyl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]phenyl}(piperidin-l- yi: methanone
2- morpholin-4-yl)-4-[4-(propan-2-yl)phenyl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N- cyclopropyl-3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]benzamide 4- biphenyl-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- 2,4-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 2-chlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- 2,5 -dimethylphenyl) -2-(morpholin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) - 1 ,7 -naphthyridine 3- 2- (morpholin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] aniline
2- morpholin-4-yl)-8-( 1 H-pyrazol-5-yl)-4- [3-( 1 H-pyrazol- 1 -yl)phenyl] - 1 ,7-naphthyridine 3- 2- (morpholin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] phenol
4- 2-fluoro-5-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 5-fluoro-2-methoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 2.4- difluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 2,3-difluorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 2,6-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2- 2- (morpholin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] aniline
4- 3.5- dichlorophenyl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- biphenyl-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- 2-chloropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- l-benzothiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 1- methyl- lH-pyrazol-5-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2- morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-5-yl)-l,7-naphthyridine
2- morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(pyridin-3-yl)-l,7-naphthyridine
4- 2- methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4- 5-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2- morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-3-yl)-l,7-naphthyridine 2-(morpholin-4-yl)-4-[ 1 -(phenylsulfonyl)- lH-indol-2-yl]-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridine
4-(2-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
{ 5- [2-(morpholin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridin-4-yl] thiophen-2-yl } methanol 4-(2-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-chloro-6-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine
4-(2-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(isoquinolin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-chloropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-fluoropyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2,6-difluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-( 1-methyl- lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7-naphthyridine tert-butyl 5-methoxy-2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-lH- indole- 1 -carboxylate
2-(morpholin-4-yl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methylthiophen-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(thiophen-2-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(thiophen-3-yl)-l,7-naphthyridine
4-(3-methylthiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(2-chloro-5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-chloro-2-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine tert-butyl 5-methyl-2-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-lH- indole- 1 -carboxylate
4-(5-chloro-2-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3,5-dimethyl-l,2-oxazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-8-yl)-l,7-naphthyridine 4-(5-methylthiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine
4-(6-ethoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4- (2-ethoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(quinolin-6-yl)-l,7-naphthyridine
4-(2-chlorothiophen-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
5- [2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-amine
2-(morpholin-4-yl)-4-(lH-pyrazol-3-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(6-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-( 1 -methyl- 1 H-pyrrol-2-yl)-2-(morpholin-4-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine 5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-ol
4-(5-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-chloro-2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(3-chlorothiophen-2-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(5-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-[2-(methylsulfanyl)pyrimidin-5-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-cyclopropyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyrimidin-2- amine
4-(isoquinolin-5-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-methyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridine-2- carboxamide
N-tert-butyl-5-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridine-3- carboxamide
4-[5-(methylsulfanyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,7-naphthyridine 3-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyridin-2-amine
methyl 4-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]thiophene-2- carboxylate
4-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7- naphthyridine 2-(mo holin-4-yl)-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(lH yrazol-5-yl)-l,7-naphthyridine 4-(5-chloro-6-ethoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(l-tert-butyl-lH-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 2-(mo holin-4-yl)-4-(piperidin-l-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
l-[2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-4-ol
N-methyl-2-(moφholin-4-yl)-N henyl-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine { l-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]pyrrolidin-2-yl}methanol N-methyl-2-(moφholin-4-yl)-N-propyl-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine 4-(azepan-l-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(3-methylpiperidin-l-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
4-(4-methylpiperidin-l-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
1- [2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]piperidine-3-carboxamide 4-(2,5-dihydro-lH-pyrrol-l-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(3,4-dihydroquinolin-l(2H)-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine 4-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(mo holin-4-yl)-8-(lH yrazol-5-yl)-l,7-naphthyridine 4-(1 -dihydro-2H-isoindol-2-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
2- (moφholin-4-yl)-8-(lH-pyrazol-5-yl)-4-[l,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl]-l,7- naphthyridine
tert-butyl l-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]-prolinate
N-methyl-N-(2-methylpropyl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4- amine
N-(3-fluorophenyl)-N-methyl-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine
4-( 1, 1 -dioxido- 1 -thia-6-azaspiro[3.3]hept-6-yl)-2-(morpholin-4-yl)-8-( lH-pyrazol-5-yl)- 1 ,7- naphthyridine
4-(3-fluoropiperidin-l-yl)-2-(mo holin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine
N-(2-fluorophenyl)-N-methyl-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-amine 1 - [2- (mo holin-4-yl) - 8 -( 1 H-pyrazol-5 -yl) -1,7 -naphthyridin-4-yl] -prolinamide
{ l-[2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridin-4-yl]piperidin-4-yl}methanol 4-(4-methoxypiperidin-l-yl)-2-(moφholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine N-(4-fluorophenyl)-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-amine
N-methyl-l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridiri-4-yl] -prolin amide
4-[4-(ethylsulfonyl)piperazin-l-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine
4-[4-(methylsulfonyl)piperazin-l-yl]-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridine N-cyclopropyl-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-amine
N-(2,2-dimethylpropyl)-N-methyl-2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphfhyridin-4- amine
{ l-[2-(morpholin-4-yl)-8-(lH-pyrazol-5-yl)-l ,7-naphthyridin-4-yl]piperidin-3-yl}methanol or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
8. The combination according to any one of claims 1 to 4, in which said component A is 2-[(3R)- 3-methylmorpholin-4-yl] -4-( 1 -methyl- 1 H-pyrazol-5-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
9. The combination according to any one of claims 1 to 8, in which said component A is 2-[(3R)- 3-methylmorpholin-4-yl] -4-( 1 -methyl- 1 H-pyrazol-5-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine and in which said component B is selected from enzalutamide and ODM-201.
10. The combination according to any one of claims 1 to 9 for use in the treatment or prophylaxis of a hyper-proliferative disease.
11. Use of the combination according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a hyper-proliferative disease.
12. The combination for use according to claim 10 or the use according to claim 11, wherein the hyper-proliferative disease is selected from prostate cancer and breast cancer.
13. A kit comprising
component A as defined in any one of claims 1, 5, 6, 7, 8 or 9;
component B as defined in any one of claim 1 to 4 or 9; and, optionally,
component C being one or more further pharmaceutical agents.
14. A kit according to claim 13, in which optionally all, both or either of said components A and B and optionally C are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
15. A pharmaceutical composition comprising a combination as defined in any one of claims 1 to 9 together with one or more pharmaceutically acceptable excipients.
16. A pharmaceutical composition according to claim 15, in which the components A and B are present in a joint formulation.
17. A pharmaceutical composition according to claim 15, in which the components A and B are present in separate formulations.
PCT/EP2018/054365 2017-02-24 2018-02-22 Combination of atr kinase inhibitors and antiandrogens WO2018153972A1 (en)

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US10772893B2 (en) 2014-08-04 2020-09-15 Bayer Pharma Aktiengesellschaft 2-(morpholin-4-yl)-1,7-naphthyridines
US11529356B2 (en) 2014-08-04 2022-12-20 Bayer Pharma Aktiengesellschaft 2-(morpholin-4-yl)-1,7-naphthyridines
US10729680B2 (en) 2016-01-14 2020-08-04 Bayer Pharma Aktiengesellschaft 5-substituted 2-(morpholin-4-yl)-1,7-naphthyridines
WO2020169538A1 (en) * 2019-02-22 2020-08-27 Bayer Aktiengesellschaft Combination of ar antagonists and targeted thorium conjugates
WO2022200251A1 (en) * 2021-03-22 2022-09-29 Astrazeneca Ab Formulation comprising ceralasertib
WO2023039125A1 (en) * 2021-09-10 2023-03-16 Teon Therapeutics, Inc. Adenosine receptor agonists for use in the treatment of cancer

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