WO2017162510A1 - Substituted quinazolinone compounds for the treatment of proliferative diseases - Google Patents

Substituted quinazolinone compounds for the treatment of proliferative diseases Download PDF

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WO2017162510A1
WO2017162510A1 PCT/EP2017/056229 EP2017056229W WO2017162510A1 WO 2017162510 A1 WO2017162510 A1 WO 2017162510A1 EP 2017056229 W EP2017056229 W EP 2017056229W WO 2017162510 A1 WO2017162510 A1 WO 2017162510A1
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alkyl
halo
alkoxy
cycloalkyl
alkylene
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PCT/EP2017/056229
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French (fr)
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Stuart James INCE
Ingo Hartung
Roman Hillig
Jörg Fanghänel
Hans Briem
Philip Lienau
Philip DENNER
Duy Nguyen
Manfred Husemann
Ulf Bömer
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Bayer Pharma Aktiengesellschaft
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Publication of WO2017162510A1 publication Critical patent/WO2017162510A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to substituted quinazolinone compounds of general formula (I) as described and defined herein, to methods of preparing 5 said compounds, to pharmaceutical compositions and combinations comprising
  • Unrestricted cell cycle progression a common feature of tumour cells, is in many cases the result of inappropriate regulation of cell cycle progression by cyclin-dependent kinases (CDKs) and linked to a loss of functional control by molecules such as pRB, p53, p16, and p21 , for example.
  • CDKs cyclin-dependent kinases
  • the oncogenic Pirn family of serine/threonine kinases belongs to those group
  • This Pirn family consists of three members which are Pim-1 , Pim-2 and Pim-3.
  • the CDK inhibitor p21 is phosphorylated by the Ser/Thr kinase Pim-1. This
  • Pim-1 is involved in the signal transduction of mitogenic cytokines via the STAT3 and STAT5 pathway (Jaster R et al. Cell Signal. 1999;
  • Pim-1 The retroviral activation of Pim-1 contributes to oncogenic transformation in vivo (Mikkers H et al. Nat.Genet. 2002; 32: 153- 159.). Pim-1 was found to be over-expressed in tumour tissue of prostate carcinomas by gene and protein expression profiling (Dhanasekaran SM et al. Nature 2001 ; 412: 822-826.; Valdman A et al. Prostate 2004; 60: 367- 371 ) and is also known to be associated with haematopoietic malignancies and lymphomas (Cuypers HT et al. Cell 1984; 37: 141 -150. Nagarajan L et al. Proc. Natl. Acad. Sci. U.S.A 1986; 83: 2556-2560. )
  • Pim-2 promotes cell survival by inhibiting apoptosis.
  • Pim-2 knockdown experiments as well as the over-expression of a Pim-2 dominant- negative mutant prevented effective survival signalling.
  • the collaboration of pim- 1 and pim-2 with myc in B-cell tumourigenesis could be demonstrated in ⁇ - ⁇ /m- i or E i-pim-2 and E imyc doubly transgenic mice. These transgenic mice display a greatly accelerated lethal B-cell tumour formation ( Allen JD et al. Oncogene 1997; 1 5: 1 133- 1 141 .; Verbeek S et al. Mol.Cell Biol. 1991 ; 1 1 : 1 176- 1 179. ).
  • Kid-1 (kinase induced by depolarization) was described as a third Ser/Thr kinase ( Feldman JD et al. J.Biol.Chem. 1998; 273: 16535-16543. ) with high homology to Pim-1 .
  • the kid- 1 gene is identical to the rat pim-3 gene that was isolated in a low-stringency homology search for additional pirn family members ( Konietzko U et al. EMBO J. 1999; 18: 3359-3369).
  • Retrovirus modulated knock-out identified Pim-1 , Pim-2 and pim-3 as primary cell survival factors for tumours co-activated with Myc (Allen JD, Berns A. Semin. Cancer Biol. 1996; 7: 299-306.
  • Pirn kinases Due to the involvement of Pirn kinases in various malignancies, a design of Pirn kinase inhibitors for the treatment of cancer and /or further diseases either mediated and/or associated with Pirn kinases is desirable.
  • WO 2008/022164 (Boehringer Ingelheim Pharma) discloses pyrazine derivatives as Pirn-inhibitors.
  • said compounds of the present invention have surprisingly been found to effectively inhibit one or more Pirn kinases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the present invention relates to compounds of general formula (I) :
  • the present invention covers compounds of formula (la) :
  • (la) independently of each other, represent a group selected from : H, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-
  • Ri and R 2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C 6 - alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, Ci-C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from :
  • Ci-C 6 -alkyl represents a substituent selected from : halo, cyano, Ci-C 6 -alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, C 3 -Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C 6 - alkylene-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, ; wherein said Ci-C 6 -al
  • R8 represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
  • R 9 represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C6-alkyl, d-Cs- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, -
  • R 10 and R 11 independently from one another, represent a group selected from : H, d-Cs-alkyl, d-do-cycloalkyl, halo-d-Cs-alkyl, d-Cs- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
  • the present invention covers compounds of formula (lb) :
  • Ri and R 2 do not simultaneously represent H; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, d-Cs-alkenyl, C 2 -Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C 6 - alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, d-C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from :
  • d-Cs-alkyl represents a group selected from : d-Cs-alkyl, C 3 -do-cycloalkyl, halo-d-Cs-alkyl, aryl, heteroaryl, d-C6-alkoxy-d-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d-C6-alkyl, d-C 6 - alkoxy, d-C6-alkoxy-d-C6-alkyl, halo-d-Cs-alkoxy-d-C6-alkyl, - NR 10 R 11 ; R 10 and R 11 , independently from one another, represent a group selected from : H, d-Cs-alkyl, C3-Cio-cycloalkyl,
  • the present invention covers compounds of formula (Ic) :
  • Ri, Rz represent H ;
  • R3 represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C 3 -Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C 6 - alkylene-heteroaryl, -Ci-C6-alkylene-C 3 -Cio-cycloalkyl, Ci-C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyan
  • Ci-C 6 -alkyl represents a substituent selected from : halo, cyano, Ci-C 6 -alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, C 3 -Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C 6 - alkylene-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, ; wherein said Ci-C 6 -al
  • R8 represents a substituent selected from : H, halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
  • R 9 represents a group selected from : d -Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci -C 6 - alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci -Cs-alkoxy-Ci-C6-alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci -Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci -C6-alkyl, Ci -C 6 - alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci -C6-alkyl ;
  • Ci -Cs-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, particularly 1 , 2 or 3 carbon atoms (“Ci -C3-alkyl”), e.g.
  • halo-Ci -C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "d - Cs-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in the same way or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said halo-Ci -C6-alkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , or - CH 2 CF 3 .
  • Ci -C6-alkoxy is to be understood as preferably 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, /so-propoxy, n-butoxy, /so-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso- pentoxy, or n-hexoxy group, or an isomer thereof.
  • halo-Ci -C6-alkoxy is to be understood as preferably 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 the same way or differently, by a halogen atom.
  • said halogen atom is F.
  • Said halo-Ci-C6-alkoxy group is, for example, -OCF3, -0CHF 2 , -0CH 2 F, - OCF 2 CF 3 , or -OCH 2 CF 3 .
  • Ci-C6-alkoxy-Ci-C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a Ci-C 6 -alkoxy group, as defined supra, e.g.
  • halo-C C6-alkoxy-Ci-C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C6-alkoxy-Ci -Cs-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.
  • said halogen atom is F.
  • Said halo-Ci-C6-alkoxy-Ci-C6-alkyl group is, for example, - CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or - CH 2 CH 2 OCH 2 CF 3 .
  • halogen atom or "halo” is to be understood as preferably meaning a fluorine, chlorine, bromine, or iodine atom.
  • C 2 -C6-alkenyl is to be understood as preferably 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, particularly 2 or 3 carbon atoms (“C 2 -C 3 -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)-buM -enyl, (Z)-buM -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, (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,
  • C 2 -C6-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C3-alkynyl").
  • Said C 2 -C 6 -alkynyl group is, for example, ethynyl, prop- 1 -ynyl, prop-2-ynyl, but- 1 -ynyl, but-2-ynyl, but-3-ynyl, pent- 1 - ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex- 1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut- 3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut- 1 -ynyl, 1 -ethylprop-2-ynyl, 3- methylpent-4-ynyl, 2-methylpent-4-y
  • C3-Cio-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, particularly 3, 4, 5, or 6 carbon atoms ("C3-C6-cycloalkyl").
  • Said C3-Cio-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g.
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
  • Said cycloalkyl ring can optionally contain one or more double bonds e.g.
  • cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated .
  • said ring can contain 2, 3, 4, or 5 carbon atoms, and 1 , 2 or 3 of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and 1 , 2 or 3 of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • Said heterocycloalkyl ring is for example, a monocyclic heterocycloalkyl ring such as an oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, or chinuclidinyl group.
  • said heterocycloalkyl ring can contain one or more double bonds, e.g.
  • 4H-pyranyl 2H-pyranyl, 3H-diazirinyl, 2, 5-dihydro- 1 H-pyrrolyl, [1 ,3]dioxolyl, 4H- [1 , 3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2, 5- dihydrothiophenyl, 2,3-dihydrothiophenyl, 4, 5-dihydrooxazolyl, or 4H- [1 ,4]thiazinyl group, or, it may be benzo fused.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono- , or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 1 3 or 14 carbon atoms (a "C6-Ci4-aryl” group), particularly a ring having 6 carbon atoms (a "C6-aryl” group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "C9-aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g.
  • heteroaryl is understood as preferably meaning a monovalent, aromatic, mono- or bicyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur, and can be monocyclic, bicyclic, or tricyclic, 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.
  • benzo derivatives thereof such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. , and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc.
  • heteroaryl is selected from pyridyl, benzofuranyl, thienyl, quinolinyl, benzothienyl, pyrazolyl, or furanyl.
  • alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or “tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH 2 - ("methylene” or “single membered tether” or e.g.
  • said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
  • C1 -C6 as used throughout this text, e.g. in the context of the definition of "Ci -Cs-alkyl”, “Ci -C 6 -haloalkyl”, “d -Cs-alkoxy”, or "C1 -C&- 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.
  • d -Cs is to be interpreted as any subrange comprised therein, e.g. Ci -Cs , C 2 -Cs , C3-C4 , Ci -C 2 , C1 -C3 , C1 -C4 , C1 -C5 C1 - Cs ; particularly Ci -C 2 , C1 -C3 , C1 -C4 , C1 -C5 , Ci -C 6 ; more particularly C1 -C4; in the case of "Ci -C6-haloalkyl" or "d -Cs-haloalkoxy" even more particularly Ci - C 2 .
  • C 2 -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.
  • C3-C10 as used throughout this text, e.g. in the context of the definition of "C3-Cio-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms.
  • C3-C10 is to be interpreted as any sub-range comprised therein, e.g. C3-C10 , C4-C9 , Cs-Cs , C 6 - C7 ; particularly C3-C6.
  • the compounds of the present invention can exist in the form of stereoisomers.
  • stereoisomers the atoms are connected sequentially in the same way, such that condensed formulae for two isomeric molecules are identical.
  • the isomers differ, however, in the way the atoms are arranged in space.
  • Configurational isomers are, in turn, comprised of enantiomers and diastereomers.
  • Enantiomers are stereoisomers which are related to each other as mirror images.
  • Enantiomers can contain any number of stereogenic centres, as long as each centre is the exact mirror image of the corresponding centre in the other molecule. If one or more of these centres differs in configuration, the two molecules are no longer mirror images.
  • Stereoisomers which are not enantiomers are called diastereomers.
  • Diastereomers which still have a different constitution are another sub-class of diastereomers, the best known of which are simple cis - trans isomers.
  • lUPAC Rules Section E Pure Appl Chem 45, 1 1 -30, 1976).
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H 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 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, viz. :
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N- oxides.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C 6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid- addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, sulphuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, 3-hydroxy-2- naphthoic, sulphamic, trifluoromethanesulphonic, benzenesulphonic, para- toluenesulphonic, methylsulphonic, naphthalinedisulphonic, citric, tartaric, stearic, lactic, oxalic
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl- glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl- aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol.
  • the present invention includes all possible salts of the compounds of the present invention 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 the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • the present invention covers compounds of formula (la), supra, in which :
  • Ri , R 2 independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci -C6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-
  • Ri and R 2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C 6 - alkylene-heteroaryl, -Ci-Cs-alkylene-C3-Cio-cycloalkyl, d-C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent
  • Ci-Ce-alkyl represents a substituent selected from : halo, cyano, d-Cs-alkyl, halo-d-Cs-alkyl, d-C 6 -alkoxy, halo-Ci-C6-alkoxy, d-C 6 -alkoxy-d- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C 6 - alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, ; wherein said
  • Ci -Cs-alkyl represents a group selected from : Ci -Cs-alkyl, C3-Cio-cycloalkyl, halo-C C 6 -alkyl, aryl, heteroaryl, Ci-C 6 -alkoxy-Ci-C 6 -alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C 6 -alkyl, Ci-C 6 - alkoxy, Ci-C 6 -alkoxy-Ci-C 6 -alkyl, halo-C C 6 -alkoxy-Ci-C 6 -alkyl, - NR 10 R 11 ; R 10 and R 11 , independently from one another, represent a group selected from : H, d -Cs-alkyl, C3-Cio
  • the present invention covers compounds of formula (la), supra, in which :
  • Ri , R 2 independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-d -C 6 - alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, d -C 6 -alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C 3 -Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl,
  • Ri and R 2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C 3 - Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, d-Cs-alkyl,
  • R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
  • R 9 represents a group selected from : Ci -Cs-alkyl, C3-Cio-cycloalkyl,
  • halo-Ci -Cs-alkyl aryl, heteroaryl, Ci-C 6 -alkoxy-Ci-C 6 -alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C 6 -alkyl, halo-Ci-C 6 -alkyl, Ci-C 6 - alkoxy, Ci-C 6 -alkoxy-Ci-C 6 -alkyl, halo-C C 6 -alkoxy-Ci-C 6 -alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-C 6 -alkyl, C3-Cio-cycloalkyl, halo-C C 6 -alkyl, Ci-C 6 - alkoxy-Ci-C 6 -alkyl, halo-Ci-C 6 -alkoxy-C C 6 -alkyl ;
  • the present invention covers compounds of formula (la), supra, in which :
  • Ri , R 2 independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C 3 -Cio-cycloalkyl,
  • R3 represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci-C6-alkyl, C 3 -do- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -Cs-alkylene-heteroaryl, -Ci -C6-alkylene-C 3 - Cio-cycloalkyl, Ci-C6-alkylene-heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C 6 -alkyl, halo-Ci-C6-alkyl,
  • R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
  • R 9 represents a group selected from : Ci-C3-alkyl, C3-C6-cycloalkyl, halo-C C3-alkyl, aryl, heteroaryl, Ci-C3-alkoxy-Ci-C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy,
  • Ci-Cs-alkoxy-Ci-C6-alkyl halo-Ci-C6-alkoxy-Ci-C6-alkyl, -NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-C3-alkyl, C3-Cio-cycloalkyl, halo-Ci-C3-alkyl, C1-C3- alkoxy-Ci-C3-alkyl, halo-Ci-C3-alkoxy-Ci-C3-alkyl ;
  • the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-
  • Ri and R 2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C 3 -Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -C6-alkylene-aryl, Ci -C 6 - alkylene-heteroaryl, -Ci -C6-alkylene-C 3 -Cio-cycloalkyl, Ci -C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently
  • R8 represent H ;
  • R 9 represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-CrCs-alkyl , aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
  • the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to
  • Ri and R 2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci -Cs-alkoxy-Ci-C6-alkyl, C 3 -Cio- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C 3 - Cio-cycloalkyl, Ci -C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci -Cs
  • R8 represent H ;
  • R 9 represents a group selected from : d-Cs-alkyl, C 3 -Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C 3 -Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
  • the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -C 6 -alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to
  • Ri and R 2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - Cs-alkoxy-Ci-C6-alkyl, halo-CrC6-alkoxy-Ci-C6-alkyl, C 3 -Cio- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C 3 - Cio-cycloalkyl, Ci-C6-alkylene- heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C 6 -alkyl, halo-
  • R8 represent H ;
  • R 9 represents a group selected from : Ci-C 3 -alkyl, C 3 -C 6 -cycloalkyl, halo-C C 3 -alkyl, aryl, heteroaryl, Ci-C 3 -alkoxy-Ci-C 3 -alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, Ci -Cs-alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci-C6-alkyl, -NR 10 R 11 ; R 10 and R 11 , independently from one another, represent a group selected from : H, Ci -C 3 -alkyl, C 3 -Cio-cycloalkyl, halo
  • the present invention covers compounds of formula (Ic), supra, in which : represent H ;
  • Ci-C6-alkyl represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C 6 - alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, d-C 6 - alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy
  • d-Cs-alkyl represents a substituent selected from : halo, cyano, d-Cs-alkyl, halo-d-Cs-alkyl, d-C 6 -alkoxy, halo-Ci-C6-alkoxy, d-C 6 -alkoxy-d- C 6 -alkyl, halo-d-C6-alkoxy-d-C6-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, d-C6-alkylene-aryl, d-C6-alkylene-heteroaryl, d-C 6 - alkylene-C 3 -Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl
  • R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
  • R 9 represents a group selected from : Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-CrCs-alkyl , aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C 6 -alkyl, halo-Ci-C6-alkyl, Ci-Ce- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-C C6-alkoxy-Ci-C6-alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-C 6 -alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl ;
  • the present invention covers compounds of formula (Ic), supra, in which : represent H ;
  • Ci-C6-alkyl represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -Cs-alkylene-heteroaryl, -Ci -Cs-alkylene-C 3 - Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, d-Cs-alkyl, halo-Ci-C6
  • d-Cs-alkyl represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR 10 R 11 ;
  • R 10 and R 11 independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C 6 - alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
  • the present invention covers compounds of formula (Ic), supra, in which : Ri, R 2 represent H ;
  • R3 represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d-
  • R 9 represents a group selected from : Ci -C3-alkyl, C3-C 6 -cycloalkyl, halo-C C3-alkyl, aryl, heteroaryl, Ci -C3-alkoxy-Ci -C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci -C 6 -alkyl, halo-Ci -C6-alkyl, Ci -C6-alkoxy, Ci -Cs-alkoxy-Ci -C6-alkyl, halo-CrC6-alkoxy-Ci -C6-alkyl, -NR 10 R 11 ; R 10 and R 11 , independently from one another, represent a group selected from : H, Ci -C3-alkyl, C3-Cio-cycloalkyl, halo-
  • the present invention covers compounds of formula (la), formula (lb) and formula (Ic) which are disclosed in the Example section of this text, infra.
  • the present invention covers a method of preparing compound of formula (la) or (lb) as defined herein, in which method intermediate compound of formula (5a) or (5b) :
  • Ri-Y, and/or R 2 -Y in which Ri and R 2 are as defined for the compound of formula (la) or (lb), respectively, as defined herein, and Y is a leaving group, such as CI, Br, I, methanesulphonate,
  • the present invention covers a method of preparing a compound of formula (Ic) as defined herein, in which method an intermediate haloketone compound of formula (3c) :
  • said intermediate haloketone compound of formula (3c) is prepared by allowing an intermediate nitrile compound of formula (2c) :
  • the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of formula (la) or (lb), particularly in the method described herein.
  • the present invention covers compounds of formula (5a) or (5b) :
  • Ri, R 2 represent H
  • R3, R 4 , R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb) supra, respectively, for the preparation of a compound of formula (la) or (lb) supra, respectively.
  • the present invention covers the use of the intermediate compounds of formula (5a) or (5b) :
  • the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of formula (Ic), particularly in the method described herein.
  • the present invention covers compounds of formula (3c) and (2c) :
  • the present invention covers the use of intermediate compounds for preparing compounds of the present invention of formula (Ic), particularly in the method described herein.
  • the present invention covers the use of com ounds of formula (3c) and (2c) :
  • Another aspect of the present invention is a method which may be used for preparing the compounds according to the present invention.
  • a suitably substituted anthranilic acid intermediate of formula (1 a,b) is converted to the corresponding nitrile of formula (2a, b) by reaction with, for example: A) cyanothioacetamide in the presence a suitable base such as, for example triethylamine, in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent; or B) cyano(methylthio)acetamide (generated in situ by the reaction of cyanothioacetamide, a suitable base, such as sodium ethoxide, and a suitable methylating agent, such as methyl iodide, in a suitable solvent such as ethanol) in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent [see for example the preparation of (4-oxo-3,4-dihydro-quinazolin-2- yl)-acetonitrile; M.
  • a suitable base such as triethylamine
  • Intermediates of formula (3a, b) may be cyclised by reaction with a suitable amine, R3-NH 2 of formula (4a, b), in the presence or absence of a suitable base, whereby no additional base is necessary if an excess of R3-NH 2 is employed, in a suitable solvent such as n-butanol, at elevated temperatures, such as for example 150 ° C under microwave irradiation, to produce an intermediate ketone of formula (5a, b).
  • a suitable amine R3-NH 2 of formula (4a, b)
  • a suitable solvent such as n-butanol
  • a suitably substituted anthranilic acid intermediate of formula ( 1 c) is converted to the corresponding nitrile of formula (2c) by reaction with, for example: A) cyanothioacetamide in the presence a suitable base such as, for example triethylamine, in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent; or B) cyano(methylthio)acetamide (generated in situ by the reaction of cyanothioacetamide, a suitable base, such as sodium ethoxide, and a suitable methylating agent, such as methyl iodide, in a suitable solvent such as ethanol) in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent [see for example the preparation of (4-oxo-3,4-dihydro-quinazolin-2-yl)-acetonitrile; M.
  • a suitable base such as, for
  • a suitable base such as triethylamine
  • intermediates of formula (3c) may be cyclised by reaction with a suitable amine, R3- NH 2 of formula (4c), in the presence or absence of a suitable base, whereby no additional base is necessary if an excess of R3- NH 2 is employed, in a suitable solvent such as n-butanol, at elevated temperatures, such as for example 150 ° C under microwave irradiation, to produce compounds of formula (Ic) of the present invention .
  • a suitable amine R3- NH 2 of formula (4c)
  • a suitable base such as n-butanol
  • R3 is p-benzoic acid methyl ester and Ri , R 2 , R 4 , R5, R6, R7, and R8 are all hydrogen .
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g.
  • Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a suitable autopurifier such as a Flashmaster II autopurifier (Biotage) and eluants such as, for example, gradients of hexane/EtOAc, DCM/ethanol or DCM/methanol.
  • a suitable autopurifier such as a Flashmaster II autopurifier (Biotage)
  • eluants such as, for example, gradients of hexane/EtOAc, DCM/ethanol or DCM/methanol.
  • the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Step A Preparation of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile
  • Step A Preparation of 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H- pyrrol-3-yl]-3H-quinazolin-4-one
  • Step B Preparation of 2-[1 -(2-fluoro-phenyl)-4-oxo-2- (2-pyrrolidin- 1 -yl- ethylamino)-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one (Compound Example 1 .0b)
  • Step A Preparation of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile
  • the compounds of the present invention have surprisingly been found to effectively inhibit one or more Pim kinases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pim kinases, such as, for example, haematological tumours, solid tumours, and /or metastases thereof, e.g.
  • Pim kinases such as, for example, haematological tumours, solid tumours, and /or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, 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.
  • the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
  • Another aspect of the present invention is therefore a method of treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pim kinases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof, by administering an effective amount of a compound of general formula (I) described herein.
  • the diseases of said method are haemotological tumours, solid tumour and/or metastases thereof.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • the compounds of the present invention be used as pharmaceutical products, the compounds or mixtures thereof may be provided in a pharmaceutical composition.
  • Another aspect of the present invention is therefore a pharmaceutical composition which contains a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in admixture with one or more suitable excipients.
  • This composition is particularly suited for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, more particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, as mentioned supra.
  • Said pharmaceutical products which may be for enteral, oral or parenteral application, contain suitably pharmaceutically acceptable organic or inorganic inert base material, e.g. purified water, gelatine, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
  • organic or inorganic inert base material e.g. purified water, gelatine, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
  • Said pharmaceutical compositions of the present invention may be provided in a solid form, e.g. as tablets, dragees, suppositories, or capsules, or in liquid form, e.g. as a solution, a suspension or an emulsion.
  • Said pharmaceutical compositions may additionally contain auxiliary substances, e.g. preservatives, stabilisers, wetting agents or emulsifiers, salts for adjusting the osmotic pressure or buffers.
  • sterile injection solutions or suspensions are preferred, especially aqueous solutions of the compounds in polyhydroxyethoxy containing castor oil.
  • Said pharmaceutical compositions of the present invention may further contain surface active agents, e.g. salts of gallenic acid, phospholipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
  • surface active agents e.g. salts of gallenic acid, phospholipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
  • talcum and/or hydrocarbon-containing carriers and binders e.g. lactose, maize and potato starch
  • Further application in liquid form is possible, for example as juice, which contains sweetener if necessary.
  • the dosage will necessarily be varied depending upon the route of administration, age, weight of the patient, the kind and severity of the illness being treated and similar factors.
  • the daily dose is in the range of 0.5 to 1 ,500 mg.
  • a dose can be administered as unit dose or in part thereof and distributed over the day. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • compounds of general formula (I) of the present invention can be used alone or, indeed in combination with one or more further drugs, particularly anti-cancer drugs or compositions thereof.
  • said combination it is possible for said combination to be a single pharmaceutical composition entity, e.g. a single pharmaceutical formulation containing one or more compounds according to general formula (I) together with one or more further drugs, particularly anti-cancer drugs, or in a form, e.g. a "kit of parts", which comprises, for example, a first distinct part which contains one or more compounds according to general formula (I), and one or more further distinct parts each containing one or more further drugs, particularly anti-cancer drugs. More particularly, said first distinct part may be used concomitantly with said one or more further distinct parts, or sequentially.
  • compounds of general formula (I) of the present invention to be used in combination with other treatment paradigms, particularly other anti- cancer treatment paradigms, such as, for example, radiation therapy.
  • the present invention thus covers a pharmaceutical combination comprising :
  • said one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, of the present invention, as described and defined herein may be administered in combination with radiation therapy.
  • Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
  • Pim-1 kinase inhibition may be quantified by employing the Pim- 1 HTRF or TR- FRET assay as described in the following paragraphs.
  • Pim- 1 kinase 5 pg/measurement point was pre-incubated in assay buffer [25 mM Hepes pH 7.5, 10 mM MgCl 2 , 1 .0 mM Dithiothreitol, 0.015% NP40, 0.01 % bovine serum albumin [BSA], protease inhibitor cocktail ("Complete without EDTA", Roche, 1 tablet per 50 ml), 0.1 mM Na 3 V0 4 ] for 30 min with 50 nl_ of test compound dissolved in 100% dimethyl-sulfoxide (DMSO) (final compound concentrations during the kinase reaction: 0 ⁇ and 0.001 - 20 ⁇ ).
  • assay buffer 25 mM Hepes pH 7.5, 10 mM MgCl 2 , 1 .0 mM Dithiothreitol, 0.015% NP40, 0.01 % bovine serum albumin [BSA], protease inhibitor cocktail ("Complete without EDTA",
  • the kinase reaction was started by addition of 3 ⁇ substrate solution (10 ⁇ adenosine- triphosphate [ATP] and 1 ⁇ peptide substrate [Biotin-Ttds-YRRRHLSFAEPG - NH 2 ], dissolved in assay buffer; numbers indicate the final concentration during the kinase reaction).
  • the reaction was terminated after 20 min incubation at 22 °C by the addition of 3 ⁇ of stop / detection solution (final concentrations: 50 mM EDTA, 50 mM Hepes, pH 7.0, 0.06% BSA, 400 mM KF, and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.05 ⁇ , CisBio international, Marcoule, France), anti- phospho-serine (0.5 nM; a phospho-specific antibody; Upstate Biotechnology, Dundee, Scotland) and Eu 3+ cryptate-conjugated rabbit anti-mouse IgG (0.75 nM; a Europium-cryptate labelled anti-mouse-lgG-antibody from CisBio international, Marcoule, France).
  • stop / detection solution final concentrations: 50 mM EDTA, 50 mM Hepes, pH 7.0, 0.06% BSA, 400 mM K
  • LANCE ® Eu-W1024-labeled anti-mouse IgG antibody can be used for TR-FRET measurement.
  • the primary anti-phospho-serine antibody recognizes an epitope consisting of the serine residue phosphorylated by the Pim-1 kinase activity and the adjacent C- terminal peptide sequence.
  • the resulting mixture was incubated for 90 min at 22 °C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the phospho-specific antibody complexed with the secondary, Europium-labelled antibody. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the Europium- labelled antibody complex to the streptavidine-XLent. Therefore, the fluorescence emissions at 665 nm and 620 nm (internal Europium reference signal) after excitation at 350 nm were measured in an HTRF / TR- FRET reader, e.g.
  • the compounds of the present invention effectively inhibit one or more Pirn kinases and are therefore suitable for the treatment or prophylaxis of diseases of 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 is mediated by one or more Pirn kinases, more particularly in which the diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are haemotological tumours, solid tumours and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

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Abstract

The present invention relates to substituted quinazolinone compounds of general formula (I) : in which R1, R2, R3, R4, R5, R6, R7, and R8 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

Description

SUBSTITUTED QUINAZOLINONE COMPOUNDS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
The present invention relates to substituted quinazolinone compounds of general formula (I) as described and defined herein, to methods of preparing 5 said compounds, to pharmaceutical compositions and combinations comprising
said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
10 BACKGROUND OF THE INVENTION
Unrestricted cell cycle progression, a common feature of tumour cells, is in many cases the result of inappropriate regulation of cell cycle progression by cyclin-dependent kinases (CDKs) and linked to a loss of functional control by molecules such as pRB, p53, p16, and p21 , for example.
15 The oncogenic Pirn family of serine/threonine kinases belongs to those group
of kinases that exert influence on cell cycle progression as well as on cell survival by their ability to inactivate apoptosis. This Pirn family consists of three members which are Pim-1 , Pim-2 and Pim-3.
20 The CDK inhibitor p21 is phosphorylated by the Ser/Thr kinase Pim-1. This
leads to a cytoplasmic localisation of p21 and promotes cell growth. (Wang Z et al. Biochim.Biophys.Acta 2002; 1593: 45-55.; Zhou BP et al. Nat. Cell Biol. 2001 ; 3: 245-252). Pim-1 is involved in the signal transduction of mitogenic cytokines via the STAT3 and STAT5 pathway (Jaster R et al. Cell Signal. 1999;
25 11 : 331 -335.; Lilly M et al. Oncogene 1992; 7: 727-732.; Matikainen S et al.
Blood 1999; 93: 1980-1991 .; Sato N et al. EMBO J. 1993; 12: 4181 -4189.; Shirogane T et al. Immunity. 1999; 1 1 : 709-719.), functions as an anti- apoptotic survival factor (Buckley AR et al. Apoptosis. 1997; 2: 518-528.; Lilly M, Kraft A. Cancer Res. 1997; 57: 5348-5355.) and confers susceptibility to carcinogenesis (Breuer M et al. Nature 1989; 340: 61 -63. ; Storer RD et al. Carcinogenesis 1995; 16: 285-293.). The retroviral activation of Pim-1 contributes to oncogenic transformation in vivo (Mikkers H et al. Nat.Genet. 2002; 32: 153- 159.). Pim-1 was found to be over-expressed in tumour tissue of prostate carcinomas by gene and protein expression profiling (Dhanasekaran SM et al. Nature 2001 ; 412: 822-826.; Valdman A et al. Prostate 2004; 60: 367- 371 ) and is also known to be associated with haematopoietic malignancies and lymphomas (Cuypers HT et al. Cell 1984; 37: 141 -150. Nagarajan L et al. Proc. Natl. Acad. Sci. U.S.A 1986; 83: 2556-2560. )
Like Pim-1 , Pim-2 promotes cell survival by inhibiting apoptosis. Pim-2 knockdown experiments as well as the over-expression of a Pim-2 dominant- negative mutant prevented effective survival signalling. The collaboration of pim- 1 and pim-2 with myc in B-cell tumourigenesis could be demonstrated in Εμ-ρ/m- i or E i-pim-2 and E imyc doubly transgenic mice. These transgenic mice display a greatly accelerated lethal B-cell tumour formation ( Allen JD et al. Oncogene 1997; 1 5: 1 133- 1 141 .; Verbeek S et al. Mol.Cell Biol. 1991 ; 1 1 : 1 176- 1 179. ). Kid-1 (kinase induced by depolarization) was described as a third Ser/Thr kinase ( Feldman JD et al. J.Biol.Chem. 1998; 273: 16535-16543. ) with high homology to Pim-1 . The kid- 1 gene is identical to the rat pim-3 gene that was isolated in a low-stringency homology search for additional pirn family members ( Konietzko U et al. EMBO J. 1999; 18: 3359-3369). Retrovirus modulated knock-out identified Pim-1 , Pim-2 and pim-3 as primary cell survival factors for tumours co-activated with Myc (Allen JD, Berns A. Semin. Cancer Biol. 1996; 7: 299-306. Breuer ML, Cuypers HT, Berns A. EMBO J. 1989; 8: 743-748. Mikkers H et al. Nat. Genet. 2002; 32: 153-159. van der Lugt NM et al. EMBO J. 1995; 14: 2536-2544). Furthermore, various pathological conditions are linked to aberrant serine/threonine kinase activity (US. Patent No. 6, 159,716) indicating that those kinases and their signalling pathways are potential targets for drug design. Inhibition of such kinases, therefore, might be useful in the prophylaxis and /or treatment of diseases associated with aberrant serine/threonine kinase activity.
Due to the involvement of Pirn kinases in various malignancies, a design of Pirn kinase inhibitors for the treatment of cancer and /or further diseases either mediated and/or associated with Pirn kinases is desirable.
Knapp et al., in Journal of Medicinal Chemistry, 2005, 48, 7604, describe imidazo[1 ,2b]pyridazines as Pim-1 inhibitors. WO 2008/058126 (Supergen Inc) discloses imidazo[1 ,2b]pyridazines and pyrazolo [1 , 5-a]pyrimidine derivatives ] as Pirn-inhibitors.
WO 2008/022164 (Boehringer Ingelheim Pharma) discloses pyrazine derivatives as Pirn-inhibitors.
However, none of the state of the art described above describes the substituted quinazolinone compounds of general formula (I) of the present invention, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as "compounds of the present invention", or their pharmacological activity. It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties. In particular, said compounds of the present invention have surprisingly been found to effectively inhibit one or more Pirn kinases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
DESCRIPTION of the INVENTION
The present invention relates to compounds of general formula (I) :
Figure imgf000006_0001
(I)
selected from :
Figure imgf000007_0001
In accordance with a first variant of the first aspect, the present invention covers compounds of formula (la) :
Figure imgf000007_0002
(la) independently of each other, represent a group selected from : H, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-d-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H or Ci-C6 alkyl ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, nitro, C Cs-alkyl, halo-Ci-C6-alkyl, d-Cs-alkoxy, halo-CrC6- alkoxy, C3-Cio-cycloalkyl ;
represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000008_0001
; wherein said Ci-C6-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, d-d-alkoxy-d- d-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, d-d-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, d-Cs- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, -
SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R8 represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
R9 represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C6-alkyl, d-Cs- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, -
NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, d-Cs-alkyl, d-do-cycloalkyl, halo-d-Cs-alkyl, d-Cs- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-Ci-C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a second variant of the first aspect, the present invention covers compounds of formula (lb) :
Figure imgf000010_0001
(lb) independently of each other, represent a group selected from : H, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-Cs-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci-C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, C Cs-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-d- Cs-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-do- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=0)NR10R11, -OC(=0)NR10R11, N(H)C(=0)0R9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=0)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, d-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, d-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d-Cs-alkyl, Ci-C6-alkoxy, halo-d-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=0)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)0R9, -N(Ci-C6- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR10R11, -NR10R11 ;
represent H ;
represents a group selected from : d-Cs-alkyl, C3-do-cycloalkyl, halo-d-Cs-alkyl, aryl, heteroaryl, d-C6-alkoxy-d-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d-C6-alkyl, d-C6- alkoxy, d-C6-alkoxy-d-C6-alkyl, halo-d-Cs-alkoxy-d-C6-alkyl, - NR10R11 ; R10 and R11, independently from one another, represent a group selected from : H, d-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-CrC6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a third variant of the first aspect, the present invention covers compounds of formula (Ic) :
Figure imgf000012_0001
(I )
in which
Ri, Rz represent H ;
R3 represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-C C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-C6-alkyl, Ci-Cs-alkoxy, halo-Ci-C6- alkoxy, C3-Cio-cycloalkyl ;
represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000013_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci -Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci - C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci -C6-alkyl)S(=0)2R9, C(=0)NR10R11 , -OC(=0)NR10R11 , -N(H)C(=0)0R9, -N(Ci -C6- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11 , -N(Ci-C6-alkyl)C(=O)NR10R11 , - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , -NR10R11 ;
R8 represents a substituent selected from : H, halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
R9 represents a group selected from : d -Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci -C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci -Cs-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11 , independently from one another, represent a group selected from : H, Ci -Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci -C6-alkyl, Ci -C6- alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci -C6-alkyl ;
or
R10 and R11 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-CrC6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The terms as mentioned in the present text have preferably the following meanings : The term "Ci -Cs-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, particularly 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl"), e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, /so-propyl, /so-butyl, sec-butyl, tert-butyl, /so-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 is methyl, ethyl, n-propyl- or /so-propyl.
The term "halo-Ci -C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "d - Cs-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in the same way or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said halo-Ci -C6-alkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3, or - CH2CF3. The term "Ci -C6-alkoxy" is to be understood as preferably 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, /so-propoxy, n-butoxy, /so-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso- pentoxy, or n-hexoxy group, or an isomer thereof.
The term "halo-Ci -C6-alkoxy" is to be understood as preferably 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 the same way or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-Ci-C6-alkoxy group is, for example, -OCF3, -0CHF2, -0CH2F, - OCF2CF3, or -OCH2CF3.
The term "Ci-C6-alkoxy-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a Ci-C6-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, /so-propoxyalkyl, butoxyalkyl, /so-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, /so-pentyloxyalkyl, hexyloxyalkyl group, in which the term "Ci -Cs-alkyl" is defined supra, or an isomer thereof.
The term "halo-C C6-alkoxy-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C6-alkoxy-Ci -Cs-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-Ci-C6-alkoxy-Ci-C6-alkyl group is, for example, - CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3, or - CH2CH2OCH2CF3.
The term "halogen atom" or "halo" is to be understood as preferably meaning a fluorine, chlorine, bromine, or iodine atom.
The term "C2-C6-alkenyl" is to be understood as preferably 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, 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)-buM -enyl, (Z)-buM -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-1 -enyl, (Z)-hex-l-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2- methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2- enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1 -enyl, (E)-2-methylbut-1-enyl, (Z)-2- methylbut-1 -enyl, (E)-1-methylbut-1-enyl, (Z)-1 -methylbut-1 -enyl, 1,1- dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 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)-1 -methylpent-3- enyl, (Z)-1-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)-1-methylpent-2-enyl, (Z)-1 -methylpent-2- enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1 -enyl, (E)-3-methylpent-1- enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1 -enyl, (Z)-2-methylpent-1- enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2- ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2- enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1 -ethylbut-2-enyl, (Z)-1- ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbuM- enyl, (E)-1 -ethylbut-1 -enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1- propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2- propylprop-1 -enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1- propylprop-1 -enyl, (E)-2-isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl, (E)- 1 -isopropylprop-1 -enyl, (Z)- 1 -isopropylprop-1 -enyl, (E)-3,3-dimethylprop- 1 - enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3- dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl. The term "C2-C6-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, prop- 1 -ynyl, prop-2-ynyl, but- 1 -ynyl, but-2-ynyl, but-3-ynyl, pent- 1 - ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex- 1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut- 3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut- 1 -ynyl, 1 -ethylprop-2-ynyl, 3- methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent- 3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4- methylpent- 1 -ynyl, 3-methylpent- 1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethyl- but-3-inyl, 1 , 1 -dimethylbut-3-ynyl, 1 , 1 -dimethylbut-2-ynyl, or 3,3-dimethyl- but- 1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop- 1 -ynyl, or prop-2-inyl.
The term "C3-Cio-cycloalkyl" is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, particularly 3, 4, 5, or 6 carbon atoms ("C3-C6-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 group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Said cycloalkyl ring can optionally contain one or more double bonds e.g. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated . The term "3- to 10-membered heterocycloalkyl" is to be understood as preferably meaning a saturated or partially unsaturated, monovalent, mono- or tricyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and 1 , 2 or 3 heteroatom-containing groups selected, independently from each other, from C(=0), 0, S, S(=0), S(=0)2, NH, NR' , wherein R' represents a Ci -C6-alkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C(=0)R9, C(=0)NR10R11 , -S(=0)2R9, -S(=0)2NR10R11 group as defined supra, it being understood that when said R' represents a C3-C6 heterocycloalkyl group, then said C3-C6 heterocycloalkyl group is present only once. Particularly, said ring can contain 2, 3, 4, or 5 carbon atoms, and 1 , 2 or 3 of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and 1 , 2 or 3 of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl"). Said heterocycloalkyl ring is for example, a monocyclic heterocycloalkyl ring such as an oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, or chinuclidinyl group. Optionally, said heterocycloalkyl ring can contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2, 5-dihydro- 1 H-pyrrolyl, [1 ,3]dioxolyl, 4H- [1 , 3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2, 5- dihydrothiophenyl, 2,3-dihydrothiophenyl, 4, 5-dihydrooxazolyl, or 4H- [1 ,4]thiazinyl group, or, it may be benzo fused.
The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono- , or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 1 3 or 14 carbon atoms (a "C6-Ci4-aryl" group), particularly a ring having 6 carbon atoms (a "C6-aryl" group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "C9-aryl" group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 1 3 carbon atoms, (a "Ci3-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci4-aryl" group), e.g. an anthranyl group. The term "heteroaryl" is understood as preferably meaning a monovalent, aromatic, mono- or bicyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur, and can be monocyclic, bicyclic, or tricyclic, 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, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. , and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc. ; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc. More particularly, heteroaryl is selected from pyridyl, benzofuranyl, thienyl, quinolinyl, benzothienyl, pyrazolyl, or furanyl.
The term "alkylene" is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether") having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH2- ("methylene" or "single membered tether" or e.g. -C(Me)2-), -CH2-CH2- ("ethylene", "dimethylene", or "two- membered tether"), -CH2-CH2-CH2- ("propylene", "trimethylene", or "three- membered tether"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene", or "four-membered tether"), -CH2-CH2-CH2-CH2-CH2- ("pentylene", "pentamethylene" or "five- membered ether"), or -CH2-CH2-CH2-CH2-CH2-CH2- ("hexylene", "hexamethylene", or six-membered tether") group. Particularly, said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms. The term "C1 -C6", as used throughout this text, e.g. in the context of the definition of "Ci -Cs-alkyl", "Ci -C6-haloalkyl", "d -Cs-alkoxy", or "C1 -C&- 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 "d -Cs" is to be interpreted as any subrange comprised therein, e.g. Ci -Cs , C2-Cs , C3-C4 , Ci -C2 , C1 -C3 , C1 -C4 , C1 -C5 C1 - Cs ; particularly Ci -C2 , C1 -C3 , C1 -C4 , C1 -C5 , Ci -C6 ; more particularly C1 -C4; in the case of "Ci -C6-haloalkyl" or "d -Cs-haloalkoxy" even more particularly Ci - 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. Ci-Ce , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-Cs ; particularly C2-C3. Further, as used herein, the term "C3-C10", as used throughout this text, e.g. in the context of the definition of "C3-Cio-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C10" is to be interpreted as any sub-range comprised therein, e.g. C3-C10 , C4-C9 , Cs-Cs , C6- C7 ; particularly C3-C6.
The compounds of the present invention can exist in the form of stereoisomers. In stereoisomers, the atoms are connected sequentially in the same way, such that condensed formulae for two isomeric molecules are identical. The isomers differ, however, in the way the atoms are arranged in space. There are two major sub-classes of stereoisomers; conformational isomers, which interconvert through rotations around single bonds, and configurational isomers, which are not readily interconvertable. Configurational isomers are, in turn, comprised of enantiomers and diastereomers. Enantiomers are stereoisomers which are related to each other as mirror images. Enantiomers can contain any number of stereogenic centres, as long as each centre is the exact mirror image of the corresponding centre in the other molecule. If one or more of these centres differs in configuration, the two molecules are no longer mirror images. Stereoisomers which are not enantiomers are called diastereomers. Diastereomers which still have a different constitution, are another sub-class of diastereomers, the best known of which are simple cis - trans isomers. In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H 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 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, viz. :
Figure imgf000023_0001
1 H-tautomer 2H-tautomer 4H-tautomer
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N- oxides.
Further, the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, 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-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
As used herein, the term "in vivo hydrolysable ester" is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-C6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-Ci-C6 alkyl esters, e.g. 1 - cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl- 1 ,3-dioxolen-2-onylmethyl ; and Ci-C6-alkoxycarbonyloxyethyl esters, e.g. 1 - methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.
Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy. A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid- addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, sulphuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, 3-hydroxy-2- naphthoic, sulphamic, trifluoromethanesulphonic, benzenesulphonic, para- toluenesulphonic, methylsulphonic, naphthalinedisulphonic, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, maleic, fumaric, D-gluconic, or sulphosalicylic acid, for example. Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl- glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl- aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol.
The present invention includes all possible salts of the compounds of the present invention 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 the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
In accordance with a particular embodiment of the first variant of the first aspect, the present invention covers compounds of formula (la), supra, in which :
Ri , R2 , independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci -C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d -Cs-alkyl, Ci-C6-alkoxy, halo-Ci -C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -Ci-Cs-alkylene-C3-Cio-cycloalkyl, d-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-d-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d-C6-alkyl, d-Cs-alkoxy, halo-d-C6- alkoxy, C3-do-cycloalkyl ;
represents a substituent selected from : halo, cyano, d-Cs-alkyl, halo-d-Cs-alkyl, d-C6-alkoxy, halo-Ci-C6-alkoxy, d-C6-alkoxy-d- Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000027_0001
; wherein said Ci-Ce-alkyl, halo-Ci -Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
represents a group selected from : Ci -Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-C C6-alkoxy-Ci-C6-alkyl, - NR10R11 ; R10 and R11 , independently from one another, represent a group selected from : H, d -Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci -C6-alkyl, d -C6- alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci -C6-alkyl ;
or
R10 and R11 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, d-C6-alkyl, halo-d -C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a more particular embodiment of the first variant of the first aspect, the present invention covers compounds of formula (la), supra, in which :
Ri , R2 , independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-d -C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, d -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d -C6-alkyl, d-C6-alkoxy, halo-d -C6- alkoxy, d-C6-alkoxy-d -Cs-alkyl, halo-d-C6-alkoxy-d -C6-alkyl, C3- do-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-d -Cs-alkyl, -C(=O)O-C3-d0-cycloalkyl, -N(H)C(=0)R9, -N(d - C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci -C6-alkyl)S(=0)2R9, C(=O)NR10R11 , -OC(=O)NR10R11 , -N(H)C(=0)OR9, -N(Ci -C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ; represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C3- Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-Cs-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Cr Cs-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=0)NR10R11, N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-Cs-cycloalkyl ; represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000029_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -
C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
R9 represents a group selected from : Ci -Cs-alkyl, C3-Cio-cycloalkyl,
halo-Ci -Cs-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-C C6-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-C6-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-CrC6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, -C(=0)CH3,
S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with an even more particular embodiment of the first variant of the first aspect, the present invention covers compounds of formula (la), supra, in which :
Ri , R2 , independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl,
Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d -Cs-alkyl, Ci-C6-alkoxy, halo-d -C6- alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci -C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, -N(H)C(=0)R9, -N(Ci - Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci -C6-alkyl)S(=0)2R9,
C(=O)NR10R11 , -OC(=O)NR10R11 , -N(H)C(=0)OR9, -N(Ci -C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci-C6-alkyl)C(=O)NR10R11 , - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ;
R3 represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci-C6-alkyl, C3-do- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -Cs-alkylene-heteroaryl, -Ci -C6-alkylene-C3- Cio-cycloalkyl, Ci-C6-alkylene-heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-Cs-cycloalkyl ; represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000032_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=0)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)0R9, -N(Ci-C6- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
R9 represents a group selected from : Ci-C3-alkyl, C3-C6-cycloalkyl, halo-C C3-alkyl, aryl, heteroaryl, Ci-C3-alkoxy-Ci-C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy,
Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, -NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-C3-alkyl, C3-Cio-cycloalkyl, halo-Ci-C3-alkyl, C1-C3- alkoxy-Ci-C3-alkyl, halo-Ci-C3-alkoxy-Ci-C3-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-Ci-C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3,
S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In accordance with a particular embodiment of the second variant of the first aspect, the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci -C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-Ci -C6-alkyl, halo-Cr C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=O)NR10R11 , -OC(=O)NR10R11 , N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci - C6-alkyl)C(=O)NR10R11 , -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -C6-alkylene-aryl, Ci -C6- alkylene-heteroaryl, -Ci -C6-alkylene-C3-Cio-cycloalkyl, Ci -C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=0)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)0R9, -N(Ci-Cs- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R4, R5,
R6, R7, and
R8 represent H ;
R9 represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-CrCs-alkyl , aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-CrC6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In accordance with a more particular embodiment of the second variant of the first aspect, the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci -C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-Ci -C6-alkyl, halo-Cr C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=O)NR10R11 , -OC(=O)NR10R11 , N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci - C6-alkyl)C(=O)NR10R11 , -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - C6-alkoxy-Ci-C6-alkyl, halo-Ci -Cs-alkoxy-Ci-C6-alkyl, C3-Cio- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C3- Cio-cycloalkyl, Ci -C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci -Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Cr Cs-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, -C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=0)NR10R11, -OC(=0)NR10R11, N(H)C(=0)0R9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=0)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
R4, R5,
R6, R7, and
R8 represent H ;
R9 represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-CrC6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In accordance with an even more particular embodiment of the second variant of the first aspect, the present invention covers compounds of formula (lb), supra, in which : independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci -C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-Ci -C6-alkyl, halo-Cr C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=O)NR10R11 , -OC(=O)NR10R11 , N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci - C6-alkyl)C(=O)NR10R11 , -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H; represents a group selected from : Ci -C6-alkyl, halo-Ci-C6-alkyl, d - Cs-alkoxy-Ci-C6-alkyl, halo-CrC6-alkoxy-Ci-C6-alkyl, C3-Cio- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -C6-alkylene-heteroaryl, -Ci -Cs-alkylene-C3- Cio-cycloalkyl, Ci-C6-alkylene- heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci -C6-alkyl, Ci-C6-alkoxy, halo-Ci -C6- alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, - C(=0)0-Ci -Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci - C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci -C6-alkyl)S(=0)2R9, C(=0)NR10R11 , -OC(=0)NR10R11 , -N(H)C(=0)0R9, -N(Ci -C6- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11 , -N(Ci-C6-alkyl)C(=O)NR10R11 , - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , -NR10R11 ;
R4, R5,
R6, R7, and
R8 represent H ;
R9 represents a group selected from : Ci-C3-alkyl, C3-C6-cycloalkyl, halo-C C3-alkyl, aryl, heteroaryl, Ci-C3-alkoxy-Ci-C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, Ci -Cs-alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci-C6-alkyl, -NR10R11 ; R10 and R11 , independently from one another, represent a group selected from : H, Ci -C3-alkyl, C3-Cio-cycloalkyl, halo-Ci -C3-alkyl, Ci -C3- alkoxy-Ci-C3-alkyl, halo-Ci -C3-alkoxy-Ci -C3-alkyl ;
or
R10 and R11 , together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-Ci -C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a particular embodiment of the third variant of the first aspect, the present invention covers compounds of formula (Ic), supra, in which : represent H ;
represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, d-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-d-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(d-Cs- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d-C6-alkyl, d-Cs-alkoxy, halo-d-C6- alkoxy, C3-Cio-cycloalkyl ;
represents a substituent selected from : halo, cyano, d-Cs-alkyl, halo-d-Cs-alkyl, d-C6-alkoxy, halo-Ci-C6-alkoxy, d-C6-alkoxy-d- C6-alkyl, halo-d-C6-alkoxy-d-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, d-C6-alkylene-aryl, d-C6-alkylene-heteroaryl, d-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000040_0001
; wherein said d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-d-C6-alkoxy, Ci-C6-alkoxy-Ci- C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci-
Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R8 represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
R9 represents a group selected from : Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-CrCs-alkyl , aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-Ce- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-C C6-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-C6-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-Ci-C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-CrC6-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a more particular embodiment of the third variant of the first aspect, the present invention covers compounds of formula (Ic), supra, in which : represent H ;
represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci- Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -Cs-alkylene-heteroaryl, -Ci -Cs-alkylene-C3- Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, d-Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Cr Cs-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-Cs-cycloalkyl ; represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000043_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents a substituent selected from : H, halo, cyano, C1-C3- alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
represents a group selected from : d-Cs-alkyl, C3-Cio-cycloalkyl, halo-C C6-alkyl, aryl, heteroaryl, Ci-C6-alkoxy-Ci-C6-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Ce-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, - NR10R11 ;
R10 and R11, independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or
R10 and R11, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-Ci-C6- alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with an even more particular embodiment of the third variant of the first aspect, the present invention covers compounds of formula (Ic), supra, in which : Ri, R2 represent H ;
R3 represents a group selected from : Ci-C6-alkyl, halo-Ci-C6-alkyl, d-
Cs-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, C3-Cio- cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci -Cs-alkylene-aryl, Ci -Cs-alkylene-heteroaryl, -Ci -Cs-alkylene-C3- Cio-cycloalkyl, Ci-C6-alkylene- heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -
C(=0)0-Ci-C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, -N(H)C(=0)R9, -N(Ci- Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
represents H ;
represents H ;
represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6-cycloalkyl ; represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000045_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Cr Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, Ci-C6- alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-C6-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-C C6-alkoxy-Ci-C6-alkyl, C3-C10- cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)OR9, -N(Ci-Cs- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ; R8 represents a substituent selected from : H, halo, cyano, C1 -C3- alkyl, halo-C C3-alkyl, Ci -C3-alkoxy, halo-Ci -C3-alkoxy, C3-C6- cycloalkyl ;
R9 represents a group selected from : Ci -C3-alkyl, C3-C6-cycloalkyl, halo-C C3-alkyl, aryl, heteroaryl, Ci -C3-alkoxy-Ci -C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci -C6-alkyl, halo-Ci -C6-alkyl, Ci -C6-alkoxy, Ci -Cs-alkoxy-Ci -C6-alkyl, halo-CrC6-alkoxy-Ci -C6-alkyl, -NR10R11 ; R10 and R11 , independently from one another, represent a group selected from : H, Ci -C3-alkyl, C3-Cio-cycloalkyl, halo-C C3-alkyl, C1 -C3- alkoxy-Ci -C3-alkyl, halo-Ci -C3-alkoxy-Ci -C3-alkyl ;
or
R10 and R11 , together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci -C6-alkyl, halo-CrC6- alkyl, Ci -C6-alkoxy, Ci -C6-alkoxy-Ci -Cs-alkyl, -C(=0)CH3, S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
It is to be understood that the present invention relates to : * any sub-combination within any embodiment of the first variant of the first aspect of the present invention of compounds of formula (la), supra ;
* any sub-combination within any embodiment of the second variant of the first aspect of the present invention of compounds of formula (lb), supra ; and
* any sub-combination within any embodiment of the third variant of the first aspect of the present invention of compounds of formula (Ic), supra.
More particularly still, the present invention covers compounds of formula (la), formula (lb) and formula (Ic) which are disclosed in the Example section of this text, infra.
In another aspect, the present invention covers a method of preparing compound of formula (la) or (lb) as defined herein, in which method intermediate compound of formula (5a) or (5b) :
Figure imgf000047_0001
(5a) (5b) in which Ri, R2 represent H, and R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb), respectively, as defined herein, is allowed to react with an electrophile of formula :
Ri-Y, and/or R2-Y, in which Ri and R2 are as defined for the compound of formula (la) or (lb), respectively, as defined herein, and Y is a leaving group, such as CI, Br, I, methanesulphonate,
to provide a compound of formula (la) or (lb) :
Figure imgf000048_0001
respectively, in which Ri, R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb), respectively, as defined herein.
In another aspect, the present invention covers a method of preparing a compound of formula (Ic) as defined herein, in which method an intermediate haloketone compound of formula (3c) :
Figure imgf000048_0002
(3c) in which X represents halogen, and R4, R5, R6, R7 and R8 are as defined for the compound of formula (Ic) as defined herein,
is allowed to react with an intermediate amine compound of general formula (4c) :
R3— NH2
(4c) in which R3 is as defined for the compound of formula (I) as defined herein, to provide a compound of formula (Ic) :
Figure imgf000049_0001
(I ) in which Ri , R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (I) as defined herein .
In an embodiment of the above-mentioned aspect for preparing a compound of formula (Ic), supra, said intermediate haloketone compound of formula (3c) is prepared by allowing an intermediate nitrile compound of formula (2c) :
Figure imgf000049_0002
(2c) in which R4, R5, R6, R7, and R8, are as defined for the compound of formula (Ic) as defined herein,
to react with an intermediate haloacyl halide compound of formula (2c' ) :
Figure imgf000049_0003
(2c' ) in which X and X', independently of each other, represent a halogen atom, thus providing said intermediate nitrile compound of formula (3c). In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of formula (la) or (lb), particularly in the method described herein. In particular, the present invention covers compounds of formula (5a) or (5b) :
Figure imgf000050_0001
in which Ri, R2 represent H, and R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb) supra, respectively, for the preparation of a compound of formula (la) or (lb) supra, respectively.
In accordance with a further aspect, the present invention covers the use of the intermediate compounds of formula (5a) or (5b) :
Figure imgf000050_0002
in which Ri, R2 represent H, and R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb) as defined herein, for the preparation of a compound of formula (la) or (lb), respectively, as defined herein. In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of formula (Ic), particularly in the method described herein. In particular, the present invention covers compounds of formula (3c) and (2c) :
Figure imgf000051_0001
(3c),
Figure imgf000051_0002
(2c)
in which X represents a halogen atom, and R4, R5, R6, R7 and R8 are as defined for the compound of formula (Ic) supra, for the preparation of a compound of formula (Ic) supra, respectively. In accordance with a further aspect, the present invention covers the use of intermediate compounds for preparing compounds of the present invention of formula (Ic), particularly in the method described herein. In particular, the present invention covers the use of com ounds of formula (3c) and (2c) :
Figure imgf000051_0003
(3c),
Figure imgf000052_0001
in which X represents a halogen atom, and R4, R5, R6, R7 and R8 are defined for the compound of formula (Ic) supra, in the preparation of compound of formula (Ic) supra, respectively.
EXPERIMENTAL SECTION
As mentioned supra, another aspect of the present invention is a method which may be used for preparing the compounds according to the present invention.
The following Table lists the abbreviations used in this paragraph, and in the Examples section. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
Abbreviation Meaning
Ac Acetyl
BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl
Boc tert-butyloxycarbonyl
Br Broad
c- cyclo-
D Doublet
Dd doublet of doublets
DCM dichloromethane
DME 1 ,2-dimethoxyethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Dppf 1 , 1 '-bis(di-phenylphosphino)ferrocene
Eq Equivalent
ESI Electrospray ionization
□HMDS lithium bis(trimethylsilyl)amide (alternative name: lithium hexamethyldisilazide
M Multiplet
mp. melting point in °C MS mass spectrometry
MW molecular weight
NMP N-methylpyrrolidinone
NMR nuclear magnetic resonance spectroscopy : chemical shifts (δ) are given in ppm.
Pd(dba)2 bis-(dibenzylideneacetone)-palladium(0) complex
Pd2(dba)3 tn's-(dibenzylideneacetone)-dipalladium(0)-chloroform complex
P(oTol)3 tri-o-tolylphosphine
q Quartet
rt room temperature
RT retention time in minutes
s Singlet
sept Septet
t, td triplet, triplet doublet
TEA triethylamine
TFA trifluoroacetic acid
THF Tetrahydrofuran
Ts para toluenesulfonyl (tosyl)
UPLC ultra performance liquid chromatography
Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
The schemes and procedures described below illustrate general synthetic routes to the compounds of formula (la), (lb) and (lc) of the present invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in the Schemes can be modified in various ways. The order of transformations exemplified in the Schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, Ri, R2, R3, R4, R5, R6, R7, or R8, can be achieved before and /or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs. Reaction schemes are outlined infra :
Synthesis of compounds of formula (la) or (lb)
Scheme 1
Figure imgf000055_0001
and/or
(la,b) R2— Y <5a'b) wherein X and X' represent halogen (X' being independent of X), Y is a leaving group, such as CI, Br, I, methanesulphonate, etc.), and R1, R2, R3, R4, R5, R6, R7 and R8 have the meaning as given for compounds of formula (la) or (lb), respectively, supra. Compounds of formula (la) or (lb) can be synthesised according to the procedure depicted in Scheme 1 . In particular, a suitably substituted anthranilic acid intermediate of formula (1 a,b) is converted to the corresponding nitrile of formula (2a, b) by reaction with, for example: A) cyanothioacetamide in the presence a suitable base such as, for example triethylamine, in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent; or B) cyano(methylthio)acetamide (generated in situ by the reaction of cyanothioacetamide, a suitable base, such as sodium ethoxide, and a suitable methylating agent, such as methyl iodide, in a suitable solvent such as ethanol) in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent [see for example the preparation of (4-oxo-3,4-dihydro-quinazolin-2- yl)-acetonitrile; M. A. Abdel Aziz et al J . Prakt. Chem. 1990, vol 332, 610- 618] . The person skilled in the art will recognise that there are many precedented methods for synthesising suitable anthranilic acids of formula (1 a, b); some anthranilic acids may be obtained commercially. Intermediates of formula (2a, b) may be converted to haloketone intermediates of formula (3a, b) by reaction with a suitable haloacyl halide of formula (2'a, b), such as chloroacetyl chloride (in the case when X = CI), in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dioxane, at temperatures ranging from room temperature to the boiling point of the solvent, preferably 50 ° C. Intermediates of formula (3a, b) may be cyclised by reaction with a suitable amine, R3-NH2 of formula (4a, b), in the presence or absence of a suitable base, whereby no additional base is necessary if an excess of R3-NH2 is employed, in a suitable solvent such as n-butanol, at elevated temperatures, such as for example 150 ° C under microwave irradiation, to produce an intermediate ketone of formula (5a, b). Similar chemistry has been described by Resnyanskaya et al (Chemistry of Heterocyclic Compounds, vol 35, No. 10, 1999, p1230) to prepare a compound in which R3 is p-benzoic acid methyl ester and Ri , R2, R4, R5, R6, R7, and R8 are all hydrogen. Finally, intermediates of formula (5a, b) are reacted with suitable electrophiles, of formula Ri -Y, and/or R2-Y, (in which Ri and R2 are as defined for the compound of general formula (I) supra, and Y is a leaving group, such as CI, Br, I, methanesulphonate, etc.), such as alkylating agents, acylating agents, sulfonylating agents or the like, in the presence of a suitable base, such as, for example, Cs2C03 or LiHMDS, in a suitable solvent such as DMF, or THF, at temperatures ranging from 0 °C to 50 °C, to furnish compounds of formula (la,b). In the case in which Ri and R2 are different and R2 is not hydrogen, the person skilled in the art will recognise that the appropriate choice of reaction conditions, such as temperature, stoichiometry or concentration may allow selective functionalisation to introduce only one Ri substituent; the R2 substituent may then be introduced by subsequent reaction with the appropriate electrophile as described above. Synthesis of compounds of formula (Ic)
Scheme 2
Figure imgf000057_0001
(Ic) wherein X and X' represent halogen (X' being independent of X), and R1 , R2, R3, R4, R5, R6, R7 and R8 have the meaning as given for formula (Ic), supra. Compounds of formula (Ic) can be synthesised according to the procedure depicted in Scheme 2. In particular, a suitably substituted anthranilic acid intermediate of formula ( 1 c) is converted to the corresponding nitrile of formula (2c) by reaction with, for example: A) cyanothioacetamide in the presence a suitable base such as, for example triethylamine, in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent; or B) cyano(methylthio)acetamide (generated in situ by the reaction of cyanothioacetamide, a suitable base, such as sodium ethoxide, and a suitable methylating agent, such as methyl iodide, in a suitable solvent such as ethanol) in a suitable solvent, such as, for example, ethanol, at temperatures ranging from room temperature to the boiling point of the solvent [see for example the preparation of (4-oxo-3,4-dihydro-quinazolin-2-yl)-acetonitrile; M. A. Abdel Aziz et al J . Prakt. Chem. 1990, vol 332, 610-618] . The person skilled in the art will recognise that there are many precedented methods for synthesising suitable anthranilic acids of formula (1 c); some anthranilic acids may be obtained commercially. Intermediates of formula (2c) may be converted to haloketone intermediates of formula (3c) by reaction with a suitable haloacyl halide of formula (2'c), such as chloroacetyl chloride (in the case when X = CI), in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dioxane, at temperatures ranging from room temperature to the boiling point of the solvent, preferably 50 ° C. Finally, intermediates of formula (3c) may be cyclised by reaction with a suitable amine, R3- NH2 of formula (4c), in the presence or absence of a suitable base, whereby no additional base is necessary if an excess of R3- NH2 is employed, in a suitable solvent such as n-butanol, at elevated temperatures, such as for example 150 ° C under microwave irradiation, to produce compounds of formula (Ic) of the present invention . Similar chemistry has been described by Resnyanskaya et al (Chemistry of Heterocyclic Compounds, vol 35, No. 10, 1999, p1230) to prepare a compound in which R3 is p-benzoic acid methyl ester and Ri , R2, R4, R5, R6, R7, and R8 are all hydrogen . The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a suitable autopurifier such as a Flashmaster II autopurifier (Biotage) and eluants such as, for example, gradients of hexane/EtOAc, DCM/ethanol or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
Further, the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Analytical UPLC-MS was performed as follows:
Column: Acquity BEH C18 1 .7μιη 50x2.1 mm
Solvent A: H20 / 0.1 % HCOOH
Solvent B: Acetonitrile Gradient: 0 min 99%A 1%B
1 .6 min 1%A 99%B
2.0 min 1%A 99%B
Flow: 0.8 mL/min
Solution: 0.5 mg/mL ACN/H20 7:3
Injection Volume: 2.0 μΐ
Detection: DAD scan range 210-400 nm
ELSD MS ESI+, ESI-, scan range 160-1000 m/z
Temperature: 60° C
Names of compounds were generated using the Autonom 2000 add-in of ISIS/Draw [MDL Information Systems Inc. (Elsevier MDL)].
A. INTERMEDIATES FOR THE PREPARATION of COMPOUNDS of FORMULA (la) and (lb) :
Intermediate Example 1.1 : Preparation of 4-chloro-2-[7-methyl-4-oxo-3,4- dihydro-1 H-quinazolin-(2Z)-ylidene]-3-oxo-butyronitrile (Intermediate 1 )
Figure imgf000061_0001
Step A: Preparation of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile
Figure imgf000061_0002
To a stirred solution of 2-cyano-thioacetamide (0.66 g, 6.62 mmol) in ethanol (17.4 mL), was added successively a solution of sodium ethoxide in ethanol (2.96 mL, 7.94 mmol) and methyl iodide (0.45 mL, 7.28 mmol). The mixture was stirred for 2 h before the addition of 2-amino-4-methyl-benzoic acid (1 g, 6.62 mmol). The mixture was heated at reflux for 4 h (the evolved gas was allowed to pass through a wash bottle containing dilute sodium hydroxide) before allowing to cool overnight at room temperature. The precipitate was filtered and the residue washed with ethanol and dried to give (7-methyl-4- oxo-3,4-dihydro-quinazolin-2-yl)-acetonitrile (0.78 g, 60%): UPLC-MS: RT = 0.85 min; m/z (ES+) 200.32, 201 .31 [MH+]; required MW = 199.21. Step B: Preparation of 4-chloro-2-[7-methyl-4-oxo-3,4-dihydro-1 H-quinazolin- (2Z)-ylidene]-3-oxo-butyronitrile (Intermediate 1 .0)
Figure imgf000062_0001
To a stirred suspension of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile (0.785 mg, 3.94 mmol) in dry dioxane (10 mL) was added triethylamine (0.63 mL, 4.53 mmol) and the mixture was heated to 50 °C (bath temperature). Chloroacetyl chloride (0.36 mL, 4.53 mmol) was added dropwise, whereupon the suspension dissolved. The reaction was heated for a further 2.5 h at this temperature, before a further portion of chloroacetyl chloride was added. The reaction was heated for a further 2 hours before allowing to cool to rt overnight. The resulting suspension was filtered and the residue washed with dioxane and dried to give the crude Intermediate 1 (contaminated with triethylamine hydrochloride): UPLC: RT = 1.00 min; m/z (ES+) 276.29, 278.28 [MH+, CI isotopes]; required MW = 275.69.
The crude solid was suspended in water, filtered, washed with water and dried to give pure 4-chloro-2-[7-methyl-4-oxo-3,4-dihydro-1 H-quinazolin-(2Z)- ylidene]-3-oxo-butyronitrile (Intermediate 1 ) (0.67 g, 62%): 1H-NMR (300 MHz, de-DMSO): δ = 7.88 (1 H, d), 7.61 (1 H, br s), 7.25 (1 H, br d), 4.49 (2H, s), 2.40 (3H, s) ppm.
The following intermediate examples were prepared analogously to the procedures described above :
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Intermediate Example 2.0 : Preparation of 2-[2-amino-1 -(2-fluoro- phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]-7-methyl-3H-quinazolin-4- one
Figure imgf000066_0001
A mixture of crude Intermediate 1 (250 mg), 2-fluoroaniline (0.26 mL) and n- butanol (1 .66 mL) were combined in a sealed vial and heated at 150 °C under microwave irradiation for 45 min. On cooling, the solid was filtered, washed with n-butanol and dried to give 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5- dihydro-1 H-pyrrol-3-yl]-7-methyl-3H-quinazolin-4-one (130 mg): 1H-NMR (300 MHz, de-DMSO): δ = 11 .78 (1 H, br s), 9.01 (1 H, br s), 8.45 (1 H, br s), 7.88 (1 H, d), 7.59 - 7.65 (1 H, m), 7.40 - 7.52 (3H, m), 7.30 - 7.36 (1 H, m), 7.10 - 7.13 (1 H, unresolved dd), 4.29 (2H, s), 2.37 (3H, s) ppm; UPLC-MS: RT = 1.07 min; m/z (ES+) 351 .36, 352.35 [MH+]; required MW = 350.35.
The following intermediate examples were prepared analogously to the procedures described above [UPLC-MS data such as retention time (RT in min) or observed mass peak were collected using the method above] :
Figure imgf000067_0001
Figure imgf000068_0001
Intermediate
Structure / Name Analytical Data
Example No.
2.7 0 1H-NMR (400 MHz, d6-DMSO) δ =
11.90 (1H, s), 8.83 (1H, s), 8.34 (1H, s), 7.98-8.02 (1H, m), 7.38-7.41 (1H, m), 7.06-7.11 (1H, m), 4.22-4.28
2-[2-amino-1-isopropyl- (1H, m), 3.87 (2H, s), 1.16 (6H, d) 4-0X0-4, 5-dihydro-1H- ppm.
pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one
2.8 0 1H-NMR (400 MHz, d6-DMSO) δ =
11.84 (1H, s), 8.70 (1H, s), 8.26 (1H,
)> s), 7.98-8.02 (1H, m), 7.36-7.39 (m,
1H), 7.06-7.09 (1H, m), 3.88 (2H, s),
2-[2-amino-1- 2.70-2.73 (1H, m), 0.77-0.80 (4H, m) cyclopropyl-4-oxo-4,5- ppm.
dihydro-1H-pyrrol-3-yl]-
7-fluoro-3H-quinazolin-
4-one
2.9 0 1H-NMR (300 MHz, d6-DMSO) δ =
11.94 (1H, s), 8.93 (1H, s), 8.36 (1H,
H2N s), 8.02-8.07 (1H, m), 7.32-7.53 (6H, b m), 7.09-7.16 (1H, m), 4.39 (2H, s)
2-[2-amino-4-oxo-1 - ppm.
phenyl-4,5-dihydro-1H- pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one Intermediate
Structure / Name Analytical Data
Example No.
2.10 0 1H-NMR (400 MHz, d6-DMS0) δ =
11.88 (1H, s), 8.92 (1H, s), 8.48 (1H, s), 8.02-8.06 (1H, m), 7.60-7.64 (1H, m), 7.40-7.50 (3H, m), 7.31-7.35
2-[2-amino-1-(2-fluoro- (1H, m), 7.10-7.15 (1H, m), 4.31 phenyl)-4-oxo-4,5- (2H, s) ppm.
dihydro-1H-pyrrol-3-yl]-
7-fluoro-3H-quinazolin-
4-one
2.11 0 1H-NMR (300 MHz, d6-DMS0) δ =
11.93 (1H, s), 8.87 (1H, s), 8.31 (1H,
H2N s), 8.01-8.07 (1H, m), 7.50-7.55 (2H, m), 7.31-7.44 (3H, m), 7.09-7.15
F
(1H, m), 4.35 (2H, s) ppm.
2-[2-amino-1-(4-fluoro- phenyl)-4-oxo-4,5- dihydro-1H-pyrrol-3-yl]-
7-bromo-3H-quinazolin-
4-one
2.12 0 1H-NMR (400 MHz, d6-DMS0) δ =
11.93 (1H, s), 8.82 (1H, s), 8.34 (1H, s), 7.93 (1H, d), 7.72 (1H, d), 7.25 (1H, dd), 4.21-4.30 (1H, m), 3.87
2-[2-amino-1-isopropyl- (2H, s), 1.15 (6H, d) ppm.
4-0X0-4, 5-dihydro-1H- pyrrol-3-yl]-7-chloro-3H- quinazolin-4-one
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
EXAMPLES of COMPOUNDS of FORMULA (la) Compound Example 1.0a: Preparation of 7-bromo-2-[1 -(2-fluoro-phenyl)-2- (2-morpholin-4-yl-ethylamino)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]-3H- quinazolin-4-one
Figure imgf000075_0002
A mixture of 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl] 3H-quinazolin-4-one (Intermediate Example 2.4) (300 mg, 0.72 mmol), Cs2CO (0.71 g, 2.17 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (CAS Nr. 3647-69-6, 202 mg, 1 .08 mmol) in DMF (7.2 ml_), under argon, was stirred at rt for 3 days. The mixture was partitioned between DCM and water, the organic extract was washed with brine, dried and concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel to give 7-bromo-2-[1 -(2-fluoro-phenyl)-2-(2-morpholin-4-yl-ethylamino)-4- oxo-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one (62 mg): 1H-NMR (300 MHz, de-DMSO): δ = 1 1 .91 (1 H, br s), 10.09 (1 H, unresolved t), 7.90 (1 H, d), 7.74 (1 H, m), 7.64 - 7.70 (1 H, m), 7.39 - 7.52 (3H, m), 7.29 - 7.35 (1 H, m), 4.21 - 4.36 (2H, m), 3.59 - 3.62 (4H, m), 2.82 - 2.97 (2H, m), 2.38 - 2.42 (2H, m), 2.30 - 2.35 (4H, m) ppm.
The following compound examples were prepared analogously to the procedures described above [UPLC-MS data such as retention time (RT in min) or observed mass peak were collected using the method described above] :
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
EXAMPLES of COMPOUNDS of FORMULA (lb)
Compound Example 1.0b : Preparation of 2-[1 -(2-fluoro-phenyl)-4- oxo-2-(2-pyrrolidin-1-yl-ethylamino)-4,5-dihydro-1 H-pyrrol-3-yl]-3H- quinazolin-4-one
Figure imgf000081_0001
Step A: Preparation of 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H- pyrrol-3-yl]-3H-quinazolin-4-one
Figure imgf000081_0002
A mixture of 4-chloro-3-oxo-2-(4-oxo-3,4-dihydroquinazolin-2(1 H)- ylidene)butanenitrile (1.5 g, 5.73 mmol, Enamine, Catalog Nr. EN300-14498), 2-fluoroaniline (0.55 mL, 5.73 mmol) and N,N-dimethylaniline (0.73 mL, 5.73 mmol) in n-butanol (28 mL) was heated at reflux for 5 h. On cooling, the precipitate was filtered and washed with n-butanol and water. The crude residue was purified by preparative HPLC to give 2-[2-amino-1 -(2-fluoro- phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one (164 mg): 1H- NMR (600 MHz, d6-DMSO): δ = 1 1.90 (1 H, s), 9.04 (1 H, br s), 8.49 (1 H, br s), 8.03 - 8.05 (1 H, m), 7.70 - 7.73 (1 H, m), 7.64 - 7.67 (1 H, m), 7.61 (1 H, d), 7.50 - 7.54 (1 H, m), 7.44 - 7.47 (1 H, m), 7.35 - 7.38 (1 H, m), 7.32 - 7.34 (1 H, m), 4.34 (2H, s) ppm; LC-MS: RT = 1 .00 min; m/z (ES+) 337.10, 338.20 [MH+]; required MW = 336.32.
Step B: Preparation of 2-[1 -(2-fluoro-phenyl)-4-oxo-2- (2-pyrrolidin- 1 -yl- ethylamino)-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one (Compound Example 1 .0b)
Figure imgf000082_0001
A mixture of 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]- 3H-quinazolin-4-one (200 mg, 0.59 mmol), Cs2C03 (0.58 g, 1 .78 mmol) and 1 - (2-chloro-ethyl)-pyrrolidine hydrochloride (CAS No. 7250-67- 1 , 152 mg, 0.89 mmol) in DMF (6 mL) was stirred at rt for 4 h before heating at 100 °C (bath temperature) for 2 h. On cooling, the mixture was partitioned between DCM and water, the organic extract was dried and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel to give 2-[1 - (2-fluoro-phenyl)-4-oxo-2- (2-pyrrolidin- 1 -yl-ethylamino)-4,5-dihydro-1 H- pyrrol-3-yl]-3H-quinazolin-4-one (85 mg): 1H-NMR (300 MHz, d6-DMSO): δ = 1 1 .88 (1 H, br s), 10.40 (1 H, t), 7.99 - 8.02 (1 H, m), 7.63 - 7.74 (2H, m), 7.39 - 7.52 (3H, m), 7.27 - 7.35 (2H, m), 4.20 - 4.36 (2H, m), 2.77 - 2.96 (2H, m), 2.51 (2H, t, partially obscured by solvent), 2.46 (4H, obscured by solvent), 1 .70 - 1 .75 (4H, m) ppm; UPLC-MS: RT = 0.72 min; m/z (ES+) 434.44 [MH+]; required MW = 433.48. Compound Example 1.1 b : Preparation of 2-[2-ethylamino-1 -(2- fluoro-phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4- one
Figure imgf000083_0001
A mixture of 2-[2-amino- -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]- 3H-quinazolin-4-one (300 mg, 0.89 mmol), Cs2C03 (0.87 g, 2.68 mmol) and ethyl bromide (0.13 ml_, 1.78 mmol) in DMF (9 ml_), under argon, was stirred at rt for 4 h before heating at 100 °C (bath temperature) for 2 h. On cooling, the mixture was partitioned between DCM and water, the organic extract was washed with brine, dried and concentrated in vacuo to give the crude product. The crude product was heated in hot MeOH, filtered and the residue was purified by chromatography on silica gel followed by preparative reverse phase HPLC to give 2-[2-ethylamino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H- pyrrol-3-yl]-3H-quinazolin-4-one (24 mg): 1H-NMR (400 MHz, d6-DMSO): δ = 11.90 (1 H, br s), 10.04 (1 H, t), 8.00 - 8.02 (1 H, m), 7.64 - 7.72 (2H, m), 7.54 (1 H, d), 7.40 - 7.52 (2H, m), 7.29 - 7.35 (2H, m), 4.21 - 4.36 (2H, m), 2.83 - 2.91 (2H, m), 1 .08 (3H, t) ppm; UPLC-MS: RT = 1.26 min; m/z (ES+) 365.40, 366.39 [MH+]; required MW = 364.38. The following compound examples may be prepared analogously to the procedures described above [UPLC-MS data such as retention time (RT in min) or observed mass peak were collected using the method described above]:
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Compound Example 2.0b : Preparation of 2-{1-(2-fluoro-phenyl)-2-[2-(4- methyl-piperazin-1 -yl)-2-oxo-ethylamino]-4-oxo-4,5-dihydro-1 H-pyrrol-3- yl}-3H-quinazolin-4-one
Figure imgf000087_0001
A mixture of 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]- 3H-quinazolin-4-one (200 mg, 0.59 mmol), Cs2C03 (0.58 g, 1 .78 mmol) and 1 - (2-chloroacetyl)-4-methyl-piperazine hydrochloride (Chess GmbH, Mannheim, Germany, 178 mg) in DMF (3.2 mL) was stirred at rt for 3 days. The mixture was partitioned between DCM and water, the organic extract was washed with brine, dried and concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel to give 2-{1 -^-fluorophenyl)^- [2- (4-methyl^iperazin-1 -yl)-2-oxo-ethylamino]-4-oxo-4,5-dih^ 1 H-pyrrol-3-yl}-3H-quinazolin-4-one (103 mg): 1H-NMR (400 MHz, d6-DMS0): δ = 1 1 .83 (1 H, s), 10.88 (1 H, t), 8.00 - 8.02 (1 H, m), 7.71 - 7.75 (1 H, m), 7.61 - 7.65 (2H, m), 7.49 - 7.55 (1 H, m), 7.39 - 7.44 (1 H, m), 7.29 - 7.34 (2H, m), 4.22 - 4.37 (2H, m), 3.67 - 3.80 (2H, m), 3.35 - 3.43 (2H, m), 2.68 - 2.78 (2H, m), 2.02 - 2.24 (7H, m) ppm.
Compound Example 3.0b : Preparation of N-[1 -(2-fluoro-phenyl)-4-oxo-3- (4-oxo-3,4-dihydro-quinazolin-2-yl)-4,5-dihydro-1 H-pyrrol-2-yl]-acetamide
Figure imgf000088_0001
To a stirred and chilled (ice water bath) solution of 2-[2-amino-1 -(2-fluoro- phenyl)-4-oxo-4,5-dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one (100 mg, 0.3 mmol) in DMF (1 .6 mL), under argon, was added LiHMDS (1 .06 M solution in THF, 0.84 mL, 0. 89 mL) dropwise by syringe. The mixture was warmed to rt over 30 min before acetyl chloride (0.025 mL, 0.36 mmol) was added dropwise. The mixture was stirred for 2 h before quenching with saturated aqueous ammonium chloride solution. The mixture was extracted with DCM and the organic extract dried and concentrated in vacuo to give the crude product, which was purified by preparative reverse phase HPLC to give N-[1 - (2-f luoro-phenyl)-4-oxo-3- (4-0X0-3, 4-dihydro-quinazolin-2-yl)-4,5-dihydro-1 H- pyrrol-2-yl]-acetamide (16 mg): 1H-NMR (300 MHz, d6-DMS0): δ = 12.45 (1 H, br s), 1 1 .66 (1 H, br s), 8.08 - 8.1 1 (1 H, m), 7.79 - 7.85 (1 H, m), 7.70 (1 H, d), 7.50 - 7.56 (1 H, m), 7.42 - 7.47 (1 H, m), 7.23 - 7.40 (3H, m), 4.66 (2H, s), 2.24 (3H, s) ppm; UPLC-MS: RT = 1 .1 1 min; m/z (ES+) 379.35, 380.35 [MH+]; required MW = 378.36. EXAMPLES of COMPOUNDS of FORMULA (lc)
Intermediate Example 1.0c: Preparation of 4-chloro-2-[7-methyl-4-oxo-3,4- dihydro-1 H-quinazolin-(2Z)-ylidene]-3-oxo-butyronitrile (Intermediate 1c)
Figure imgf000089_0001
Step A: Preparation of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile
Figure imgf000089_0002
To a stirred solution of 2-cyano-thioacetamide (0.66 g, 6.62 mmol) in ethanol (17.4 mL), was added successively a solution of sodium ethoxide in ethanol (2.96 mL, 7.94 mmol) and methyl iodide (0.45 mL, 7.28 mmol). The mixture was stirred for 2 h before the addition of 2-amino-4-methyl-benzoic acid (1 g, 6.62 mmol). The mixture was heated at reflux for 4 h (the evolved gas was passed through a wash bottle containing dilute sodium hydroxide) before allowing to cool overnight at room temperature. The precipitate was filtered and the residue washed with ethanol and dried to give (7-methyl-4-oxo-3,4- dihydro-quinazolin-2-yl)-acetonitrile (0.78 g, 60%): UPLC-MS: RT = 0.85 min; m/z (ES+) 200.32, 201 .31 [MH+]; required MW = 199.21. Step B: Preparation of 4-chloro-2-[7-methyl-4-oxo-3,4-dihydro-1 H-quinazolin- (2Z)-ylidene]-3-oxo-butyronitrile (Intermediate 1 .0c)
Figure imgf000090_0001
To a stirred suspension of (7-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)- acetonitrile (0.785 mg, 3.94 mmol) in dry dioxane (10 mL) was added triethylamine (0.63 mL, 4.53 mmol) and the mixture was heated to 50 °C (bath temperature). Chloroacetyl chloride (0.36 mL, 4.53 mmol) was added dropwise, whereupon the suspension dissolved. The reaction was heated for a further 2.5 h at this temperature, before a further portion of chloroacetyl chloride was added. The reaction was heated for a further 2 hours before allowing to cool to rt overnight. The resulting suspension was filtered and the residue washed with dioxane and dried to give the crude Intermediate 1 (contaminated with triethylamine hydrochloride): UPLC: RT = 1.00 min; m/z (ES+) 276.29, 278.28 [MH+, CI isotopes]; required MW = 275.69.
The crude solid was suspended in water, filtered, washed with water and dried to give pure 4-chloro-2-[7-methyl-4-oxo-3,4-dihydro-1 H-quinazolin-(2Z)- ylidene]-3-oxo-butyronitrile (Intermediate 1c) (0.67 g, 62%): 1H-NMR (300 MHz, de-DMSO): δ = 7.88 (1 H, d), 7.61 (1 H, br s), 7.25 (1 H, br d), 4.49 (2H, s), 2.40 (3H, s) ppm.
The following intermediate examples were prepared analogously to the procedures described above :
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Example 1.0c : Preparation of 2-[2-amino-1 -(2-fluoro-phenyl)-4- 4,5-dihydro-1 H-pyrrol-3-yl]-7-methyl-3H-quinazolin-4-one
Figure imgf000094_0001
A mixture of crude Intermediate 1c (250 mg), 2-fluoroaniline (0.26 mL) and n- butanol (1 .66 mL) were combined in a sealed vial and heated at 150 °C under microwave irradiation for 45 min. On cooling, the solid was filtered, washed with n-butanol and dried to give 2-[2-amino-1 -(2-fluoro-phenyl)-4-oxo-4,5- dihydro-1 H-pyrrol-3-yl]-7-methyl-3H-quinazolin-4-one (130 mg): 1H-NMR (300 MHz, de-DMSO): δ = 11 .78 (1 H, br s), 9.01 (1 H, br s), 8.45 (1 H, br s), 7.88 (1 H, d), 7.59 - 7.65 (1 H, m), 7.40 - 7.52 (3H, m), 7.30 - 7.36 (1 H, m), 7.10 - 7.13 (1 H, unresolved dd), 4.29 (2H, s), 2.37 (3H, s) ppm; UPLC-MS: RT = 1.07 min; m/z (ES+) 351 .36, 352.35 [MH+]; required MW = 350.35.
The following compound examples were prepared analogously to the procedures described above [UPLC-MS data such as retention time (RT in min) or observed mass peak were collected using the method above]:
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit one or more Pim kinases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof. In accordance with another aspect therefore, the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pim kinases, such as, for example, haematological tumours, solid tumours, and /or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, 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.
Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
Another aspect of the present invention is therefore a method of treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pim kinases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof, by administering an effective amount of a compound of general formula (I) described herein.
Preferably, the diseases of said method are haemotological tumours, solid tumour and/or metastases thereof.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
In order that the compounds of the present invention be used as pharmaceutical products, the compounds or mixtures thereof may be provided in a pharmaceutical composition.
Another aspect of the present invention is therefore a pharmaceutical composition which contains a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in admixture with one or more suitable excipients. This composition is particularly suited for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, more particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by one or more Pirn kinases, as mentioned supra.
Said pharmaceutical products, which may be for enteral, oral or parenteral application, contain suitably pharmaceutically acceptable organic or inorganic inert base material, e.g. purified water, gelatine, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
Said pharmaceutical compositions of the present invention may be provided in a solid form, e.g. as tablets, dragees, suppositories, or capsules, or in liquid form, e.g. as a solution, a suspension or an emulsion. Said pharmaceutical compositions may additionally contain auxiliary substances, e.g. preservatives, stabilisers, wetting agents or emulsifiers, salts for adjusting the osmotic pressure or buffers.
For parenteral applications, (including intravenous, subcutaneous, intramuscular, intravascular or infusion), sterile injection solutions or suspensions are preferred, especially aqueous solutions of the compounds in polyhydroxyethoxy containing castor oil.
Said pharmaceutical compositions of the present invention may further contain surface active agents, e.g. salts of gallenic acid, phospholipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof. For oral application tablets, dragees or capsules with talcum and/or hydrocarbon-containing carriers and binders, e.g. lactose, maize and potato starch, are preferred. Further application in liquid form is possible, for example as juice, which contains sweetener if necessary. The dosage will necessarily be varied depending upon the route of administration, age, weight of the patient, the kind and severity of the illness being treated and similar factors. The daily dose is in the range of 0.5 to 1 ,500 mg. A dose can be administered as unit dose or in part thereof and distributed over the day. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
It is possible for compounds of general formula (I) of the present invention to be used alone or, indeed in combination with one or more further drugs, particularly anti-cancer drugs or compositions thereof. Particularly, it is possible for said combination to be a single pharmaceutical composition entity, e.g. a single pharmaceutical formulation containing one or more compounds according to general formula (I) together with one or more further drugs, particularly anti-cancer drugs, or in a form, e.g. a "kit of parts", which comprises, for example, a first distinct part which contains one or more compounds according to general formula (I), and one or more further distinct parts each containing one or more further drugs, particularly anti-cancer drugs. More particularly, said first distinct part may be used concomitantly with said one or more further distinct parts, or sequentially. In addition, it is possible for compounds of general formula (I) of the present invention to be used in combination with other treatment paradigms, particularly other anti- cancer treatment paradigms, such as, for example, radiation therapy.
The present invention thus covers a pharmaceutical combination comprising :
- one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, of the present invention, as described and defined herein ; and
- one or more agents selected from : 1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, 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, atezolizumab, 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, carbamazepine 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, hydroxycarbamide, 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, lasocholine, 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, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, 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, pembrolizumab, 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-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, rucaparib, 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.
Alternatively, said one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, of the present invention, as described and defined herein may be administered in combination with radiation therapy. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Biological assay: Pim-1 Kinase Assay
Pim-1 kinase inhibition may be quantified by employing the Pim- 1 HTRF or TR- FRET assay as described in the following paragraphs.
Commercial, N-terminal GST-tagged recombinant human full length Pim-1 (Upstate Biotechnology, Dundee, Scotland; Catalogue no. : 14-573) expressed in f. coli and purified by glutathione-agarose affinity chromatography was used for the biochemical kinase assay. As substrate for the kinase reaction the biotinylated peptide biotin-Ttds-YRRRHLSFAEPG (C-terminus in amide form) was used which can be purchased, e.g. from the company JPT Peptide Technologies GmbH (Berlin, Germany). The sequence of the peptide is purely artificial and not derived from any known protein.
Assay description:
The assay was performed in black 384-well plates (small volume; Greiner, Germany; #784076) or in black 1536-well plates (Greiner, Germany; #782076). 2 μΐ Pim- 1 kinase (5 pg/measurement point) was pre-incubated in assay buffer [25 mM Hepes pH 7.5, 10 mM MgCl2, 1 .0 mM Dithiothreitol, 0.015% NP40, 0.01 % bovine serum albumin [BSA], protease inhibitor cocktail ("Complete without EDTA", Roche, 1 tablet per 50 ml), 0.1 mM Na3V04] for 30 min with 50 nl_ of test compound dissolved in 100% dimethyl-sulfoxide (DMSO) (final compound concentrations during the kinase reaction: 0 μΜ and 0.001 - 20 μΜ). The kinase reaction was started by addition of 3 μΐ substrate solution (10 μΜ adenosine- triphosphate [ATP] and 1 μΜ peptide substrate [Biotin-Ttds-YRRRHLSFAEPG - NH2], dissolved in assay buffer; numbers indicate the final concentration during the kinase reaction). The reaction was terminated after 20 min incubation at 22 °C by the addition of 3 μΐ of stop / detection solution (final concentrations: 50 mM EDTA, 50 mM Hepes, pH 7.0, 0.06% BSA, 400 mM KF, and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.05 μΜ, CisBio international, Marcoule, France), anti- phospho-serine (0.5 nM; a phospho-specific antibody; Upstate Biotechnology, Dundee, Scotland) and Eu3+ cryptate-conjugated rabbit anti-mouse IgG (0.75 nM; a Europium-cryptate labelled anti-mouse-lgG-antibody from CisBio international, Marcoule, France). As an alternative to Eu3+ cryptate- labelled anti-mouse IgG, LANCE® Eu-W1024-labeled anti-mouse IgG antibody (Perkin Elmer, Boston, MA, USA) can be used for TR-FRET measurement. The primary anti-phospho-serine antibody recognizes an epitope consisting of the serine residue phosphorylated by the Pim-1 kinase activity and the adjacent C- terminal peptide sequence.
The resulting mixture was incubated for 90 min at 22 °C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the phospho-specific antibody complexed with the secondary, Europium-labelled antibody. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the Europium- labelled antibody complex to the streptavidine-XLent. Therefore, the fluorescence emissions at 665 nm and 620 nm (internal Europium reference signal) after excitation at 350 nm were measured in an HTRF / TR- FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 620 nm was taken as the measure for the amount of phosphorylated substrate peptide. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition) and IC50 values were calculated by a 4 parameter fit using an in house software. It will be apparent to persons skilled in the art that assays for other Pirn kinases may be performed in analogy using the appropriate reagents.
Selected results are presented in the following Table:
Example ICso (Pim-1 )
1.9a 9.9 μΜ
1.12a 0.11 μΜ
1.1 b 1.09 μΜ
2.0b 0.19 μΜ
1.7c 110 ηΜ
1.12c 230 ηΜ
1.14c 4200 ηΜ Thus the compounds of the present invention effectively inhibit one or more Pirn kinases and are therefore suitable for the treatment or prophylaxis of diseases of 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 is mediated by one or more Pirn kinases, more particularly in which the diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are haemotological tumours, solid tumours and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Claims

1. A com ound of general formula (I) :
Figure imgf000115_0001
Figure imgf000115_0002
in which :
Ri, R2 in formula (la) :
independently of each other, represent a group selected from : H, Ci-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-CrC6- alkoxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, G-Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-CrCs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=0)NR10R11, -OC(=0)NR10R11, -N(H)C(=0)0R9, -N(Ci-C6- alkyl)C(=0)0R9, -N(H)C(=0)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ;mula (lb) :
independently of each other, represent a group selected from : H, CrCs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-d-d- alkoxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, d-d-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, C C6-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-d-d- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-d- C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H;mula (lc) represent H ;
lae (la) and (lb) represents a group selected from : d-d-alkyl, halo-CrCs-alkyl, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-d-d-alkoxy-d-d- alkyl, C2-C6-alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10- membered heterocycloalkyl, aryl, heteroaryl, d-Cs-alkylene-aryl, d -d-alkylene-heteroaryl, -Ci -d-alkylene-d-do-cycloalkyl, Ci -C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C3-
Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, -
SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R3 in formula (lc) represents a group selected from : Ci-C6-alkyl, halo-Ci-C6- alkyl, Ci-C6-alkoxy-C C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-C6- alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, -C C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R4 in formula (la) represents H or Ci-C6-alkyl ;
R4 in formulae (lb) and (lc) represents H ;
R5 in formulae (la), (lb) and (lc) represents H ; R6 in formulae (la) and (Ic) represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
R6 in formula (lb) represents H ;
R7 in formulae (la) and (Ic) represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene- heteroaryl, Ci-C6-alkylene-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-Cs-alkyl ; wherein said Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2-C6- alkenyl, C2-Cs-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene- heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-Cs-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-C C6-alkyl, Ci-C6- alkoxy, halo-d-Cs-alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-d-C6- alkoxy-C C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11,
N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
R7 in formula (lb) represents H ; R8 in formulae (la) and (Ic) represent a substituent selected from : H, halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-d-Cs-alkoxy, C3-Cio-cycloalkyl ;
R8 in formula (lb) represents H ;
R9 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C6-alkyl,
C3-Cio-cycloalkyl, halo-Ci -Cs-alkyl, aryl, heteroaryl, Ci-C6-alkoxy- Ci -Cs-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci -Cs-alkyl, halo-Cr Cs-alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-
Ci-Cs-alkyl, -NR10R11 ;
R10 and R11 in formulae (la), (lb) and (Ic) independently from one another, represent a group selected from : H, Ci -Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci -Cs-alkyl, C C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-C C6- alkyl ;
or
R10 and R11 in formulae (la), (lb) and (Ic), together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci -C6-alkyl, -C(=0)CH3, -S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1 , wherein :
Ri, R2 , in formula (la) :
independently of each other, represent a group selected from : H, Ci-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci-C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-Cs-alkyl, halo-Ci-Cs-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ;rmula (lb) :
independently of each other, represent a group selected from : H, C Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, C C6-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci-C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, CrCs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-C C6-alkyl, halo-Cr Cs-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H;mula (lc) represent H ; R3 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C6- alkyl, halo-Ci-C6-alkyl, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy- Ci-Cs-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10- membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl,
Ci -C6-alkylene-heteroaryl, -Ci -C6-alkylene-C3-Cio-cycloalkyl, Ci -C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, - C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci- C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6-alkyl)S(=0)2R9, C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, -N(Ci-Cs- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6-alkyl)C(=O)NR10R11, - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -NR10R11 ;
R4 in formulae (la), (lb) and (Ic) represents H ;
R5 in formulae (la), (lb) and (Ic) represents H ;
R6 in formulae (la) and (Ic) represents a substituent selected from : H, halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C3-Cio-cycloalkyl ;
R6 in formula (lb) represents H ;
R7 in formulae (la) and (Ic) represents a substituent selected from : halo, cyano, d-Cs-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000121_0001
; wherein said d-Cs-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-Cs-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-d-Cs-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Cr Cs-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -
C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, - N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-Cs- alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, - N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6- alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -
NR10R11 ;
R7 in formula (lb) represents H ;
R8 in formulae (la) and (Ic) represents a substituent selected from : H, halo, cyano, Ci-C3-alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-CrC3- alkoxy, C3-C6-cycloalkyl ;
R8 in formula (lb) represents H ;
R9 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C6-alkyl,
C3-Cio-cycloalkyl, halo-Ci -Cs-alkyl , aryl, heteroaryl, Ci-C6-alkoxy- Ci -Cs-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Cr Cs-alkyl, Ci-C6-alkoxy, C C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy- Ci -Cs-alkyl, -NR10R11 ;
R10 and R11 in formulae (la), (lb) and (Ic) : independently from one another, represent a group selected from : H, d -Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci -C6-alkyl, d -C6- alkoxy-Ci-C6-alkyl, halo-Ci -C6-alkoxy-Ci -C6-alkyl ;
or
R10 and R11 in formulae (la), (lb) and (Ic), together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, d-Cs-alkyl, halo-CrCs-alkyl, Ci-C6-alkoxy, Ci -C6-alkoxy-Ci-Cs-alkyl, -C(=0)CH3, -S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound according to claim 1 or 2, wherein :
Ri , R2 , in formula (la) :
independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-d -C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, d-C6-alkynyl, d -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -Cs-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d -C6-alkyl, d-C6-alkoxy, halo-d -C6- alkoxy, d-C6-alkoxy-d -C6-alkyl, halo-d-C6-alkoxy-d -C6-alkyl, C3- do-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -
C(=0)0-d -Cs-alkyl, -C(=0)0-C3-do-cycloalkyl, -N(H)C(=0)R9, -N(d - Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(d -C6-alkyl)S(=0)2R9, C(=O)NR10R11 , -OC(=O)NR10R11 , -N(H)C(=0)OR9, -N(Ci -C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci-C6-alkyl)C(=O)NR10R11 , - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ; rmula (lb) :
independently of each other, represent a group selected from : H, d-Cs-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-d-C6- alkoxy-Ci-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, d-C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, C C6-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-Ci-C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-Ci-C6-alkyl, CrCs-alkoxy, halo-C C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-d- C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-do- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H;mula (lc) represent H ;
lae (la), (lb) and (lc) represents a group selected from : d-C6- alkyl, halo-Ci-C6-alkyl, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-d-C6-alkoxy- CrCs-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, - Ci-Cs-alkylene-C3-Cio-cycloalkyl, Ci-C6-alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, d-Cs-alkyl, halo-d-C6-alkyl, d-Cs-alkoxy, d-C6-haloalkoxy, d-C6-alkoxy-d-C6-alkyl, halo-d- Cs-alkoxy-d-C6-alkyl, C3-do-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)0H, -C(=0)0-d-C6-alkyl, -C(=0)0-C3-do- cycloalkyl, -N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-Cs-alkyl)S(=0)2R9, -C(=0)NR10R11, -OC(=0)NR10R11, N(H)C(=0)0R9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=0)NR10R11, -N(Ci- C6-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
R4 in formulae (la), (lb) and (Ic) represents H ;
R5 in formulae (la), (lb) and (Ic) represents H ;
R6 in formulae (la) and (Ic) represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3-alkoxy, C3-C6- cycloalkyl ;
R6 in formula (lb) represents H ;
R7 in formulae (la) and (Ic) represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000125_0001
; wherein said Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-C C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-Cs-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-d-Cs-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Cr Cs-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, - C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, - N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6- alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, - N(Ci-Cs-alkyl)C(=0)OR9, -N(H)C(=0)NR10R11, -N(Ci-Cs- alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, -
NR10R11 ;
R7 in formula (lb) represents H ;
R8 in formulae (la) and (Ic) represents a substituent selected from : H, halo, cyano, Ci-C3-alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-Ci-C3- alkoxy, C3-C6-cycloalkyl ;
R8 in formula (lb) represents H ;
R9 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C6-alkyl,
C3-Cio-cycloalkyl, halo-d-Cs-alkyl, aryl, heteroaryl, d-C6-alkoxy- d-Cs-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d-Cs-alkyl, halo-d- Cs-alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-d-C6-alkoxy- d-Cs-alkyl, -NR10R11 ;
R10 and R11, in formulae (la), (lb) and (Ic) :
independently from one another, represent a group selected from : H, Ci-Cs-alkyl, C3-Cio-cycloalkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl ;
or
R10 and R11, in formulae (la), (lb) and (Ic), together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci-C6-alkyl, halo-d-Cs-alkyl, d-C6-alkoxy, d-Cs-alkoxy-d-Cs-alkyl, -C(=0)CH3, -S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound according to any one of claims 1 to 3, wherein :
Ri, R2 , in formula (la) : independently of each other, represent a group selected from : H, Ci-C6-alkyl, halo-CrCs-alkyl, Ci -Cs-alkoxy-Ci-C6-alkyl, halo-d-C6-alkoxy-d -C6- alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, Ci-C6-alkylene-aryl, d -C6- alkylene-heteroaryl, -Ci -Cs-alkylene-C3-Cio-cycloalkyl, d -C6- alkylene-3- to 10-membered heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d -C6-alkyl, Ci-C6-alkoxy, halo-d -C6- alkoxy, Ci-C6-alkoxy-Ci -Cs-alkyl, halo-Ci-C6-alkoxy-Ci -C6-alkyl, C3- Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -
C(=0)0-Ci -Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -N(H)C(=0)R9, -N(Ci - C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci -C6-alkyl)S(=0)2R9, C(=O)NR10R11 , -OC(=O)NR10R11 , -N(H)C(=0)OR9, -N(Ci -C6- alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(Ci-C6-alkyl)C(=O)NR10R11 , - SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11 , -NR10R11 ;
with the proviso that Ri and R2 do not simultaneously represent H ; Ri , R2 , in formula (lb) :
independently of each other, represent a group selected from : H, d -Cs-alkyl, halo-d-C6-alkyl, d-C6-alkoxy-d -Cs-alkyl, halo-d -C6- alkoxy-d-C6-alkyl, C2-Cs-alkenyl, C2-C6-alkynyl, d -C6-alkylene- aryl, Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci -C6-alkylene-3- to 10-membered heterocycloalkyl, -C(=0)-d -C6- alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, nitro, d -Cs-alkyl, halo-d-C6-alkyl, d -Cs-alkoxy, halo-d -C6-alkoxy, d-C6-alkoxy-d -C6-alkyl, halo-d - C6-alkoxy-d-C6-alkyl, C3-do-cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(=0)OH, -C(=0)0-d-C6-alkyl, -C(=0)0-C3-do- cycloalkyl, -N(H)C(=0)R9, -N(d-Cs-alkyl)C(=0)R9, -N(H)S(=0)2R9, - N(Ci-C6-alkyl)S(=0)2R9, -C(=O)NR10R11 , -OC(=O)NR10R11 ,
N(H)C(=0)OR9, -N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11 , -N(d - Cs-alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 , =0 ;
with the proviso that Ri and R2 do not simultaneously represent H; Ri, R2 in formula (Ic) represent H ;
R3 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C6- alkyl, halo-Ci-C6-alkyl, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy- CrC6-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6-alkylene-heteroaryl, - Ci -Cs-alkylene-C3-Cio-cycloalkyl, Ci -C6-alkylene-heterocycloalkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-d-Cs-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Cr Cs-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, - C(=0)OH, -C(=0)0-Ci-Cs-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -
N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6- alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, - N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-Cs- alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
R4 in formulae (la), (lb) and (Ic) represents H ;
R5 in formulae (la), (lb) and (Ic) represents H ;
R6 in formulae (la) and (Ic) represents a substituent selected from : H, halo, hydroxy, cyano, Ci-C3-alkyl, Ci-C3-alkoxy, halo-C C3-alkoxy, C3-C6- cycloalkyl ;
R6 in formula (lb) represents H ;
R7 in formulae (la) and (Ic) represents a substituent selected from : halo, cyano, Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-CrC6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl,
Figure imgf000129_0001
; wherein said Ci-C6-alkyl, halo-C C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-Cs-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C2- Cs-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, Ci-C6-alkylene-aryl, Ci-C6- alkylene-heteroaryl, Ci-C6-alkylene-C3-Cio-cycloalkyl, Ci-C6- alkylene-3- to 10-membered heterocycloalkyl, -S(=0)2-Ci-Cs-alkyl is optionally further substituted one or more times, in the same way or differently, with a further substituent selected from : halo, hydroxy, cyano, nitro, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-Cs-alkoxy, Ci-Cs-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci- Cs-alkyl, C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl, - C(=0)OH, -C(=0)0-Ci-C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, - N(H)C(=0)R9, -N(Ci-C6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-Cs- alkyl)S(=0)2R9, -C(=O)NR10R11, -OC(=O)NR10R11, -N(H)C(=0)OR9, - N(Ci-C6-alkyl)C(=0)OR9, -N(H)C(=O)NR10R11, -N(Ci-C6- alkyl)C(=O)NR10R11, -SR9, -S(=0)R9, -S(=0)2R9, -S(=O)2NR10R11, - NR10R11 ;
R7 in formula (lb) represents H ;
R8 in formulae (la) and (Ic) represents a substituent selected from : H, halo, cyano, Ci-C3-alkyl, halo-C C3-alkyl, Ci-C3-alkoxy, halo-CrC3- alkoxy, C3-C6-cycloalkyl ;
R8 in formula (lb) represents H ;
R9 in formulae (la), (lb) and (Ic) represents a group selected from : Ci-C3-alkyl,
C3-Cs-cycloalkyl, halo-Ci-C3-alkyl, aryl, heteroaryl, Ci-C3-alkoxy-Ci- C3-alkyl ; wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, hydroxy, cyano, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6- alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-Cs-alkoxy-Ci-C6-alkyl, -
NR10R11 ; R10 and R11, in formulae (la), (lb) and (lc) :
independently from one another, represent a group selected from : H, Ci -C3-alkyl, C3-Cio-cycloalkyl, halo-Ci -C3-alkyl, C1 -C3- alkoxy-Ci -C3-alkyl, halo-Ci -C3-alkoxy-Ci -C3-alkyl ;
or
R10 and R11, in formulae (la), (lb) and (lc), together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently with a substituent selected from : halo, hydroxy, Ci -C6-alkyl, halo-d-Cs-alkyl, Ci -C6-alkoxy,
Ci -C6-alkoxy-Ci -C6-alkyl, -C(=0)CH3, -S(=0)2CH3 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 5. The compound of formula (la) according to any one of claims 1 to 4, which is selected from the group consisting of :
7-bromo-2-[1 -(2-fluoro-phenyl)-2-(2-morpholin-4-yl-ethylamino)-4-oxo-4,5- dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one ;
7-bromo-2-[1 -(2-fluoro-phenyl)-2-(2-methoxy-ethylamino)-4-oxo-4,5-dihydro- 1 H-pyrrol-3-yl]-3H-quinazolin-4-one ;
7-bromo-2-[2-(2-dimethylamino-ethylamino)-1 -(2-fluoro-phenyl)-4-oxo-4,5- dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one ;
7-bromo-2-[1 -(2-fluoro-phenyl)-4-oxo-2-(2-piperidin-1 -yl-ethylamino)-4,5- dihydro-1 H-pyrrol-3-yl]-3H-quinazolin-4-one ;
2-[1 -(2-fluoro-phenyl)-2-(2-morpholin-4-yl-ethylamino)-4-oxo-4,5-dihydro-1 H- pyrrol-3-yl]-7-methoxy-3H-quinazolin-4-one ;
2-[1 -(2-fluoro-phenyl)-4-oxo-2-(2-piperidin-1 -yl-ethylamino)-4,5-dihydro-1 H- pyrrol-3-yl]-7-methoxy-3H-quinazolin-4-one ;
2-[1 -(2-fluoro-phenyl)-2-(2-methoxy-ethylamino)-4-oxo-4,5-dihydro-1 -H-pyrrol- 3-yl]-7-methoxy-3H-quinazolin-4-one ; 2-[1-(2-fluoro^henyl)-2-methylamino-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7- methoxy-3H-quinazolin-4-one ;
2- [1-(2-fluoro-phenyl)-2-(2-methoxy-ethylamino)-4-oxo-4,5-dihydro-1H-pyrrol-
3- yl]-7-methoxy-3H-quinazolin-4-one ;
2-[2-dimethylamino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7- methoxy-3-methyl-3H-quinazolin-4-one ;
7-fluoro-2-[1-(2-fluoro-phenyl)-2-methylamino-4-oxo-4,5-dihydro-1H-pyrrol-3- yl]-3H-quinazolin-4-one ;
7-fluoro-2-[1-(2-fluoro-phenyl)-2-(2-morpholin-4-yl-ethylamino)-4-oxo-4,5- dihydro-1H-pyrrol-3yl]-3H-quinazolin-4-one ; and
2-[2-(2-dimethylamino-ethylamino)-1-(2-fluoro-phenyl)-4-oxo-4,
5-dihydro-1H- pyrrol-3yl]-7-fluoro-3H-quinazolin-4-one.
6. The compound of formula (lb) according to any one of claims 1 to 4, which is selected from the group consisting of :
2-[1-(2-fluoro-phenyl)-4-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-4,5-dihydro-1H- pyrrol-3-yl]-3H-quinazolin-4-one ;
2-[2-ethylamino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-3H- quinazolin-4-one ;
2-[1-(2-fluoro-phenyl)-2-(2-methoxy-ethylamino)-4-oxo-4,5-dihydro-1H- pyrrol-3-yl]-3H-quinazolin-4-one ;
2-[2-(3-dimethyl-amino-propylamino)-1 -(2-fluoro-phenyl)-4-oxo-4,5- dihydro-1H-pyrrol-3-yl]-3H-quinazolin-4-one ;
2-[1-(2-fluoro-phenyl)-4-oxo-2-(2-piperidin-1 -yl-ethylamino)-4,5- dihydro-1H-pyrrol-3-yl]-3H-quinazolin-4-one ;
2-{1-(2-fluoro-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-oxo-4,5- dihydro-1H-pyrrol-3-yl}-3H-quinazolin-4-one formate ;
2-[2- (2-dimethylamino-ethylamino)- 1 - (2-f luoro-phenyl)-4-oxo-4, 5- dihydro-1H-pyrrol-3-yl]-3H-quinazolin-4-one ; 2-[1-(2-fluoro-phenyl)-2-(2-morpholin-4-yl-ethylamino)-4-oxo-4,5- dihydro-1H-pyrrol-3-yl]-3H-quinazolin-4-one ;
2-{1-(2-fluoro-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]- 4-oxo-4,5-dihydro-1H-pyrrol-3-yl}-3H-quinazolin-4-one ; and
N-[1 -(2-fluoro-phenyl)-4-oxo-3- (4-0X0-3, 4-dihydro-quinazolin-2-yl)-4, 5- dihydro-1H-pyrrol-2-yl]-acetamide.
7. The compound of formula (lc) according to any one of claims 1 to 4, which is selected from the group consisting of :
2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7- methyl-3H-quinazolin-4-one ;
2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7- methoxy-3H-quinazolin-4-one ;
2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-8-methoxy- 3H-quinazolin-4-one ;
2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-6,7- dimethoxy-3H-quinazolin-4-one ;
2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-bromo-3H- quinazolin-4-one ;
2-[2-amino-1-cyclopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-bromo-3H- quinazolin-4-one ;
2-[2-amino-1-isopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-bromo-3H- quinazolin-4-one ;
2-[2-amino-1-isopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one ;
2-[2-amino-1-cyclopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one ;
2-[2-amino-4-oxo-1 -phenyl-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro-3H-quinazolin- 4-one ; 2-[2-amino-1-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one ;
2-[2-amino-1-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-bromo-3H- quinazolin-4-one ;
2-[2-amino-1-isopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-chloro-3H- quinazolin-4-one ;
2-[2-amino-1-ethyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-methanesulfonyl-3H- quinazolin-4-one ;
2-[2-amino-4-oxo-1 -phenyl-4,5-dihydro-1H-pyrrol-3-yl]-7-methanesulfonyl-3H- quinazolin-4-one ;
2-[2-amino-1-cyclobutyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-methanesulfonyl- 3H-quinazolin-4-one ;
2-[2-amino-1-isopropyl-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-methanesulfonyl- 3H-quinazolin-4-one ;
2-[2-amino-1-(2-methoxy-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-bromo- 3H-quinazolin-4-one ;
2-[2-amino-4-oxo-1 -phenyl-4,5-dihydro-1H-pyrrol-3-yl]-7-chloro-3H-quinazolin- 4-one ;
2-{2-amino-1-[3-(4-methyl-piperazin-1yl)-phenyl]-4-oxo-4,5-dihydro-1H-pyrrol- 3-yl}-7-fluoro-3H-quinazolin-4-one ;
2-[2-amino-1 (1 -methyl- 1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-1H-3-pyrrol] -7- fluoro-3H-quinazolin-4-one ;
2-[2-amino-4-oxo-1 -pyridin-3-yl-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro-3H- quinazolin-4-one ;
2-(2-amino-4-oxo-1 -o-tolyl-4,5-dihydro-1-pyrrol-3-yl)-7-fluoro-3quinazolin-4- one ;
2-[2-amino-1-(2,6-difluoro-phenyl)-4-oxo-4,5-dihydro-1H-pyrrol-3-yl]-7-fluoro- 3H-quinazolin-4-one ; and
2-{2-amino-1-[2-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-4-oxo-4,5- dihydro-1H-pyrrol-3-yl}-7-bromo-3H-quinazolin-4-one.
8. A method of preparing a compound of formula (la) or (lb) according to any one of claims 1 to 6, in which method an intermediate compound of general formula (5a) or (5b) :
Figure imgf000134_0001
(5a) (5b) in which Ri , R2 represent H, and R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb), respectively, in any one of claims 1 to 6, is allowed to react with an electrophile of formula :
Ri -Y, and/or R2-Y, in which Ri and R2 are as defined for the compound of formula (la) or (lb), respectively, in any one of claims 1 to 6, and Y is a leaving group, such as CI, Br, I, methanesulphonate,
to provide a compound of formula (la) or (lb) :
Figure imgf000134_0002
respectively, in which Ri, R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb), respectively, in any one of claims 1 to 6.
9. A method of preparing a compound of formula (lc) according to any one of claims 1 to 4 and 7, in which method an intermediate haloketone compound of formula (3c) :
Figure imgf000135_0001
(3c) in which X represents halogen, and R4, R5, R6, R7 and R8 are as defined for the compound of formula (lc) according to any one of claims 1 to 4 and 7, is allowed to react with an intermediate amine compound of general formula (4c) :
R3— NH2
(4c) in which R3 is as defined for the compound of formula (I) according to any one of claims 1 to 4 and 7,
to provide a compound of formula (lc) :
Figure imgf000135_0002
(lc) in which Ri, R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (I) according to any one of claims 1 to 4 and 7.
10. The method according to claim 9, wherein said intermediate haloketone compound of formula (3c) is prepared by allowing an intermediate nitrile compound of formula (2c) :
Figure imgf000136_0001
(2c) in which R4, R5, R6, R7, and R8, are as defined for the compound of formula (lc) according to any one of claims 1 to 4 and 7,
to react with an intermediate haloacyl halide compound of formula (2c') :
Figure imgf000136_0002
(2c') in which X and X', independently of each other, represent a halogen atom, thus providing said intermediate nitrile compound of formula (3c).
11. A compound of general formula (I), or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 7, for use in the treatment or prophylaxis of a disease.
12. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 7, and a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical combination comprising :
- one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 7 ;
and
- one or more agents selected from :
1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, 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, atezolizumab, 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, carbamazepine 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, hydroxycarbamide, 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, lasocholine, 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, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, 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, pembrolizumab, 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-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, rucaparib, 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.
14. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 7, for the preparation of a medicament for the prophylaxis or treatment of a disease.
15. Use according to claim 14, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by one or more Pirn kinases, more particularly in which the disease of uncontrolled cell growth, proliferation and /or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and /or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
16. Use of a compound of general formula (5a, b) :
Figure imgf000140_0001
(5a,b) in which Ri , R2 represent H, and R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (la) or (lb) in any one of claims 1 to 6, for the preparation of a compound of formula (la) or (lb), respectively, according to any one of claims 1 to 6.
17. A haloketone compound of formula (3c) :
Figure imgf000141_0001
(3c) in which X represents a halogen atom, and R4, R5, R6, R7 and R8 are defined for the compound of formula (Ic) in any one of claims 1 to 4 and 7.
18. A nitrile compound of formula (2c) :
Figure imgf000141_0002
in which R4, R5, R6, R7 and R8 are as defined for the compound of formula (I) in any one of claims 1 to 4 and 7.
19. Use of a haloketone compound of formula (3c) according to claim 17 for the preparation of a compound of formula (Ic) according to any one of claims 1 to 4 and 7.
20. Use of a nitrile compound of formula (2c) according to claim 18 for the preparation of a compound of formula (Ic) according to any one of claims 1 to 4 and 7.
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