HK1168791B - Substituted imidazoquinoxalines - Google Patents
Substituted imidazoquinoxalines Download PDFInfo
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- HK1168791B HK1168791B HK12109599.2A HK12109599A HK1168791B HK 1168791 B HK1168791 B HK 1168791B HK 12109599 A HK12109599 A HK 12109599A HK 1168791 B HK1168791 B HK 1168791B
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- quinoxalin
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- benzamide
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Description
The present invention relates to substituted imidazoquinoxaline compounds of general formula (I) as described and defined herein, 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, and to intermediate compounds for preparing said compounds.
Background
The present invention relates to compounds that inhibit Mps-1 (monopolar spindle 1) kinase (also known as tyrosine threonine kinase, TTK). Mps-1 is a bispecific Ser/Thr kinase that plays an important role in the activation of mitotic checkpoints (also known as spindle checkpoints, spindle assembly checkpoints), thereby ensuring proper chromosome segregation during mitosis [ Abrieu a et al, Cell, 2001, 106, 83-93 ]. Each dividing cell needs to ensure that the replicated chromosome is equally divided into two daughter cells. After entry into mitosis, chromosomes bind to spindle microtubules at their kinetochore. Mitotic checkpoint is a supervised mechanism that is in an activated state as long as unbound kinetochore is present, which prevents mitotic cells from entering the anaphase of division and thereby allows the unbound chromosomes to complete cell division [ suijkerbijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24-31; musacchio A and Salmonon ED, Nat Rev Mol Cell biol, 2007, 8, 379-93 ]. Once all kinetocomes bind to the mitotic spindle in the correct amphoteric, i.e. bipolar, manner, cells enter anaphase and complete mitosis by checkpoint. Mitotic checkpoints are composed of a complex network formed by a number of essential proteins, including members of the MAD (mitotic block-deficient protein, MAD1-3) and Bub (benzimidazole budding inhibition, Bub) families, the dynein CENP-E, Mps-1 kinase, and other components, many of which are overexpressed in proliferating cells (e.g., Cancer cells) [ Yuan B et al, Clinical Cancer Research, 2006, 12, 405-10 ]. An important role for Mps-1 kinase activity in mitotic checkpoint signaling has been demonstrated by shRNA-silencing, chemogenetics, and chemical inhibitors of Mps-1 kinase [ JellumaN et al, PLos ONE, 2008, 3, e 2415; jones MH et al, Current Biology, 2005, 15, 160-65; dorer RK et al, Current Biology, 2005, 15, 1070-76; schmidt M et al, EMBO Reports, 2005, 6, 866-72 ].
There is ample evidence to link reduced but incomplete mitotic checkpoint function with aneuploidy and tumorigenesis [ Weaver BA and Cleveland DW, Cancer Research, 2007, 67, 10103-5; king RW, Biochimica et Biophysica Acta, 2008, 1786, 4-14 ]. In contrast, complete inhibition of mitotic checkpoints has been confirmed to lead to severe chromosomal missegregation and induction of apoptosis in tumor cells [ Kops GJ et al, Nature Reviews Cancer, 2005, 5, 773-85; schmidt M and Medema RH, Cell Cycle, 2006, 5, 159-63; schmidt M and bases H, Drug Resistance Updates, 2007, 10, 162-81 ]. Thus, abrogation of mitotic checkpoints by pharmacological inhibition of Mps-1 kinase or other components of mitotic checkpoints represents a novel approach to the treatment of proliferative disorders including solid tumors such as cancers and sarcomas, leukemias, and lymphoid malignancies, or other disorders associated with uncontrolled cellular proliferation.
WO97/019079(Biomedica Foscama Industria Chimico-pharmaceutical s.p.a.) relates to imidazo [1,2-a ] quinoxalin-4-amines having adenosine antagonist activity for use as therapeutically active compounds for psychiatric and neurological disorders of the central nervous system. The imidazo [1,2-a ] quinoxalin-4-amine is substituted in position 1 by a hydrogen atom or a methyl group.
WO02/060386(Bristol-Myers Squibb Company) relates to methods of preventing and treating inflammatory and immune-related diseases or disorders using inhibitors of IkB kinase (IKK); it particularly relates to specific IKK inhibitors 4- (2' -aminoethyl) amino-1, 8-dimethylimidazo (1, 2-a) quinoxaline and benzimidazoloquinoxalines.
WO2007/109813(Novartis AG) relates to compositions comprising imidazoquinoxaline compounds as immunomodulators, and to methods of administering such compounds to enhance an immune response in a subject. The imidazoquineThe quinoxaline being substituted in position 4 by-NH2A group or a di (4-methoxybenzyl) amino group.
WO 2008/117225(Mutabilis SA) relates to imidazoheteroaryl derivatives which inhibit Dlta enzymatic activity of gram positive bacteria and are useful in the treatment of gram positive bacterial infections. The imidazoheteroaryl derivatives include those having-NHCH at the 4-position2CH2CH2OR5 substituent (R5 is H OR a substituent as defined herein).
WO 2009/024824A 1(AstraZeneca UK Limited) relates to 2-anilinopurin-8-ones having inhibitory activity on the spindle checkpoint kinase Tyrosine Threonine Kinase (TTK)/monopolar spindle 1(Mps-1) for the treatment of proliferative diseases.
However, none of the above background art describes a substituted imidazoquinoxaline compound of general formula (I) of the present invention, a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture thereof, or a pharmacological activity thereof, as described and defined herein and hereinafter referred to as "compound of the present invention". It has now been found that said compounds of the invention have surprisingly advantageous properties, which form the basis of the present invention.
In particular, it has surprisingly been found that said compounds of the invention effectively inhibit Mps-1 kinase and are therefore useful in the treatment or prevention of diseases caused by, or accompanied by, uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, such as haematological tumours, solid tumours and/or metastases thereof, such as leukaemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, peripheral brain tumours, peripheral brain, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.
Disclosure of Invention
According to a first aspect, the present invention relates to a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same:
wherein:
R1is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, C2-C10-alkenyl-, C2-C10-alkynyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C1-C6Alkylene-aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halogeneration-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R2represents-CN, -NR9R10、-OR9、C2-C10-alkenyl-, C2-C10-alkynyl-, aryl-, heteroaryl-, C1-C6Alkylene-aryl-, C1-C6-an alkylene-heteroaryl group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；R3、R4、R5、R6、R7：
Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10、C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C1-C6Alkylene-aryl radical, C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl or C1-C6-alkylene-3-to 10-membered heterocycloalkyl; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R8、R9、R10：
Each independently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcMay be the same or different and is selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
The terms mentioned herein preferably have the following meanings:
the term "halogen atom" or "halogen/halo" is understood to mean a fluorine, chlorine, bromine or iodine atom.
The term "C1-C10Alkyl is understood as preferably meaning a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1,2, 3,4, 5, 6, 7,8, 9 or 10 carbon atoms, in particular having 1,2, 3,4, 5 or 6 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C)1-C3-alkyl "), methyl, ethyl, n-propyl or isopropyl.
The term "halo-C1-C10Alkyl is understood to mean preferably a straight-chain or branched, saturated monovalent hydrocarbon radical, where the term "C" is1-C10-alkyl "is as defined above and wherein one or more hydrogen atoms are replaced by halogen atoms in the same or different manner, i.e. independently of each other. In particular, the halogen atom is F. Said halo-C1-C10Alkyl is, for example, -CF3、-CHF2、-CH2F、-CF2CF3or-CH2CF3。
The term "C1-C10Alkoxy is to be understood as preferably meaning a straight-chain or branched, saturated monovalent hydrocarbon radical of the formula-O-alkyl, where the term "alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy or n-hexoxy, or isomers thereof.
The term "halo-C1-C10Alkoxy is understood as preferably meaning a straight-chain or branched, saturated, monovalent C radical as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner1-C10-alkoxy groups. In particular, the halogen atom is F. Said halo-C1-C10Alkoxy is, for example, -OCF3、-OCHF2、-OCH2F、-OCF2CF3or-OCH2CF3。
The term "C1-C10-alkoxy-C1-C10Alkyl is understood to preferably denote-C in which one or more hydrogen atoms are defined as above, in the same or different manner1-C10Alkoxy substituted straight-chain or branched saturated monovalent alkyl radicals as defined above, for example methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkylArylalkyl, sec-butoxyalkyl, pentoxyalkyl, isopentoxyalkyl, hexoxyalkyl, wherein the term "C1-C10-alkyl "is as defined above, or isomers thereof.
The term "halo-C1-C10-alkoxy-C1-C10Alkyl is understood to preferably mean a straight-chain or branched, saturated, monovalent-C radical as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner1-C10-alkoxy-C1-C10-an alkyl group. In particular, the halogen atom is F. Said halo-C1-C10-alkoxy-C1-C10Alkyl is, for example, -CH2CH2OCF3、-CH2CH2OCHF2、-CH2CH2OCH2F、-CH2CH2OCF2CF3or-CH2CH2OCH2CF3。
The term "C1-C10Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4, 5, 6, 7,8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-C3-alkenyl "), it being understood that in case the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, m, (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-1-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, and mixtures thereof, 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, methyl-1-propenyl, methyl-4-enyl, methyl-3-enyl, methyl-2-pentenyl, ethyl-, (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-ethylbut-1-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) vinyl, but-1, 3-dienyl, penta-1, 4-dienyl, hex-1, 5-dienyl or methylhexadienyl. In particular, the radicals are vinyl or allyl。
The term "C2-C10Alkynyl is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which comprises one or more triple bonds and comprises 2,3, 4, 5, 6, 7,8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms ("C")2-C3-alkynyl "). Said C is2-C10Alkynyl 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-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-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-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-C10Cycloalkyl "is understood to mean preferably a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring which contains 3,4, 5, 6, 7,8, 9 or 10 carbon atoms, in particular 3,4, 5 or 6 carbon atoms (" C)3-C6-cycloalkyl "). Said C is3-C10Cycloalkyl is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, such as a perhydropentalene or decaline ring. The cycloalkyl ring may optionally contain one or more double bonds, for example a cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, wherein the ring is fused to the moleculeThe bond between the other moieties (whether saturated or unsaturated) may be at any carbon atom of the ring.
The term "3-to 10-membered heterocycloalkyl" is understood to mean preferably a saturated or partially unsaturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 2,3, 4, 5, 6, 7,8 or 9 carbon atoms and one or more heteroatom containing groups selected from: c (═ O), O, S, S (═ O), S (═ O)2NH, NR ', wherein R' represents C as defined above1-C6-alkyl, -C1-C6Alkyl-aryl, C3-C6-cycloalkyl, C3-C6Heterocycloalkyl, C (═ O) R9、C(＝O)NR10R11、-S(＝O)2R9、-S(＝O)2NR10R11It is to be understood that when said R' represents C3-C6When it is heterocycloalkyl, said C3-C6Heterocycloalkyl is present only once. In particular, the ring may comprise 2,3, 4 or5 carbon atoms and one or more of the above-mentioned heteroatom-containing groups ("3-to 6-membered heterocycloalkyl"), more particularly, the ring may comprise 4 or5 carbon atoms and one or more of the above-mentioned heteroatom-containing groups ("5-to 6-membered heterocycloalkyl"). The heterocycloalkyl group is, for example, a monocyclic heterocycloalkyl ring such as an oxiranyl group, a glycidyloxy group (oxiranyl group), an aziridinyl group, an azetidinyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an oxopyrrolidinyl group, an imidazolidinyl group, an oxoimidazolidinyl group, a pyrazolidinyl group, a pyrrolinyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a 4-methylpiperazinyl group, a trithianyl group or a quinuclidinyl group. Optionally, the heterocycloalkyl ring may contain one or more double bonds, such as 4H-pyranyl, 2H-pyranyl, 3H-bisaziridinyl, 2, 5-dihydro-1H-pyrrolyl, [1, 3]]Dioxolyl, 4H- [1, 3, 4[ ]]Thiadiazinyl, 2, 5-dihydrofuryl, 2, 3-dihydrofuryl, 2, 5-dihydrothienyl, 2, 3-dihydrothienyl, 4, 5-dihydrooxazolyl or 4H- [1, 4[ ]]The thiazinyl group, or the heterocycloalkyl ring, can be benzo-fused.
The term "aryl" is understood to mean preferably a monovalent, aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7,8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C6-C14Aryl "), in particular a ring having 6 carbon atoms (" C)6Aryl), such as phenyl, biphenyl, or a ring having 9 carbon atoms ("C)9-aryl "), such as indanyl or indenyl, or a ring having 10 carbon atoms (" C10Aryl), such as tetralinyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl "), for example anthracenyl.
The term "heteroaryl" is understood as preferably meaning a monovalent aromatic mono-or bicyclic aromatic ring system which has 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms ("5-to 14-membered heteroaryl"), in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises at least one heteroatom which may be identical or different, such as oxygen, nitrogen or sulfur, and which may be mono-, bi-or tricyclic and in each case additionally benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or azanylAnd (4) a base. More particularly, the heteroaryl group is selected from pyridyl, benzofuranyl, benzisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl, benzothienyl, pyrazolyl or furanyl. Alternatively, the heteroaryl group may be a1, 3-benzodioxolyl group or a1, 4-benzodioxinyl group.
The term "alkylene" is understood to mean preferably an optionally substituted hydrocarbon chain (or "chain") having 1,2, 3,4, 5 or 6 carbon atoms, i.e. -CH which is optionally substituted2- ("methylene" or "monobasic chain" or such as-C (Me))2-)、-CH2-CH2- ("ethylene", "dimethylene" or "dibasic chain"), -CH2-CH2-CH2- ("propylene", "trimethylene" or "triad"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene" or "tetrabasic"), -CH2-CH2-CH2-CH2-CH2- ("Pentylene", "pentamethylene" or "five-membered chain") or-CH2-CH2-CH2-CH2-CH2-CH2- ("hexamethylene", "hexamethylene" or "six-membered chain"). In particular, the methylene chain has 1,2, 3,4 or5 carbon atoms, more particularly 1 or 2 carbon atoms.
As used throughout this document, the term "C1-C6At C1-C6-alkyl group "," C1-C6-haloalkyl "," C1-C6-alkoxy "or" C1-C6-haloalkoxy "is understood in the context of the definition to mean an alkyl group having from 1 to 6 limited number of carbon atoms, i.e. 1,2, 3,4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to1-C6"is to be understood as meaning any subrange comprised therein, such as C1-C6、C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6(ii) a In particular C1-C2、C1-C3、C1-C4、C1-C5、C1-C6(ii) a More particularly C1-C4(ii) a In "C1-C6-haloalkyl "or" C1-C6-haloalkoxy "is even more particularly C1-C2。
Similarly, the term "C" as used herein2-C6", as used throughout this document, e.g., at" C2-C6-alkenyl "and" C2-C6-alkynyl "is understood in the context of its definition to mean alkenyl or alkynyl groups having a limited number of carbon atoms from 2 to 6, i.e. 2,3, 4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to2-C6"is to be understood as meaning any subrange comprised therein, such as C2-C6、C3-C5、C3-C4、C2-C3、C2-C4、C2-C5(ii) a In particular C2-C3。
In addition, the term "C" as used herein3-C10", as used throughout this document, e.g., at" C3-C10-cycloalkyl "is understood in the context of the definition of" cycloalkyl "to mean cycloalkyl having 3 to 10 limited numbers of carbon atoms, i.e. 3,4, 5, 6, 7,8, 9 or 10 carbon atoms, in particular 3,4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to3-C10"is to be understood as meaning any subrange comprised therein, such as C3-C10、C4-C9、C5-C8、C6-C7(ii) a In particular C3-C6。
The term "one or more times" as used herein, for example in the definition of a substituent of a compound of the general formula according to the invention, is to be understood as meaning "one, two, three, four or five times, in particular one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
When the plural form of the words compound, salt, polymorph, hydrate, solvate and the like are used herein, it is to be understood that reference to a compound, salt, polymorph, isomer, hydrate, solvate and the like in the singular is also intended.
The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms may exist in either the (R) or (S) configuration, resulting in a racemic mixture in the case of one asymmetric center and a diastereomeric mixture in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound.
The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are contemplated to be within the scope of the present invention.
Preferred compounds are those that produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the invention are included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.
Optical isomers may be obtained by resolution of the racemic mixture according to conventional methods, for example by formation of diastereomeric salts using an optically active acid or base, or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, e.g., by chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Another different method of separating optical isomers involves the use of chiral chromatography (e.g., a chiral HPLC column) with or without conventional derivatization, which can be optimally selected to maximize separation of the enantiomers. Suitable chiral HPLC columns are produced by Diacel, such as chiralel OD and chiralel OJ, all of which are routinely selected. Enzymatic separation may also be used with or without derivatization. Likewise, the optically active compounds of the present invention can be obtained by chiral synthesis using optically active starting materials.
To distinguish the different types of isomers from each other, reference is made to IUPAC RulesSection E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of the invention, either as single stereoisomers or as any mixture of said isomers in any proportion. The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the invention may be achieved by any suitable art of chromatography, for example chromatography, particularly, for example, chiral chromatography.
In addition, the compounds of the present invention may exist in tautomeric forms. For example, any compound of the invention comprising a pyrazole moiety as heteroaryl may, for example, exist as a 1H tautomer or a 2H tautomer, even as a mixture of any amount of the two tautomers, or any compound of the invention comprising a triazole moiety as heteroaryl may, for example, exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, even as a mixture of any amount of the 1H, 2H, and 4H tautomers:
the present invention includes all possible tautomers of the compounds of the invention, either as single tautomers or as any mixtures of said tautomers, in any ratio.
In addition, the compounds of the present invention may exist in the form of N-oxides, which are defined as compounds of the present invention in which at least one nitrogen is oxidized. The present invention includes all such possible N-oxides.
The invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.
The compounds of the invention may be present in the form of hydrates or solvates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, there may be semi- (hemi-) solvates or hydrates, (semi- (hemi-) solvates or hydrates, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.
In addition, the compounds of the invention may be present in free form, for example in the form of a free base, a free acid or a zwitterion, or in the form of a salt. The salt may be any salt, organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.
The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "Pharmaceutical Salts," J.pharm.Sci.1977, 66, 1-19.
Suitable pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention which carry a nitrogen atom in the chain or ring and which are sufficiently basic, for example with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisufuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, Mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
In addition, another suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as 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-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris (hydroxymethyl) aminomethane, aminopropanediol, sovak base, 1-amino-2, 3, 4-butanetriol. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and dibutyl sulfate; and diamyl sulfate, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and the like.
Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of a variety of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by various known methods.
The present invention includes all possible salts of the compounds of the invention, which may be single salts or any mixture of said salts in any proportion.
The term "in vivo hydrolysable ester" as used herein is understood to mean an in vivo hydrolysable ester of a compound of the invention which comprises a carboxy or hydroxy group, for example a pharmaceutically acceptable ester which can be hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for the carboxyl group include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, in particular benzyl esters, C1-C6Alkoxymethyl esters, e.g. methoxymethyl ester, C1-C6Alkanoyloxymethyl esters, e.g. pivaloyloxymethyl ester, phthalidyl ester, C3-C8cycloalkoxy-carbonyloxy-C1-C6Alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1, 3-dioxole-2-carbonylmethyl (1, 3-dioxolen-2-onylmethyl ester), such as 5-methyl-1, 3-dioxole-2-carbonylmethyl ester; and C1-C6Alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, and the esters may be formed on any of the carboxyl groups of the compounds of the invention.
In vivo hydrolysable esters of compounds of the invention which contain a hydroxy group include inorganic acid esters (e.g. phosphate esters), [ α ] acyloxyalkyl ethers and related compounds which are cleaved by in vivo hydrolysis of the ester to form the parent hydroxy group. Examples of [ α ] acyloxyalkyl ethers include acetoxymethyl ether and 2, 2-dimethylpropionyloxymethyl ether. The selection of groups which form in vivo hydrolysable esters with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl groups (to form alkyl carbonates), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl groups (to form carbamates), dialkylaminoacetyl and carboxyacetyl groups. The present invention includes all such esters.
In addition, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
According to a second aspect, the present invention comprises a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:
R1is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, C2-C10-alkenyl-, C2-C10-alkynyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, C1-C6Alkylene-aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R2Represents an aryl-or heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH,-C(＝O)O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R3、R4、R5、R6、R7：
Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10、C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C1-C6Alkylene-aryl radical, C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl or C1-C6-alkylene-3-to 10-membered heterocycloalkyl; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R8、R9、R10：
Each of which isIndependently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
According to a third aspect of the invention, the invention comprises a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:
R1is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, C2-C10-alkenyl-, C2-C10-alkynyl-, C3-C10-Cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, C1-C6Alkylene-aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is selected fromThe following substituents are substituted one or more times in the same or different manner: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R2Represents an aryl-or heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R3、R4、R5、R6、R7：
Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6Alkyl radical, C1-C6-alkoxy, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-C(＝O)NR9R10、-NR9R10(ii) a Wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10；
R8、R9、R10：
Each independently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, C2-C10-alkenyl-, C2-C10-alkynyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl, C1-C6Alkylene-aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is substituted in the same or different manner by a substituent selected from
Substitution one or more times: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R2represents-CN, -NR9R10、-OR9、C2-C10-alkenyl-, C2-C10-alkynyl-, aryl-, heteroaryl-, C1-C6Alkylene-aryl-, C1-C6-an alkylene-heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R3、R4、R5、R6、R7Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10、C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C1-C6Alkylene-aryl radical, C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl or C1-C6-alkylene-3-to 10-membered heterocycloalkyl; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyanoNitro group, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R8、R9、R10Each independently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R2Represents an aryl-or heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R3、R4、R5、R6、R7Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10、C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C1-C6Alkylene-aryl radical, C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl or C1-C6-alkylene-3-to 10-membered heterocycloalkyl; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R8、R9、R10Each independently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-,HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, C2-C10-alkenyl-, C2-C10-alkynyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, C1-C6Alkylene-aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R2Represents an aryl-or heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, nitro-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-C (═ O) n (h) -C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, -C (═ O) -C1-C6-alkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -OC (═ O) -C1-C6-alkyl, -OC (═ O) -C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspectThe invention relates to compounds of formula (I) wherein R3、R4、R5、R6、R7Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group or a group selected from: c1-C6Alkyl radical, C1-C6-alkoxy, n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-C(＝O)NR9R10、-NR9R10(ii) a Wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) R8、-N(C1-C6-alkyl) C (═ O) R8、-N(H)S(＝O)2R8、-N(C 1-C6-alkyl) S (═ O)2R8、-C(＝O)NR9R10、-OC(＝O)NR9R10、-N(H)C(＝O)OR8、-N(C1-C6-alkyl) C (═ O) OR8、-N(H)C(＝O)NR9R10、-N(C1-C6-alkyl) C (═ O) NR9R10、-SR8、-S(＝O)R8、-S(＝O)2R8、-S(＝O)2NR9R10、-NR9R10。
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R8、R9、R10Each independently represents a hydrogen atom, C1-C6-alkyl, halo-C1-C6-alkanesGroup HO-C1-C6-alkyl-, cyano-C1-C6-alkyl-, C2-C10-alkynyl-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl, H2NC(＝O)-C1-C6-alkyl-, C1-C6-alkyl-n (h) C (═ O) -C1-C6-alkyl-, H2NS(＝O)2-C1-C6-alkyl-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10Cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, C1-C6Alkylene-aryl, -C1-C6-alkylene-heteroaryl, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6-alkyl, halo-C1-C6Alkyl radical, HO-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C10-cycloalkyl, aryl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-C6-alkyl, halo-C1-C6Alkyl radical, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy-C1-C6Alkyl radical, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -C (═ O) OH, -C (═ O) O-C1-C6-alkyl, -C (═ O) O-C3-C10-cycloalkyl, -n (h) C (═ O) -C1-C6-alkyl, -N (h) C (═ O) -heteroaryl, -N (C)1-C6-alkyl) C (═ O) -C1-C6-alkyl, -n (h) S (═ O)2-C1-C6-alkyl, -N (C)1-C6-alkyl) S (═ O)2-C1-C6-alkyl, -C (═ O) NH2、-C(＝O)N(H)-C1-C6-alkyl, -C (═ O) N (C)1-C6-alkyl groups)2、-OC(＝O)NH2、-OC(＝O)N(H)-C1-C6-alkyl, -OC (═ O) N (C)1-C6-alkyl groups)2、-N(H)C(＝O)O-C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) O-C1-C6-alkyl, -n (h) C (═ O) NH2、-N(H)C(＝O)N(H)-C1-C6-alkyl, -N (h) C (═ O) N (C)1-C6-alkyl groups)2、-N(C1-C6-alkyl) C (═ O) NH2、-N(C1-C6-alkyl) C (═ O) n (h) -C1-C6-alkyl, -N (C)1-C6-alkyl) C (═ O) N (C)1-C6-alkyl groups)2、-S-C1-C6-alkyl, -S (═ O) -C1-C6-alkyl, -S (═ O)2-C1-C6-alkyl, -S (═ O)2NH2、-S(＝O)2N(H)-C1-C6-alkyl, -S (═ O)2N(C1-C6-alkyl groups)2、-NH2、-N(H)-C1-C6-alkyl, -N (C)1-C6-alkyl groups)2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C＝O)-Ra、
-CH2CH2CH2O(C＝O)-ORa、
-CH2CH2CH2O(C＝O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C10-alkyl-, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, halo-C1-C10-alkoxy-C1-C10-alkyl-, -C1-C6alkylene-C3-C10-A cycloalkyl group;
wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, C1-C6-alkyl-, halo-C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, C3-C10-cycloalkyl-, 3-to 10-membered heterocycloalkyl-.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R2Represents an aryl-or heteroaryl-group; wherein said group is substituted by-C (═ O) NR9R10Once and optionally substituted with a substituent selected from: halogen-, hydroxy-, cyano-, C1-C6-alkyl-, halo-C1-C6-alkyl-.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R2Represents an aryl-or heteroaryl-group; wherein said group is substituted once with-C (═ O) NH-cyclopropyl and is optionally substituted with a substituent selected from: halogen-, hydroxy-, cyano-, C1-C6-alkyl-, halo-C1-C6-alkyl-.
In another embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R7Represents a hydrogen atom.
It is to be understood that the present invention relates to any sub-composition of the compounds of general formula (I) described above within the scope of any embodiment of the present invention.
More specifically, the present invention includes compounds of formula (I) as disclosed in the examples section below.
According to another aspect, the present invention relates to a process for preparing a compound of the present invention, said process comprising the steps described herein.
According to another aspect, the present invention relates to intermediate compounds useful in the preparation of the compounds of the present invention of general formula (I), in particular the processes described herein. Specifically, the present invention includes compounds of general formula (4):
wherein R is1、R3、R4、R5、R6And R7A compound of formula (I) as defined in the claims and Y represents a halogen atom.
According to yet another aspect, the present invention relates to the use of a compound of formula (4) as described above for the preparation of a compound of the present invention of formula (I) as described above.
Experimental part
As noted above, another aspect of the present invention is a process that can be used to prepare the compounds of the present invention.
The following table lists the abbreviations used in this section and in the examples section. Describing the NMR peak patterns as shown in the spectra, possible higher order effects (higher order effects) were not considered.
| Abbreviations | Means of |
| Ac | Acetyl group |
| Br | Width of |
| c- | Annular glass fiber |
| D | Double peak |
| Dd | Double doublet |
| DCM | Methylene dichloride |
| DIPEA | N, N-diisopropylethylamine |
| DMF | N, N-dimethylformamide |
| DMSO | Dimethyl sulfoxide |
| dppf | 1, 1' -bis (diphenylphosphino) ferrocene |
| Eq | Equivalent weight |
| ESI | Electrospray ionization |
| K2CO3 | Potassium carbonate |
| KOH | Potassium hydroxide |
| M | Multiple peaks |
| MS | Mass spectrometry |
| MW | Molecular weight |
| NBS | N-bromosuccinimide |
| NMP | N-methyl pyrrolidone |
| NMR | Nuclear magnetic resonance spectroscopy: chemical shifts (. delta.) are expressed in ppm |
| Pd(dppf)Cl2 | 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride |
| Pd(OAc)2 | Palladium acetate (II) |
| POCl3 | Phosphorus oxychloride |
| P(oTol)3 | Tri (o-tolyl) phosphine |
| P2O5 | Phosphorus pentoxide |
| Q | Quartet peak |
| Rt | At room temperature |
| RT | Retention time in minutes |
| S | Single peak |
| sept | Seven-fold peak |
| T | Triplet peak |
| TEA | Triethylamine |
| TFA | Trifluoroacetic acid |
| THF | Tetrahydrofuran (THF) |
| UPLC | Ultra-high performance liquid chromatography |
The routes and methods described below illustrate general synthetic routes for the compounds of general formula (I) of the present invention and are not limiting. It will be apparent to those skilled in the art that the order of transformations illustrated in the schemes can be varied in a variety of ways. Thus, the order of transformations illustrated in the schemes is not limiting. In addition, substituent R can be achieved before and/or after the exemplified transformation1、R2、R2a、R3、R4、R5、R6Or R7Interconversion of any one of the above. These modifications may beSuch as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functionality that allows for further interconversion of substituents. Suitable protecting Groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., t.w.greene and p.g.m.wuts in Protective Groups in organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. In addition, it is possible; two or more successive steps may be carried out without work-up between the steps, for example a "one-pot" reaction as is well known to the person skilled in the art.
The first reaction route is listed below:
synthesis of Compounds of the general formula (I)
Wherein R is1、R2、R3、R4、R5、R6And R7Has the meaning defined above for the general formula (I), Y is a halogen atom as defined above and Z represents a "suitable functional group", R2R of the compound-Z2Can be coupled to the carbon atom carrying Y of compound (4) by a coupling reaction via said functional group, thereby using said R2A group replaces said Y.
R2aAnd R2Have the same definition.
The compounds of general formula (I) can be synthesized according to the procedures outlined in scheme 1.
The 2-amino-3-chloroquinoxaline intermediates of general formula (I) are commercially available or can be synthesized according to scheme 2.
Synthesis of 2-amino-3-chloroquinoxaline intermediates
Those skilled in the art will also recognize that: there are many existing methods for the synthesis of suitable 2-amino-3-chloroquinoxaline intermediates of formula (I); some 2-amino-3-chloroquinoxaline intermediates are commercially available. As depicted in scheme 2, one possible route to the 2-amino-3-chloroquinoxaline intermediate is the conversion of a commercially available and suitably substituted o-aminoaniline (A) to the corresponding 1, 4-dihydroquinoxaline-2, 3-dione intermediate (B) by condensation with diethyl oxalate. By POCl3The intermediate (B) is chlorinated to give 2, 3-dichloroquinoxaline (C) [ see for example the preparation of 2, 3-dichloro-6-fluoroquinoxaline; s. Ceccarelli et al,/Eur.J.Med.Chem.33 (1998)943-]. Aminolysis of the 2, 3-dichloroquinoxaline intermediate gives the desired 2-amino-3-chloroquinoxaline intermediate (1). Those skilled in the art will recognize that regioisomers that require separation by known methods such as flash chromatography can be generated based on the substitution pattern of the 2, 3-dichloroquinoxaline intermediate.
For route 1:
the appropriately substituted 2-amino-3-chloroquinoxaline intermediates of formula (I) are converted to the corresponding 4-chloroimidazo [1,2-a ] quinoxalines of formula (2) by reaction with α -halo keto derivatives such as 2-bromo-1, 1-diethoxyethane [ see, e.g., S.Parra et al,/European Journal of Medicinal Chemistry 36(2001)255-264] in a suitable solvent system such as THF and water at a temperature between room temperature and the boiling point of the solvent. Those skilled in the art will recognize that regioisomers that require separation by known methods such as flash chromatography can be generated based on the substitution pattern of the 2-amino-3-chloroquinoxaline intermediate.
The intermediate of formula (2) can be converted to the 1-halo-4-chloroimidazo [1,2-a ] quinoxaline intermediate of formula (3) by reaction with a suitable halogenating agent, such as NBS, in the presence of a suitable solvent, such as NMP, at a temperature between room temperature and the boiling point of the solvent, preferably at room temperature.
Intermediates of formula (3) can be converted to substituted 2-amino-7-haloquinoxaline intermediates (4) by reaction with a suitable amine [ see, e.g., c.deleuze-Masque' fa et al,/bioorg.med.chem.12 (2004)1129-1139] in a suitable solvent such as DMF or NMP at a temperature between room temperature and the boiling point in the presence of a suitable base such as DIPEA.
As described in scheme 1 above, by reaction with formula R2The compounds of formula (I) in which R is a substituent of formula (I) can be converted directly into the substituted 2-amino-7-haloquinoxaline intermediates (4) by coupling reactions, for example, in particular metal-catalyzed coupling reactions2As defined above for the compounds of general formula (I) and Z represents a "suitable functional group", said R2R of the compound-Z2Can be coupled to the carbon atom carrying Y of compound (4) via said functional group, thereby using said R2A group replaces said Y. Such "suitable functional groups", i.e. R2Examples of Z in-Z include, for example, boronic acid, R2-B(OH)2Or boric acid ester, R2-B(OC1-C6-alkyl groups)2. Alternatively, in such coupling, R2Z in-Z may be, for example, an amine R-N-H (R)2R-N), phenol R-O-H (R)2Activated hydrogen atoms of alkynes R-C ≡ C-H (R2 ═ R-C ≡ C), alkenes R-C ═ C-H (R2 ═ R-C ═ C), or metal ions, for example zn (cn)2(R2CN) Zn2+The activated hydrogen atom or metal ion allows coupling in the presence of a suitable catalyst (such as mentioned below) and optionally a suitable base (such as mentioned below) in an optionally present suitable solvent.
For intermediate (4), an example of Y is, for example, Br.
Examples of such coupling reactions can be found in textbooks with the following headings: "Metal-CatalyzedCross-Coupling Reactions", Armin de Meijere (Editor), Diederich(Editor)September 2004，Wiley Interscience ISBN：978-3-527-30518-6。
optionally, the coupling reaction is carried out in a suitable catalyst (such as Pd (OAc)2And P (oTol)3) And optionally in the presence of a suitable base such as potassium carbonate, in an optionally present suitable solvent such as THF.
Also as depicted in scheme 1 above, can be prepared by reaction with the formula R2a-Z Compound the coupling reaction described above is carried out to convert substituted 2-amino-7-haloquinoxaline intermediate (4) to intermediate (5), wherein R2aAs defined above, and Z represents a "suitable functional group" as defined above, said R2aR of the compound-Z2aCan be coupled to the carbon atom bearing Y of compound (4) via said functional group by a coupling reaction as described above, thus using said R2aThe group replaces the Y, thus providing intermediate (5). Intermediate (5) is then converted to the compound of formula (I) by one or more additional transformations. These modifications may be, for example, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art such as amide bond formation.
The compounds and intermediates prepared according to the process of the invention may require purification. Purification of organic compounds is well known to those skilled in the art and there are several methods of purifying the same. In some cases, no purification is necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, the compounds can be purified by chromatography, particularly flash chromatography, using, for example, a pre-packed silica gel column (e.g., Isolute from Separtis)Flash silica gel or IsoluteFlash NH2 silica gel) in combination with a suitable chromatographic system such as Flashmaster II (Separtis) or Isolera system (Biotage) and an eluent such as hexane/EtOAc or DCM/methanol gradient. In some cases, the compounds can be purified by preparative HPLC using, for example, a Waters automated purifier equipped with a diode array detector and/or an online electrospray ionization mass spectrometer in combination with a suitable pre-packed reverse phase column and an eluent (e.g., a gradient of water and acetonitrile that may contain, for example, trifluoroacetic acid, formic acid, or ammonia).
Analytical UPLC-MS was performed as follows:
the method A comprises the following steps: the system comprises the following steps: UPLC Acquity (Waters) and Waters ZQ mass spectrometers with PDA detectors; column: acquity BEH C181.7 μm 2.1x50 mm; temperature: 60 ℃; solvent A: water + 0.1% formic acid; solvent B: acetonitrile; gradient: 99% a → 1% a (1.6min) → 1% a (0.4 min); flow rate: 0.8 mL/min; sample introduction volume: 1.0. mu.l (sample concentration 0.1mg-1 mg/mL); and (3) detection: PDA scanning range 210-.
The names of the compounds were generated using the ICS naming tool of the Autonom 2000 plug-in from ISIS/Draw [ MDL Information Systems Inc. (Elsevier MDL) ] or ACD labs.
Intermediate example 1-1: preparation of 1-bromo-4-chloroimidazo [1,2-a ] quinoxaline
Step A: preparation of 4-chloroimidazo [1,2-a ] quinoxaline
To 2-amino-3-chloroquinoxaline (25.5g, 141.8mmol) at rt in water/THF 1: 1(500 m)L) to the stirred suspension was added 2-bromo-1, 1-diethoxyethane (83.8g, 425.4mmol) in one portion. After stirring at rt for 1h, the mixture was heated to reflux with stirring for 3h, followed by stirring at rt for another 15 h. The pH of the mixture was adjusted to pH 8 by addition of solid sodium carbonate, then the mixture was extracted with ethyl acetate (3 × 500mL), and the combined organic extracts were dried over sodium sulfate. Removing the solvent to obtain 4-chloroimidazo [1,2-a ] as an orange-white (orange-white) solid]Quinoxaline (63g, 93%):1H-NMR(300MHz，d6-DMSO)：δ＝9.05(d，1H)，8.51(dd，1H)，8.1(dd，1H)，7.99(d，1H)，7.89(td，1H)，7.76(td，1H)ppm。UPLC-MS：RT＝0.88min；m/z 204.6[MH+](ii) a Theoretical MW 203.6.
And B: preparation of 1-bromo-4-chloroimidazo [1,2-a ] quinoxaline
To 4-chloroimidazo [1,2-a ] at rt]NBS (25.2g, 141.8mmol) was added in one portion to a stirred suspension of quinoxaline (28.9g, 141.8mmol) in THF/NMP 2: 1(300 mL). After stirring for 18h, an additional 12.6g (70.9mmol) NBS was added and the mixture stirred at rt for an additional 2 h. After the THF portion of the organic phase was removed by evaporation in vacuo, water (500mL) was added. The precipitate was filtered, the residue washed with water and dried to give 1-bromo-4-chloroimidazo [1,2-a as an off-white solid]Quinoxaline (35g, 78.6%):1H-NMR(300MHz，d6-DMSO)：δ＝12.42(1H，s)，8.19(1H，s)，7.75(1H，d)，7.44(2H，m)ppm。UPLC-MS：RT＝1.14min；m/z284.6[MH+](ii) a Theoretical MW is 283.5.
Intermediate examples 1-2: preparation of 1-bromo-4-chloro-7, 8-dimethylimidazo [1,2-a ] quinoxaline
Step A: preparation of 6, 7-dimethyl-1, 4-dihydroquinoxaline-2, 3-dione
A mixture of 4, 5-dimethylbenzene-1, 2-diamine (60g) and diethyl oxalate (600mL) was heated at reflux for 1h, then cooled. The precipitate 6, 7-dimethyl-1, 4-dihydroquinoxaline-2, 3-dione is filtered off and washed with 96% ethanol to give 38g of the title compound. ESI-MS: m/z 191.1[ MH+]，403.3[2MNa+](ii) a Theoretical MW is 190.2.
And B: preparation of 2, 3-dichloro-6, 7-dimethylquinoxaline
6, 7-dimethyl-1, 4-dihydroquinoxaline-2, 3-dione (105g), freshly distilled phosphorus oxychloride (315mL) and N, N-dimethylaniline (70mL) were heated at reflux for 90min, then cooled and slowly poured into stirring ice water. The precipitate is filtered off, washed with water and dried in a vacuum desiccator over KOH/P2O5And drying. Extraction with benzene (3000mL) and concentration of the filtered extract under reduced pressure gave 63g of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝7.79(2H，s)，2.45(6H，s)ppm。
And C: preparation of 3-chloro-6, 7-dimethylquinoxalin-2-ylamine
Cooling 2, 3-dichloro-6, 7-bis with dry ice in a sealed containerA mixture of methylquinoxalines (30g) in 300mL THF. Ammonia gas was bubbled for 10min, then the mixture was heated to 100 ℃ and maintained for 20 h. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 14g of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝7.43(1H，s)，7.37(1H，s)，7.00(2H，s)，2.28(6H，s)ppm。
Step D: preparation of 4-chloro-7, 8-dimethylimidazo [1,2-a ] quinoxaline
To a stirred suspension of 3-chloro-6, 7-dimethylquinoxalin-2-ylamine (30.9g, 0.16mol) in water/THF 1: 1(540mL) was added bromoacetaldehyde diethyl acetal (94.6g, 0.48mol) and 5g PPTS in one portion at room temperature. After stirring at room temperature for 1h, the mixture was heated to reflux with stirring for 3h and then stirred at room temperature for a further 15 h. The pH of the mixture was adjusted to pH 8 by adding solid sodium carbonate. The precipitate formed is filtered off to yield 25g of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝8.85(1H，s)，8.19(1H，s)，7.73(1H，bs)，7.80(1H，bs)，3.60(6H，s)ppm。
Step E: preparation of 1-bromo-4-chloro-7, 8-dimethylimidazo [1,2-a ] quinoxaline
To 4-chloro-7, 8-dimethylimidazo [1,2-a ] at room temperature]NBS (26.3g, 0.148mol) was added in one portion to a stirred suspension of quinoxaline (32.2g, 0.148mol) in THF/NMP 2: 1(312 mL). After stirring for 18h, additional NBS (13.1g, 0.074mol) was added and the mixture was stirred at room temperature for an additional 2 h. The THF portion of the organic phase was removed by evaporation in vacuo and water (520mL) was added. The precipitate was filtered and the residue was washed with water, diethyl etherAnd dried to yield 35g of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝8.54(1H，s)，7.75(1H，s)，7.40(1H，s)，2.20(6H，s)ppm。
Intermediate examples 1-3: preparation of 1-bromo-4-chloro-7, 8-difluoroimidazo [1,2-a ] quinoxaline
Step A: preparation of 6, 7-difluoro-1, 4-dihydroquinoxaline-2, 3-dione
6, 7-difluoro-1, 4-dihydroquinoxaline-2, 3-dione was prepared in analogy to the procedure of step A of intermediate example 1-2. 90% of the title compound is obtained.
And B: preparation of 2, 3-dichloro-6, 7-difluoroquinoxaline
2, 3-dichloro-6, 7-difluoroquinoxaline was prepared analogously to the procedure of intermediate example 1-2, step B, to give 60% of the title compound.
And C: preparation of 3-chloro-6, 7-difluoroquinoxalin-2-ylamine
Preparation of 3-chloro-6, 7-difluoroquinoxalin-2-ylamine analogously to the procedure of step C of intermediate example 1-2Stirring in DMF for 20h at rt gave 50% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝7.78(1H，t)，7.51(1H，t)，7.40(2H，s)ppm。
Step D: preparation of 4-chloro-7, 8-difluoroimidazo [1,2-a ] quinoxaline
4-chloro-7, 8-difluoroimidazo [1,2-a ] quinoxaline is prepared analogously to the operation of intermediate example 1-2, step D, to give 75% of the title compound.
Step E: preparation of 1-bromo-4-chloro-7, 8-difluoroimidazo [1,2-a ] quinoxaline
Preparation of 1-bromo-4-chloro-7, 8-difluoroimidazo [1,2-a ] in analogy to the procedure of step E of intermediate examples 1-2]Quinoxaline to give 82% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝9.00(1H，t)，8.20(1H，t)，7.92(1H，s)ppm。
Intermediate examples 1-4: preparation of 1-bromo-4-chloro-8-fluoroimidazo [1,2-a ] quinoxaline
Step A: preparation of 6-fluoro-1, 4-dihydroquinoxaline-2, 3-dione
6-fluoro-1, 4-dihydroquinoxaline-2, 3-dione was prepared in analogy to the procedure of intermediate example 1-2, step A, to give 90% of the title compound.
And B: preparation of 2, 3-dichloro-6-fluoroquinoxaline
2, 3-dichloro-6-fluoroquinoxaline is prepared analogously to the operation of intermediate example 1-2, step B, to give 60% of the title compound.
And C: preparation of 3-chloro-6-fluoroquinoxalin-2-ylamine
3-chloro-6-fluoroquinoxalin-2-ylamine was prepared in analogy to the procedure of intermediate example 1-2, step C, by stirring in DMF for 20h at rt to give 50% of the title compound.
Step D: preparation of 4-chloro-8-fluoroimidazo [1,2-a ] quinoxaline
Preparation of 4-chloro-8-fluoroimidazo [1,2-a ] in analogy to the procedure of step D of intermediate examples 1-2]Quinoxaline to give 75% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝8.88(1H，s)，8.40(1H，d)，8.05(1H，dd)，7.87(1H，s)，7.52(1H，t)ppm。
Step E: preparation of 1-bromo-4-chloro-8-fluoroimidazo [1,2-a ] quinoxaline
Preparation of 1-bromo-4-chloro-8-fluoroimidazo [1,2-a ] in analogy to the procedure of step E of intermediate examples 1-2]Quinoxaline to give 82% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝8.79(1H，d)，8.08(1H，dt)，7.92(1H，s)，7.59(1H，t)ppm。
Intermediate examples 1-5: preparation of 1-bromo-4-chloro-7-cyanoimidazo [1,2-a ] quinoxaline
Step A: preparation of 6-cyano-1, 4-dihydroquinoxaline-2, 3-dione
6-cyano-1, 4-dihydroquinoxaline-2, 3-dione was prepared in analogy to the procedure of intermediate example 1-2, step A, to yield 90% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝12.24(1H，s)，12.13(1H，s)，7.55(1H，d)，7.40(1H，s)，7.25(1H，d)ppm。
And B: preparation of 2, 3-dichloro-6-cyanoquinoxaline
2, 3-dichloro-6-cyanoquinoxaline was prepared analogously to the procedure of intermediate example 1-2, step B, to give 50% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝8.79(1H，s)，8.22(2H，s)ppm。
And C: preparation of 3-chloro-7-cyanoquinoxalin-2-ylamine
3-chloro-7-cyanoquinoxalin-2-ylamine was prepared in analogy to the procedure of intermediate example 1-2, step C, by stirring in DMF for 20h at rt to give 50% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝9.06(1H，s)，8.62(1H，d)，8.60(1H，s)，8.24(1H，d)，7.97(1H，s)ppm。
Step D: preparation of 4-chloro-7-cyanoimidazo [1,2-a ] quinoxaline
Preparation of 4-chloro-7-cyanoimidazo [1,2-a ] in analogy to the procedure of step D of intermediate examples 1-2]Quinoxaline to give 75% of the title compound. ESI-MS: m/z 229.1[ MH+](ii) a Theoretical MW is 228.6.
Step E: preparation of 1-bromo-4-chloro-7-cyanoimidazo [1,2-a ] quinoxaline
Preparation of 1-bromo-4-chloro-7-cyanoimidazo [1,2-a ] in analogy to the procedure of step E of intermediate examples 1-2]Quinoxaline to give 82% of the title compound.1H-NMR(300MHz，d6-DMSO)：δ＝9.31(1H，d)，8.68(1H，s)，8.23(1H，d)，8.08(1H，s)ppm。
Intermediate example 2-1: preparation of (1-bromoimidazo [1,2-a ] quinoxalin-4-yl) isobutylamine
1-bromo-4-chloroimidazo [1,2-a ] in a microwave reactor at room temperature]To a stirred solution of quinoxaline (14.13g, 50mmol) in NMP (400mL) was added isobutylamine (9.94mL, 100mmol) and DIPEA (26.13mL, 150 mmol). The solution was heated at 170 ℃ for 60min under microwave irradiation. After cooling, water was added to the solution and the precipitate was filtered, the residue was washed with water and dried to give (1-bromoimidazo [1, 2-a)]Quinoxalin-4-yl) isobutylamine (14.89g, 93.3%):1H-NMR(300MHz，d6-DMSO)：δ＝9.17(1H，d)，8.01(1H，d)，7.92(1H，s)，7.78(1H，dd)，7.70(1H，dd)ppm。UPLC-MS：RT＝1.14min；m/z 284.6[MH+](ii) a Theoretical MW is 283.5.
Example 1-1: preparation of 1- [4- (4-isobutylaminoimidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3- [4- (4-methylpiperazin-1-ylmethyl) -3-trifluoromethylphenyl ] urea
1- [4- (4-methylpiperazin-1-ylmethyl) -3-trifluoromethylphenyl]-3- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxolane-2-yl) phenyl]Urea (244mg, 0.47mmol) was dissolved in potassium carbonate (1.41mL, 1M in water) and THF (1mL) and stirred at rt in a sealed vial overnight. Adding (1-bromoimidazo [1,2-a ]]Quinoxalin-4-yl) isobutylamine (75mg, 0.235mmol), Pd (OAc)2(10.6mg, 0.047mmol) and P (oTol)3(28.6mg, 0.094mmol) and the mixture was heated under microwave irradiation at 140 ℃ for 40 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 1- [4- (4-isobutylaminoimidazo [1,2-a ]]Quinoxalin-1-yl) phenyl]-3- [4- (4-methylpiperazin-1-yl)Methyl) -3-trifluoromethylphenyl]Urea (24.8mg, 14%):1H-NMR(300MHz，d6-DMSO)：δ＝9.30(1H，s)，9.24(1H，s)，7.98(1H，s)，7.68-7.50(6H，m)，7.47(3H，m)，7.27(2H，m)，6.93(1H，dd)，3.51(2H，s)，3.37(2H，dd)，2.38(8H，br s)，2.19(3H，s)，2.09(1H，sept)，0.91(6H，d)ppm；UPLC-MS：RT＝1.03min；m/z(ES+)631.7[MH+](ii) a Theoretical MW is 630.7.
Examples 1 to 2: preparation of N-cyclopropyl-4- (4-isobutylaminoimidazo [1,2-a ] quinoxalin-1-yl) benzamide
Reacting (1-bromoimidazo [1,2-a ]]Quinoxalin-4-yl) isobutylamine (20mg, 0.07mmol), [4- [ (cyclopropylamino) carbonyl]Phenyl radical]Boric acid (21.8mg, 0.11mmol), Pd (dppf) Cl2(1.26mg, 0.007mmol) and potassium carbonate (212. mu.L, 1M in water) were mixed in 2mL of NMP in a sealed vial and heated at 140 ℃ for 40min under microwave irradiation. After cooling, the solution was filtered and subjected to preparative HPLC to give N-cyclopropyl-4- (4-isobutylaminoimidazo [1,2-a ]]Quinoxalin-1-yl) benzamide (2.86mg, 10%):1H-NMR(300MHz，d6-DMSO)：δ＝8.60(1H，d)，7.97(2H，d)，7.71(1H，t)，7.69(2H，d)，7.54(1H，d)，7.52(1H，s)，7.28(1H，dd)，7.19(1H，d)，6.91(1H，dd)，3.39(2H，dd)，2.86(1H，m)，2.09(1H，sept)，0.96(6H，d)，0.70(2H，d)，0.55(2H，d)ppm；UPLC-MS：RT＝1.14min；m/z(ES+)400.4[MH+](ii) a Theoretical MW is 399.5.
Examples 1 to 3: preparation of 1-ethyl-3- [4- (4-isobutylaminoimidazo [1,2-a ] quinoxalin-1-yl) phenyl ] urea
Using 1-ethyl-3- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxolane-2-yl) phenyl]Urea (137mg, 0.47mmol) 1-ethyl-3- [4- (4-isobutylaminoimidazo [1,2-a ] was prepared in analogy to example 1.2]Quinoxalin-1-yl) phenyl]Urea (21mg, 20.6%) and was subjected to preparative HPLC:1H-NMR(300MHz，d6-DMSO)：δ＝8.75(1H，s)，7.62(1H，t)，7.53(3H，m)，7.44(3H，m)，7.28(2H，m)，6.91(1H，dd)，6.26(1H，dd)，3.37(2H，dd)，3.12(2H，m)，2.09(1H，sept)，1.03(3H，t)，0.90(6H，d)ppm；UPLC-MS：RT＝1.07min；m/z(ES+)403.5[MH+](ii) a Theoretical MW is 402.5.
Examples 1 to 4: preparation of 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
0.1mmol of (1-bromoimidazo [1, 2-a)]Quinoxalin-4-yl) isobutylamine (intermediate example 2.1, 1mL, 0.1M in NMP), 0.15mmol of 2, 3-dihydro-1, 4-benzodioxin-6-ylboronic acid (0.3mL, 0.5M in NMP, 1.5eq), 0.02mmol of Pd (dppf) Cl2(0.533mL, 0.0375M in NMP, 0.2eq) and 0.3mmol K2CO3(0.3mL, 1M in water, 3eq) was mixed in a sealed vial and heated under microwave irradiation at 130 ℃ for 60 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 8.1mg (22%) of 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -N- (2-methylpropyl) imidazo [1, 2-a%]Quinoxaline-4-amines. UPLC-MS: RT ═ 1.26 min; m/z (ES +)375.4 MH+](ii) a Theoretical MW is 374.4.
The following compounds were prepared similarly using the appropriate boronic acid derivatives [ LC-MS data, such as retention time (RT in minutes) or mass peaks observed, were collected using LC-MS method a unless explicitly stated ]:
example 2.1: preparation of N-cyclopropyl-4- [4- (2-hydroxyethylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
Reacting (1-bromo-4-chloroimidazo [1,2-a ]]Quinoxaline (intermediate example 1.1, 1mL, 0.2M in NMP), 2-aminoethanol (2eq, 0.8mL, 0.5M in NMP) and DIPEA (3eq, 103 μ L) were mixed in a sealed vial and heated under microwave irradiation at 170 ℃ for 60 min. After cooling, [4- [ (cyclopropylamino) carbonyl ] is added]Phenyl radical]Boric acid (1.5eq, 0.3mL, 1M in NMP), Pd (dppf) Cl2(0.1eq, 533. mu.L, 0.0375M in NMP) and potassium carbonate (600. mu.L, 1M in water) and the mixture was heated at 140 ℃ for 40min under microwave irradiation. After cooling, the solution was filtered and subjected to preparative HPLC to give N-cyclopropyl-4- [4- (2-hydroxyethylamino) imidazo [1,2-a]Quinoxalin-1-yl]Benzamide (10.19mg, 13%): UPLC-MS: RT ═ 0.82 min; m/z (ES +)388.4 MH+](ii) a Theoretical MW is 387.4.
The following compounds are prepared analogously using the appropriate intermediates example 1.x, the appropriate amine and the appropriate boronic acid derivative [ LC-MS data such as retention time (RT in min) or mass peak observed are collected using LC-MS method a unless explicitly stated ]:
example 3.1: preparation of 4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (1H-pyrazol-3-yl) benzamide
0.1mmol of 4- {4- [ (2-methylpropyl) amino]Imidazo [1,2-a ]]Quinoxalin-1-yl } benzoic acid (1.0mL, 0.1M in NMP) (example 1.5), 0.2mmol of 1H-pyrazol-3-amine (1mL, 0.5M in NMP, 2eq), 0.2mmol of HATU (1mL, 0.5M in NMP, 2eq) and 0.4mmol of NMM (0.133mL, 3M in NMR, 4eq) were mixed, shaken at rt for 24H, and subjected to preparative HPLC to give 7.6mg of 4- {4- [ (2-methylpropyl) amino group]Imidazo [1,2-a ]]Quinoxalin-1-yl } -N- (1H-pyrazol-3-yl) benzamide (18%): UPLC-MS: RT ═ 1.04 min; m/z (ES +)426.5 MH+](ii) a Theoretical MW 425.5.
The following compound examples are prepared similarly to the procedures described above using the appropriate amine [ LC-MS data, such as retention time (RT in minutes) or mass peaks observed, are collected using LC-MS method a unless explicitly stated ]:
in addition, the compounds of formula (I) of the present invention may be converted to any of the salts described herein by any method known to those skilled in the art. Similarly, any salt of the compound of formula (I) of the present invention may be converted to the free compound by any method known to those skilled in the art.
Pharmaceutical compositions of the compounds of the invention
The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These compositions can be used to achieve a desired pharmacological effect by administration to a patient in need thereof. For purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to a patient at concentrations consistent with effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is preferably an amount that results in or affects the particular condition being treated. The compounds of the present invention may be administered together with a pharmaceutically acceptable carrier in any effective conventional dosage unit form including immediate release, sustained release and timed release formulations in the following manner: oral, parenteral, topical, nasal, ocular (ophthalmic), sublingual, rectal, vaginal administration and the like.
For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges (lozenes), melt gels (melts), powders, solutions, suspensions or emulsions and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard or soft capsule type, comprising, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of the present invention can be compressed into tablets with conventional tablet bases (e.g., lactose, sucrose, and corn starch) and in combination with: binders such as acacia, corn starch or gelatin, disintegrating agents such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia for assisting disintegration and dissolution of the tablets after administration, lubricants such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate for improving the flowability of the tablet granulation and preventing adhesion of the tablet materials to the surfaces of the tablet dies and punches, and dyes, colorants and flavouring agents such as peppermint, oil of wintergreen or cherry flavouring for improving the organoleptic properties of the tablets and making them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.
The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as liquid paraffin, or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, for example gum acacia and gum tragacanth, (2) natural phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative such as methyl and propyl parabens as well as flavoring and coloring agents.
The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable doses of the compounds, preferably in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides or acetylated glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, sodium lauryl sulfate, sodium, Carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Exemplary oils useful in the parenteral formulations of the invention are those derived from petroleum, animal, vegetable or synthetic sources, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quats, and mixtures.
The parenteral compositions of the invention will generally contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5 to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.
Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide and propylene glycol.
The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated according to known methods using: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any less irritating fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.
Another formulation used in the methods of the invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous delivery of a controlled amount of a compound of the present invention. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. patent No. 5,023,252 to 1991, published on 6/11, which is incorporated herein by reference). Such patches may be configured for continuous, pulsed, or on-demand delivery of the agent.
Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.
It may be desirable or necessary to deliver the pharmaceutical composition to a patient by a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques such as administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. Such implantable delivery systems for transporting agents to specific anatomical locations of the body are described in U.S. patent No. 5,011,472, published 4-30 1991.
The compositions of the present invention also necessarily or optionally include other conventional pharmaceutically acceptable formulation ingredients, often referred to as carriers or diluents. Conventional procedures for preparing such compositions into suitable dosage forms may be used. Such ingredients and procedures include those described in the following references, all of which are incorporated herein by reference: powell, M.F. et al, "Complex of Excipients for molecular formulas" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-; strickley, R.G "partial Formulations of Small Molecule Therapeutics marked in the United States (1999) -Part-l" PDAjournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and the same Use in Injectable Products" PDA journal Pharmaceutical Science & Technology 1997, 51(4), 166- "171.
Common pharmaceutical ingredients that may be used to formulate the composition for the intended route of administration include:
acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
alkalizing agents (examples include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));
adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);
aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl2F2、F2ClC-CClF2And CClF3)；
Air displacement agents (air displacement agents) (examples include, but are not limited to, nitrogen and argon);
antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);
antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);
antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
adhesive substances (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);
buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);
a carrier (examples include, but are not limited to, acacia syrup, flavoring elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection)
Chelating agents (examples include, but are not limited to, sodium edetate and edetic acid);
coloring agents (examples include, but are not limited toRed No.3、Red No.20、Yellow No.6、Blue No.2、Green No.5、Orange No.5、Red No.8, caramel, and Red iron oxide).
Clarifying agents (examples include, but are not limited to, bentonite);
emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glycerol monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);
encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);
flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);
humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);
abrasives (examples include, but are not limited to, mineral oil and glycerin);
oils (examples include, but are not limited to, peanut oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);
ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);
penetration enhancers (transdermal delivery) (examples include, but are not limited to, mono-or polyhydric alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);
plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);
solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);
hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);
suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));
surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, octoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);
suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, kaolin, methylcellulose, tragacanth and magnesium aluminum silicate);
sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol, and sucrose);
tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);
tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);
tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);
tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac);
tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);
tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, crospovidone, sodium alginate, sodium starch glycolate, and starch);
tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);
tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);
tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);
tablet polishes (examples include, but are not limited to, carnauba wax and white wax);
thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);
tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);
viscosity enhancers (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and gum tragacanth); and
wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
The pharmaceutical composition of the present invention can be exemplified as follows:
sterile IV solution: sterile water for injection can be used to prepare a 5mg/mL solution of the desired compound of the invention, with the pH adjusted as necessary. The solution was diluted with sterile 5% dextrose to 1-2mg/mL for administration, and administered as an IV infusion over about 60 min.
Lyophilized powder for IV administration: sterile formulations can be prepared with (i)100-1000mg of the desired compound of the invention in lyophilized powder form, (ii)32-327mg/mL sodium citrate, and (iii)300-3000mg dextran 40. By sterile injectionThe formulation is reconstituted with saline or 5% dextrose to a concentration of 10-20mg/mL, then further diluted with saline or 5% dextrose to 0.2-0.4mg/mL and administered as an IV bolus or IV infusion over 15-60 minutes.
Intramuscular injection suspension: the following solutions or suspensions can be prepared for intramuscular injection:
50mg/mL of the desired Water-insoluble Compound of the invention
5mg/mL sodium carboxymethylcellulose
4mg/mL TWEEN 80
9mg/mL sodium chloride
9mg/mL benzyl alcohol
Hard capsule: a large number of unit capsules were prepared by filling standard two-piece hard capsules with 100mg of powdered active ingredient, 150mg of lactose, 50mg of cellulose and 6mg of magnesium stearate.
Soft capsule: a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by positive displacement pump into molten gelatin to form soft capsules containing 100mg of the active ingredient. The capsules were washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible drug mixture.
Tablet formulation: a number of tablets were prepared by conventional procedures such that the dosage unit contained 100mg of active ingredient, 0.2mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275mg of microcrystalline cellulose, 11mg of starch and 98.8mg of lactose. Suitable aqueous and non-aqueous coatings may be employed to increase palatability, improve appearance and stability, or delay absorption.
Immediate release tablet/capsule: these are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the drug. Mixing the active ingredients inLiquids containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-state extraction techniques. The pharmaceutical compound can be tableted with a viscoelastic and thermoelastic sugar and a polymer or effervescent component to produce a porous matrix that is quick-releasing without the need for water.
Combination therapy
The compounds of the present invention may be administered as the sole agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the present invention may be combined with known agents and the like that are resistant to hyperproliferative diseases or other indications, as well as mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, or anti-hormones.
The additional agent may be aldesleukin, alendronic acid, alpha-interferon (Alfaferone), alitretinoin, allopurinol, sodium allopurinol for injection (Aloprim), palonosetron hydrochloride injection (Aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasetron, Ardasipine injection (Anzmet), alfa bepotastine injection (Aranesp), Arglabin, arsenic trioxide, exemestane, 5-azacytidine, azathioprine, BCG or Tice BCG, amastatin b bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, busulfan, calcitonin, alemtuzumab (Campatath), capecitabine, carboplatin, bicalutamide, cefaclonimine, Cefossilvicolic, western butyric acid, melbine, melphalan, chlorambucil, clindamycin, chlorambucil, berdolac, clonidine, clodronabine, cisplatin, clodronabiraterone, cisplatin, clodronide (Camptocline), platinum, clorac, clodronine, clodronide, clodronine, clodronabine, cyclophosphamide, cytarabine, carbamazepine, dactinomycin, daunorubicin citrate liposome (DaunoXome), dexamethasone sodium phosphate, estradiol valerate, dinil interleukin fusion 2 toxin (Denileukin diftitox), methylprednisolone, deslorelin, dexrazoxane, diethylstilbestrol, fluconazole, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprolide acetate (Eligard), labyrinase injection (Elitek), epirubicin hydrochloride injection (Ellence), aprepitant capsule (Emend), epirubicin, alfa eptin alfa, alfa fariptin (Epogen), etaplatin, levamisole, estradiol (Estrace), estradiol, estramustine sodium phosphate, ethisterol, amifostine, etidronic acid, etoposide, favudine, favulat, favudine, flufavudine, Finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosetabine, fulvestrant, gamma-globulin (Gamma-globulin), gemcitabine, gemumab, imatinib mesylate (Gleevec), carmustine (Gliadel), goserelin, granisetron hydrochloride, histrelin, topotecan (Hymtcain), hydrocortisone, erythroxylynonenine (ezhro-hydroxyynyladenine), hydroxyurea, temozolomab, idarubicin, ifosfamide, alpha interferon, alpha 2 interferon, alpha-2A interferon, alpha-2B interferon, alpha-n 1 interferon, alpha-n 3 interferon, beta interferon, gamma-1 a interferon, gamma-2A interferon, interleukin, alpha-2A interferon, alpha-2B interferon, Interferon alpha-2 b (intron a), gefitinib tablet (Iressa), irinotecan, granisetron, lentinan sulfate (lentinan sulfate), letrozole, leucovorin, leuprorelin acetate, levamisole, calcium levofolinate (levofolinic acid calcium salt), levothyroxine sodium, Levoxyl, lomustine, lonidamine, dronabinol, dichloromethyldiethylamine (meclorethamine), mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen tablet (Menest), 6-mercaptopurine, mesna, methotrexate, Metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modenal, myocin, nedaplatin, filgrastim (neulata), interleukin 11 (neugeura), recombinant nella, leucite, OCT, nsertine, nserin C, octreotide, oxpocetine, oxepin, medroxyprine, medroxyprogen, 6-5, medroxyprogen, cefxadine, oxaliplatin, paclitaxel, prednisone sodium phosphate (Pediapred), pemetrase, Pegasys, pentostatin, streptolysin (pisibanil), pilocarpine hydrochloride, pirarubicin, plicamycin, porphelin, prednistin, prednisolone, prednisone, equine estrogens, procarbazine, recombinant human erythropoietin alpha, raltitrexed, recombinant human interferon beta 1a injection (Rebif), rhenium-186, etidronate (etidronate), rituximab, roscovitine (Roferon-A), romopeptide, pilocarpine hydrochloride (Salagen), octreotide, sargrastim, semustine, Sizopyran, sobromotene, prednisolone, fosmenacin, dry cell therapy, streptozocin, strontium chloride 89, levothyroxine sodium, talosin, tamsulosin, loxifene, testotene, testotendine, paclitaxel, temozolol, leucinolone, pemphitin, pemphimosel, pemphimosine, pemphigus, pemphigozide, prednisone, and its, Teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (Trexall), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, RDEA 119, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, vilizine, dexrazoxane, neat stastatin ester (zinostatin stimamer), danesetron, ABI-progesterone, Acolbifene, interferon gamma-1 b (Actimmuune), Affinitaitak, aminopterin, azoxifene, Asoprisnil, actamtan, atramtuzumab, sorafenib (sorafenib), Bevacizumab (CCI), Avastin-779, Czocine-CDC, ciprofloxacin acetate, Clostreptoxib, Avsiloxib-77501, Clostreptacon, Decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, Edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, ibandronic acid, interferon gamma, pegylated interferon alpha-2 b (intron-PEG), ixabepilone (ixabepilone), keyhole limpet hemocyanin (keyhole liprocyanin), L-651582, lanreotide, lasofoxifene, Libra, Lonafarnib, mirofen, Minodronate (Minodronate), MS-209, MTP-PE liposomes, MX-6, nafarelin, nemorubicin, neovastat, nolatresenen, Oblimersen, Onco-TCS, Paidem, paclitaxel, Miracoxifene, Naquart-21, Naquarrel-401, Levaquone, Levadamine, Navigna-3, Nawarfarabine, Navigna, Nafarabine, Navigna, Nafarabine, Navigna, Na, Satraplatin, cetomalcidol, T-138067, erlotinib hydrochloride tablets (Tarceva), Taxoprexin, alpha-1 thymosin, thiazolufrine, tipifarnib (tipifarnib), tirapazamine, TLK-286, toremifene, transamid-107R, valcephrad, vapreotide, vatalanib (vatalanib), verteporfin, vinflunine, Z-100, zoledronic acid, or combinations thereof.
Optional anti-hyperproliferative agents that may be added to the compositions include, but are not limited to, compounds listed in the cancer chemotherapeutic regimen of the merck index 11 (1996) (incorporated by reference), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, dichloromethyldiethylamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, meclofen, meclofenoxate, dactinomycin, and other drugs, Vinblastine, vincristine, and vindesine.
Other anti-hyperproliferative agents suitable for use with The compositions of The present invention include, but are not limited to, those compounds recognized in Goodman and Gilman's The Pharmacological Basis of Therapeutics (NitthCondition), edited by Molinoff et al, McGraw-Hill, pp.1225-1287, (1996) (incorporated herein by reference) for The treatment of neoplastic disease, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, red hydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorometholone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, medroxyprogesterone, medetotan, and The like, Paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan.
The compounds of the invention may also be administered in combination with a protein therapeutic. Such protein therapeutics suitable for use in the treatment of cancer or other angiogenic disorders and suitable for use with the compositions of the invention include, but are not limited to, interferons (e.g., alpha, beta, or gamma interferons), hyperactive monoclonal antibodies, Tuebingen, TRP-1 protein vaccines, Colostrinin, anti-FAP antibodies, YH-16, gimumab, infliximab, cetuximab, trastuzumab, dinil interleukin fusion 2 toxin, rituximab, alpha 1 thymosin, bevacizumab, mecamylamine, omprex, natalizumab, rhMBL, MFE-CP1+ 2767-P, ABT-ErbB 2-specific immunotoxin, SGN-35, MT-103, linline, AS-1402, B43-genistein, L-19 series radioimmunotherapy agents, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r (m) CRP, MORAB-009, Avisuramine (aviscumine), MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, Voloximab (volociximab), PRO-1762, lexatuzumab (lexatuzumab), SGN-40, pertuzumab (pertuzumab), EMD-273, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tegafur peptide (tigotide), CAT-3888, labetazumab (labetazumab), radiolabeled pertuzumab (Labetuzumab), radioisotope-crosslinked trastuzumab of eming particles, EM-Acuk-1421, interleukin (Hitachi), HPV-7, HPV-3516, HPV-30625, and, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, agovacizumab (oregomab), ofatumumab, zalutumumab (zalutumumab), betheumatin interleukin (cindrekin bestudox), WX-G250, Albuferon, aflibercept, denosumab (denosumab), vaccine, CTP-37, efungumab (efungumab) or 131I-chTNT-1/B. Monoclonal antibodies that may be used as protein therapeutics include, but are not limited to, molobuzumab-CD 3, abciximab, edrecolomab, daclizumab, gemtuzumab (gentuzumab), alemtuzumab, ibritumomab (ibritumomab), cetuximab, bevacizumab, efalizumab (efalizumab), adalimumab (adalimumab), omalizumab (omalizumab), moruzumab-CD 3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
In general, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:
(1) produces better efficacy in reducing tumor growth or even eliminating tumors than either agent administered alone,
(2) allowing for the administration of smaller amounts of the administered chemotherapeutic agent,
(3) providing a chemotherapeutic treatment that is well tolerated by patients and has fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,
(4) allowing the treatment of a broader spectrum of different cancer types in mammals, particularly humans,
(5) providing a higher response rate in the treated patient,
(6) provides longer survival in the treated patient compared to standard chemotherapy treatment,
(7) provide longer tumor progression time, and/or
(8) At least as good efficacy and tolerability as the agents used alone are obtained as compared to known cases where other cancer agents produce antagonistic effects in combination.
Method for sensitizing cells to radiation
In a different embodiment of the invention, the compounds of the invention can be used to sensitize cells to radiation. That is, treatment of cells with a compound of the invention prior to radiation therapy of the cells makes the cells more susceptible to DNA damage and cell death than they would be if the cells were not subjected to any treatment with a compound of the invention. In one aspect, a cell is treated with at least one compound of the invention.
Accordingly, the present invention also provides a method of killing cells, wherein one or more compounds of the invention are administered to the cells along with conventional radiation therapy.
The invention also provides methods of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention to cause or induce cell death prior to treating the cell. In one aspect, after treating the cells with one or more compounds of the invention, the cells are treated with at least one compound, at least one method, or a combination thereof to cause DNA damage for inhibiting the function of normal cells or killing the cells.
In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention sensitizes the cell to cell death, the cell is treated with at least one DNA-damaging agent to kill the cell. DNA damaging agents that may be used in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-ray, ultraviolet radiation), carcinogens, and mutagenic agents.
In another embodiment, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to: activating a cellular signal transduction pathway (which causes DNA damage when the pathway is activated), inhibiting a cellular signal transduction pathway (which causes DNA damage when the pathway is inhibited), and inducing a biochemical change in a cell (wherein the change causes DNA damage). By way of non-limiting example, DNA repair pathways in a cell may be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in a cell.
In one aspect of the invention, the compounds of the invention are administered prior to irradiation or other induction that causes DNA damage to cells. In another aspect of the invention, the compounds of the invention are administered concurrently with irradiation or other induction that causes DNA damage to cells. In yet another aspect of the invention, the compounds of the invention are administered immediately after the onset of irradiation or other induction that causes DNA damage to cells.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
As described above, it has surprisingly been found that the compounds of the present invention effectively inhibit Mps-1 and are therefore useful for the treatment or prevention of diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, or an inappropriate cellular immune response or an inappropriate cellular inflammatory response, particularly wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, e.g. hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, diseases with inappropriate cellular immune response or inappropriate cellular inflammatory response, and in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.
Thus, according to another aspect, the present invention relates to 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 prevention of a disease, as described above.
Thus, another particular aspect of the present invention is the 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, as described above, for the prophylaxis or treatment of a disease.
Accordingly, another particular aspect of the present invention is the use of a compound of general formula (I) as described above for the preparation of a pharmaceutical composition for the treatment or prevention of a disease.
The diseases mentioned in the first two paragraphs are diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, such as hematological tumors, solid tumors and/or metastases thereof, e.g. leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, inflammatory diseases, Endocrine tumors, breast tumors and other gynecological tumors, urological tumors including renal tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.
In the context of the present invention, in particular in the context of an "inappropriate immune response or inappropriate cellular inflammatory response" as used herein, the term "inappropriate" is understood to preferably mean a response which is weaker or stronger than the normal response and which is associated with, causes or leads to the pathology of the disease.
Preferably, the use is for the treatment or prevention of a disease, wherein the disease is a hematological tumor, a solid tumor and/or metastases thereof.
Methods of treating hyperproliferative disorders
The present invention relates to methods of treating hyperproliferative disorders in mammals using the compounds of the present invention and compositions thereof. The compounds may be used to inhibit, block, reduce, etc., cell proliferation and/or cell division and/or induce apoptosis. The method comprises administering to a mammal, including a human, in need thereof an amount of a compound of the present invention, a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, and the like, effective to treat the condition. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, Benign Prostatic Hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. Such conditions also include lymphomas, sarcomas and leukemias.
Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to, small cell lung cancer and non-small cell lung cancer as well as bronchial adenomas and pleural pneumococcal tumors.
Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and brain astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.
Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.
Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.
Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urinary tract cancer, and human papillary renal cancer.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, and non-melanoma skin cancer.
Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip cancer, oral cavity cancer, and squamous cell. Lymphomas include, but are not limited to, aids-related lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, burkitt's lymphoma, hodgkin's disease, and central nervous system lymphoma.
Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.
Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist in other mammals with similar etiologies, and can be treated by administering the pharmaceutical compositions of the present invention.
Reference throughout this document to the use of the term "treating" or "treatment" is conventional, e.g., for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder such as sarcoma, and the like.
Methods of treating kinase disorders
The invention also provides methods for treating disorders associated with abnormal mitogen extracellular kinase activity including, but not limited to, stroke, heart failure, hepatomegaly, cardiac enlargement, diabetes, alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, septic shock, or asthma.
An effective amount of a compound of the invention may be used to treat such disorders, including those diseases mentioned in the background section above (e.g., cancer). Moreover, such cancers and other diseases may be treated with the compounds of the present invention regardless of the mechanism of action and/or the relationship of the kinase to the condition.
The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes abnormal expression or activity of the gene encoding the kinase or the polypeptide encoded thereby. Examples of such aberrant activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that produce constitutively active or highly active kinase activity; gene mutation, deletion, substitution, addition, and the like.
The present invention also provides methods of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) and diastereomeric forms thereof. Kinase activity may be inhibited in cells (e.g., in vitro) or in cells of a mammalian subject, particularly a human patient in need of treatment.
Methods of treating angiogenic disorders
The invention also provides methods of treating conditions and diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and abnormal expression of angiogenesis can be harmful to an organism. Many pathological states are associated with growth of unrelated (extra) blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [ Aiello et al, New engl.j.med.1994, 331, 1480; peer et al, Lab.invest.1995, 72, 638], age-related macular degeneration [ AMD; see Lopez et al invest, opthalmols, vis, 1996, 37, 855], neovascular glaucoma, psoriasis, retrocrystallic fibroplasia, angiofibroma, inflammation, Rheumatoid Arthritis (RA), restenosis, in-stent restenosis, restenosis following vascular grafts, and the like. In addition, the increased blood supply associated with cancerous and tumor tissue promotes growth, resulting in rapid tumor enlargement and metastasis. In addition, the growth of new blood and lymph vessels in tumors provides an exit route for cancerous cells (renegade cells), promoting metastasis and leading to the spread of cancer. Thus, the compounds of the present invention may be used to treat and/or prevent any of the aforementioned angiogenic disorders, e.g., by inhibiting and/or reducing angiogenesis; inhibit, block, reduce, etc., endothelial cell proliferation or other types associated with angiogenesis, and cause cell death or apoptosis of such cells.
Dosage and administration
Effective dosages of the compounds of the present invention for the treatment of each of the desired indications can be readily determined based on standard laboratory techniques known to evaluate compounds for the treatment of hyperproliferative and angiogenic disorders, by standard toxicity tests, as well as by standard pharmacological tests for determining treatment of the disorders described hereinabove in mammals, and by comparing these results with those of known drugs used to treat these disorders. The amount of active ingredient administered in the treatment of one of these conditions may vary widely depending on the following considerations: the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient to be treated, and the nature and extent of the condition being treated.
The total amount of active ingredient to be administered is generally from about 0.001mg/kg to about 200mg/kg body weight/day, and preferably from about 0.01mg/kg to about 20mg/kg body weight/day. A clinically useful dosing regimen will be one to three times daily dosing to once every four weeks. In addition, a "drug withdrawal period" (where no drug is administered to the patient for a certain period of time) may be advantageous for the overall balance between pharmacological efficacy and tolerability. A unit dose may contain from about 0.5mg to about 1500mg of the active ingredient and may be administered one or more times per day, or less than once per day. The average daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques, may preferably be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200mg/kg of total body weight. The average daily vaginal dosage regimen is preferably 0.01-200mg/kg total body weight. The average daily topical dosage regimen is preferably 0.1-200mg administered one to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01-200 mg/kg. The average daily inhaled dose regimen is preferably from 0.01 to 100mg/kg of total body weight.
The specific starting and maintenance dosage regimen for each patient will, of course, vary depending upon the following factors: the nature and severity of the condition as determined by the clinician, the activity of the particular compound used, the age and general health of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. Thus, the desired therapeutic regimen and the amount of a compound of the invention, pharmaceutically acceptable salt, ester or composition thereof to be administered can be determined by one skilled in the art using routine therapeutic testing.
Preferably, the disease of the method is a hematological tumor, a solid tumor and/or metastases thereof.
The compounds of the invention are particularly useful for the treatment and prevention (i.e. prevention) of tumor growth and metastasis, in particular of solid tumors of all indications and stages, with or without prior treatment of said tumor growth.
Methods for determining specific pharmacological or pharmaceutical properties are well known to those skilled in the art.
The example assay experiments described herein are intended to illustrate the invention and the invention is not limited to the examples provided.
And (3) biological determination: proliferation assay
HeLa human cervical tumor cells (ATCC CCL-2) were inoculated at a concentration of 3000 cells/well into 96-well plates in 200. mu.l DMEM/HAMS F12 medium supplemented with 2mM L-glutamine and 10% fetal bovine serum. After 24 hours, the cells of one plate (zero plate) were stained with crystal violet while the medium in the other plate was replaced with fresh medium (200. mu.l) to which the test substance was added at various concentrations (0. mu.M and 0.01-30. mu.M; final concentration of solvent dimethylsulfoxide 0.5%). The cells are cultured for 4 days in the presence of the test substance. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed for 15 minutes at room temperature by adding 20. mu.l/measurement point of 11% glutaraldehyde solution. After three cycles of washing the fixed cells with water, the plates were dried at room temperature. Cells were stained by adding 100. mu.l/measurement point of a 0.1% crystal violet solution (pH 3.0). After three cycles of washing the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100. mu.l/measurement point of 10% acetic acid solution. The extinction was determined photometrically at a wavelength of 595 nm. The change in cell number, in percent, was calculated by normalizing the measurements to the extinction value (═ 0%) of the zero-point plate and to the extinction (═ 100%) of the untreated (0 μm) cells. IC50 values were determined by 4-parameter fitting using the company's software.
Mps-1 kinase assay
The biotinylated substrate peptide was phosphorylated by the human kinase Mps-1. Detection of phosphorylated products was achieved by homogeneous time-resolved fluorescence resonance energy transfer (HTRF) from europium-labeled anti-phospho-serine/threonine antibody as donor to streptavidin labeled with cross-linked allophycocyanin (SA-XLent) as acceptor. Test compounds inhibit kinase activity.
N-terminal GST-tagged human full-length recombinant Mps-1 kinase (purchased from Invitrogen, Karslruhe, Germany, cat. No. PV4071) was used. Biotinylated peptide-amino acid sequence PWDPDDADITEILG (amide form at the C-terminus, from Biosynthan GmbH, Berlin) was used as substrate for the kinase reaction.
For the assay, 50nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black, small-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), Mps-1 was added in assay buffer [0.1mM sodium orthovanadate, 10mM MgCl. MgCl. ]2、2mM DTT、25mM Hepes pH 7.7、0.05％ BSA、0.001％ Pluronic F-127]2 μ l of (b) and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to Mps-1 before the kinase reaction started. The kinase reaction was then initiated by adding a solution of 16.7. mu.M ATP and 1.67. mu.M peptide in assay buffer of 3. mu.l and the resulting mixture was incubated at 22 ℃ for a reaction time of 60 min. The concentration of Mps-1 in the assay was adjusted to the activity of the enzyme batch and a concentration was chosen that was suitable to bring the assay in the linear range, typical enzyme concentrations were in the range of about 1nM (final concentration in 5 μ Ι assay volume). Mu.l of HTRF detection reagent solution (100mM Hepes pH 7.4, 0.1% BSA, 40mM EDTA, 140nM streptavidin-XLent [ #61GSTXL, Fa. Cis BioInternational, Marcoule, France) was added]1.5nM anti-phospho (Ser/Thr) -europium-antibody [ # AD0180, PerkinElmer LAS, Rodgau-Jugesheim, Germany]) The reaction was terminated.
The resulting mixture was incubated at 22 ℃ for 1h to bind the phosphorylated peptide to the anti-phospho (Ser/Thr) -europium-antibody. The amount of phosphorylated substrate was then assessed by measuring the resonance energy transfer from the europium-labeled anti-phosphate (Ser/Thr) antibody to streptavidin-XLent. Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured in an HTRF plate reader such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (PerkinElmer LAS, Rodgau-Jugesheim, Germany). The ratio of the emissions at 665nm and 622nm was taken as a measure of the amount of phosphorylated substrate. Will countNormalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Test compounds were tested on the same microtiter plate at 10 different concentrations in the range of 20 μ M to 1nM (20 μ M, 6.7 μ M, 2.2 μ M, 0.74 μ M, 0.25 μ M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, serial dilutions prepared by 1: 3 serial dilution at the level of 100-fold concentration of stock solution prior to assay), each concentration being done in duplicate, and the IC calculated by 4-parameter fitting using internal software50The value is obtained.
Spindle Assembly checkpoint assay
The spindle assembly checkpoint ensures that chromosomes separate properly during mitosis. Upon entry into mitosis, chromosomes begin to concentrate and become phosphorylated with histone H3 on serine 10. Dephosphorylation of histone H3 on serine 10 occurred late in the cleavage and ended early in the end of the cleavage. Thus, histone H3 phosphorylation on serine 10 can be used as a cell marker for mitosis. Nocodazole is a microtubule destabilizing substance. Consequently, nocodazole interferes with microtubule dynamics and mobilizes spindle assembly checkpoints. Cells arrest in the G2/M transition phase of mitosis and have phosphorylated histone H3 on serine 10. Spindle checkpoint inhibition by Mps-1 inhibitors abrogates mitotic block in the presence of nocodazole and cells prematurely complete mitosis. This change was detected by a decrease in cells with histone H3 phosphorylation on serine 10. This reduction was used as a marker to determine the ability of the compounds of the invention to induce mitotic breakthrough (mitotic breakthrough).
Cultured human cervical tumor cell line HeLa (ATCCCL-2) was seeded at 2500 cells/well into 384-well microtiter plates in 20. mu.l Dulbeco's medium (w/o phenol Red, w/o sodium pyruvate, w 1000mg/ml glucose, w pyridoxine) supplemented with 1% (v/v) glutamine, 1% (v/v) penicillin, 1% (v/v) streptomycin, and 10% (v/v) peptide bovine serum. After overnight incubation at 37 ℃, cells were added to nocodazole at 10 μ l/well to a final concentration of 0.1 μ g/ml. Cultivation methodAfter 24h of culture, the cells were arrested in the G2/M phase of cell cycle progression. Test compounds (0. mu.M, and 0.005. mu.M-10. mu.M; final concentration of solvent DMSO is 0.5% (v/v)) dissolved in dimethyl sulfoxide (DMSO) were added at various concentrations. Cells were incubated at 37 ℃ for 4h in the presence of test compounds. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in Phosphate Buffered Saline (PBS) overnight at 4 ℃ and then 0.1% (v/v) Triton X in PBS at room temperatureTM100 for 20min and blocked with 0.5% (v/v) Bovine Serum Albumin (BSA) in PBS for 15min at room temperature. After washing with PBS, 20. mu.l/well of an antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Upstate, Cat # 16-222; 1: 200 dilution) was added to the cells and incubated at room temperature for 2H. The cells were then washed with PBS, 20. mu.l/well HOECHST 33342 dye solution (5. mu.g/ml) was added to the cells and the cells were incubated for 12min at room temperature in the dark. Cells were washed twice with PBS, then covered with PBS and stored at 4 ℃ until used for analysis. With Perkin Elmer OPERATMThe High-Content Analysis plate reader obtains images. MetaXpress with image analysis software from Molecular devicesTMThe images were analyzed using a cell cycle application module. In this assay, two markers, HOECHST 33342 and phosphorylated histone H3 on serine 10, were measured. HOECHST 33342 labels the DNA and is used to count cell numbers. Staining of phosphorylated histone H3 on serine 10 determines the number of mitotic cells. Mps-1 inhibition decreased the number of mitotic cells in the presence of nocodazole, indicating an inappropriate mitotic progression. Further analysis of the raw assay data by four parameter logistic regression analysis to determine the IC of each test compound50The value is obtained.
Similar assays for other Mps kinases using appropriate reagents will be apparent to those skilled in the art.
Selected results are shown in the following table:
accordingly, the compounds of the present invention effectively inhibit one or more Mps-1 kinases and are therefore suitable for the treatment or prevention of diseases caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by Mps-1, more particularly wherein said diseases caused by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response are hematological tumors, solid tumors, and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, tumors, and the like, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.
Claims (24)
1. A compound of formula (I), a salt thereof, or a mixture thereof:
wherein:
R1represents a linear or branched, saturated monovalent hydrocarbon radical having 2,3, 4, 5, 6, 7,8, 9 or 10 carbon atoms, halo-C1-C10-alkyl-, HO-C1-C10-alkyl-, C1-C10-alkoxy-C1-C10-alkyl-, aryloxy-C1-C10-alkyl-, aryl-, C1-C6Alkylene-heteroaryl-, -C1-C6alkylene-C3-C10-cycloalkyl, -C1-C6-alkylene- (3-to 10-membered heterocycloalkyl), -C1-C6Alkylene-aryl, -C1-C6-an alkylene-heteroaryl group;
wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, cyano-, C1-C6-alkyl-, C1-C6-alkoxy-, -N (H) C (= O) R8、-N(H)S(=O)2R8、-C(=O)NR9R10、-N(H)C(=O)OR8、-S(=O)2NR9R10、-NR9R10；
R2Represents an aryl-or heteroaryl-group; wherein optionally said group is substituted one or more times, in the same or different manner, by a substituent selected from: halogen-, hydroxy-, C1-C6-alkyl-, halo-C1-C6-alkyl-, HO-C1-C6-alkyl-, C1-C6-alkoxy-, -C (= O) -C1-C6-alkyl, -C (= O) OH, -N (H) C (= O) R8、-C(=O)NR9R10、-N(H)C(=O)NR9R10、-SR8、-S(=O)2R8；
R3、R4、R5、R6、R7：
Each independently represents a hydrogen atom, a halogen atom, a cyano group or C1-C6-an alkyl group;
R8、R9、R10：
each independently represents a hydrogen atom, C1-C6Alkyl radical, HO-C1-C6-alkyl-, H2NC(=O)-C1-C6-alkyl-, C1-C6-alkyl radical-N(H)C(=O)-C1-C6-alkyl-, H2NS(=O)2-C1-C6-alkyl-, C2-C6-alkynyl, C3-C10-cycloalkyl, 3-to 10-membered heterocycloalkyl, aryl, heteroaryl, -C1-C6-alkylene-heteroaryl, -C1-C6-an alkylene-3-to 10-membered heterocycloalkyl group;
wherein said C3-C10-cycloalkyl is optionally substituted one or more times by: halogen atom, cyano group, C1-C6Alkyl radical, HO-C1-C6-alkyl or heteroaryl;
wherein optionally said aryl group is substituted one or more times, in the same or different manner, by a substituent selected from the group consisting of: halo-C1-C6-alkyl, -C1-C6-alkylene-3-to 10-membered heterocycloalkyl, -N (H) C (= O) -C1-C6-alkyl, -n (h) C (= O) -heteroaryl, -C (= O) NH2；
Or
R9、R10Together with the nitrogen atom to which they are attached represent a 3-to 10-membered heterocycloalkyl group;
with the following conditions:
R1is not-CH2CH2CH2OH、
-CH2CH2CH2O(C=O)-Ra、
-CH2CH2CH2O(C=O)-ORa、
-CH2CH2CH2O(C=O)-CHRaNRbRc，
Wherein R isa、Rb、RcSame or different and selected from H, C1-C10Alkyl radical, C2-C10-alkenyl, C2-C10-alkynyl, phenyl and heteroaryl.
2. The compound of claim 1, wherein:
R2represents aryl-or heteroaryl-radicalClustering; wherein said group is substituted by-C (= O) NR9R10Substituted once and optionally with a substituent selected from: halogen-, hydroxy-, C1-C6-alkyl-, halo-C1-C6-alkyl-.
3. The compound of claim 1, wherein:
R2represents an aryl-or heteroaryl-group; wherein said group is substituted once with-C (= O) NH-cyclopropyl and optionally substituted with a substituent selected from: halogen-, hydroxy-, C1-C6-alkyl-, halo-C1-C6-alkyl-.
4. The compound of claim 1 selected from the group consisting of:
1-ethyl-3- [4- (4-isobutylaminoimidazo [1,2-a ] quinoxalin-1-yl) -phenyl ] urea
1- (2-fluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (4-methoxy-2-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (2, 5-difluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N-cyclopropyl-4- {4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- [4- (benzylamino) imidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- [2- (2-oxoimidazolidin-1-yl) ethyl ] benzamide
N- [2- (methylamino) -2-oxoethyl ] -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- [2- (pyridin-3-yl) ethyl ] benzamide
N- {4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl } -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (1-methylcyclopropyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzoic acid
1- (2-Fluoropyridin-3-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (2, 3-difluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (3-fluoro-4-methoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- (5-methylthiophen-2-yl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- (6-methylpyridin-3-yl) imidazo [1,2-a ] quinoxalin-4-amine
2-chloro-N-cyclopropyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-methyl-5- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } pyridine-2-carboxamide
N-cyclopropyl-4- {4- [ (4-sulfamoylbenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (pyridin-3-yl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (2-sulfamoylethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-propylbenzamide
N- (2-hydroxyethyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (4-sulfamoylphenyl) benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- [1- (pyridin-2-yl) cyclopropyl ] benzamide
1- [4- (4-isobutylamino-imidazo [1,2-a ] quinoxalin-1-yl) -phenyl ] -3- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl ] urea
1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (2-fluoro-3-methoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] quinoxalin-4-amine
1- (1, 3-benzodioxol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
3- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenol
1- (1H-indol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
2-chloro-N-methyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (3-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (2-methylbenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (morpholin-4-yl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- (4- { [2- (2-oxoimidazolidin-1-yl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- {4- [ (4-cyanobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- {4- [ (1-methyl-1H-pyrazol-3-yl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- [3- (2-oxopyrrolidin-1-yl) propyl ] benzamide
N- (3-carbamoylphenyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (1-methyl-1H-pyrazol-3-yl) benzamide
N- {3- [ (4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzoyl) amino ] phenyl } pyridine-3-carboxamide
1- (4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) ethanone
1- (1H-indazol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N-cyclopropyl-4- [4- (2-hydroxy-ethylamino) -imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- {4- [ (3-methylbenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (2-methoxybenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- [4- (ethylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- [4- ({4- [ (methylsulfonyl) amino ] phenyl } amino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N- (1-benzylpiperidin-4-yl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- {3- [ (4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzoyl) amino ] phenyl } pyridine-4-carboxamide
N- (2-methylpropyl) -1- [4- (methylsulfonyl) phenyl ] imidazo [1,2-a ] quinoxalin-4-amine
1- (1H-indazol-6-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N-cyclopropyl-4- (4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (4-methoxyphenyl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (4-sulfamoylphenyl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (2-phenoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N, N-diethyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (1-hydroxypropan-2-yl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (2-methylcyclopropyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- [1- (hydroxymethyl) cyclopropyl ] -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4-isobutylamino-imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- (4-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- [4- (methylthio) phenyl ] imidazo [1,2-a ] quinoxalin-4-amine
1- (2-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (1H-indol-6-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
1- (isoquinolin-5-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N-methyl-3- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (2-methylpropyl) -1- [2- (trifluoromethyl) phenyl ] imidazo [1,2-a ] quinoxalin-4-amine
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenol
1- (2-fluoro-4-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
4- {4- [ (3-chlorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- {4- [ (2-phenylethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- [4- (phenylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- {4- [ (cyclopropylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [4- (pyrrolidin-1-yl) butyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- (4- { [2- (4-fluorophenyl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (1H-pyrazol-3-yl) benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (prop-2-yn-1-yl) benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- [2- (pyridin-4-yl) ethyl ] benzamide
1-Ethyl-N- {3- [ (4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzoyl) amino ] phenyl } -1H-pyrazole-5-carboxamide
N- (2-methylpropyl) -1-phenylimidazo [1,2-a ] quinoxalin-4-amine
N-methyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (2-methylpropyl) -1- (thien-2-yl) imidazo [1,2-a ] quinoxalin-4-amine
1- (4-ethoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- (pyridin-3-yl) imidazo [1,2-a ] quinoxalin-4-amine
N- (2-methylpropyl) -1- (pyridin-4-yl) imidazo [1,2-a ] quinoxalin-4-amine
N- (3- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzyl) acetamide
N-cyclopropyl-4- [4- (pentylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- (4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (2-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (3-fluorophenyl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- {4- [ (1, 3-benzodioxol-5-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-ethyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (2-carbamoylphenyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- [3- (acetylamino) phenyl ] -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (2-fluorocyclopropyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N, N-dimethyl-4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (2-methoxypyrimidin-5-yl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
(4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) (pyrrolidin-1-yl) methanone
N- (2-methylpropyl) -1- (thien-3-yl) imidazo [1,2-a ] quinoxalin-4-amine
1- (3, 4-Dimethoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a ] quinoxalin-4-amine
(4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) methanol
2- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenol
N- (2-methylpropyl) -1- (1H-pyrazol-3-yl) imidazo [1,2-a ] quinoxalin-4-amine
N-cyclopropyl-4- {4- [ (4-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [3- (dimethylamino) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (3-phenylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (4- { [2- (pyridin-4-yl) ethyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- ({1- [4- (cyclopropylcarbamoyl) phenyl ] imidazo [1,2-a ] quinoxalin-4-yl } amino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide
N- (2-amino-2-oxoethyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (3-amino-3-oxopropyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N- (1-cyanocyclopropyl) -4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N- (2-sulfamoylethyl) benzamide
N-cyclopropyl-4- [ 8-fluoro-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- (4- {7, 8-difluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
N- {2- [ (7, 8-difluoro-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) amino ] ethyl } acetamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
[3- ({1- [ 3-chloro-4- (cyclopropylcarbamoyl) phenyl ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-4-yl } amino) propyl ] carbamic acid tert-butyl ester
N-cyclopropyl-4- [4- (ethylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- {7, 8-dimethyl-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (2, 3-dihydroxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (4- {4- [ (2-methoxyethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- {4- [ (2-hydroxyethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (4- { [3- (1H-imidazol-1-yl) propyl ] amino } -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- {4- [ (cyclopropylmethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } -2-chloro-N-cyclopropylbenzamide
[3- ({1- [ 3-chloro-4- (cyclopropylcarbamoyl) phenyl ] -7-cyanoimidazo [1,2-a ] quinoxalin-4-yl } amino) propyl ] carbamic acid tert-butyl ester
N-cyclopropyl-4- { 8-fluoro-4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- [4- (ethylamino) -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl ] benzamide
4- [4- (butylamino) -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
1- (4- { 8-fluoro-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 8-fluoro-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- [4- (8-fluoro-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-N-cyclopropyl-4- [ 8-fluoro-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (furan-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- {4- [7, 8-difluoro-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] phenyl } -3-methylurea
4- [4- (butylamino) -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl ] -2-chloro-N-cyclopropylbenzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-sulfamoylethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- {4- [4- (benzylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] phenyl } -3-methylurea
1- (4- {7, 8-dimethyl-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- {7, 8-dimethyl-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
4- (7-cyano-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
4- (7-cyano-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
1- [4- (7-cyano-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-4- { 7-cyano-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (4- { 8-fluoro-4- [ (2,2, 2-trifluoroethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- [4- (8-fluoro-4- { [3- (1H-imidazol-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (4-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (4- {7, 8-difluoro-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- (7, 8-difluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- [4- (butylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
N-cyclopropyl-4- {4- [ (furan-2-ylmethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- {4- [4- (ethylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] phenyl } -3-methylurea
2-chloro-N-cyclopropyl-4- (7, 8-dimethyl-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- (7, 8-dimethyl-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- [4- (butylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] -2-chloro-N-cyclopropylbenzamide
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- [ 7-cyano-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- [ 7-cyano-4- (ethylamino) imidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- [4- (butylamino) -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- (4- { [2- (acetylamino) ethyl ] amino } -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
1- (4- { 8-fluoro-4- [ (2-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 8-fluoro-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- (8-fluoro-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- [4- (ethylamino) -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl ] benzamide
4- (4- { [2- (acetylamino) ethyl ] amino } -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
1- (4- {7, 8-difluoro-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
4- (4- { [2- (acetylamino) ethyl ] amino } -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide
2-chloro-N-cyclopropyl-4- (7, 8-difluoro-4- { [3- (1H-imidazol-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (7, 8-difluoro-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- {4- [7, 8-dimethyl-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] phenyl } -3-methylurea
1- [4- (7, 8-dimethyl-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
1- [4- (4- { [3- (1H-imidazol-1-yl) propyl ] amino } -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- {4- [ (2, 3-dihydroxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- { 7-cyano-4- [ (3-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
1- (4- { 7-cyano-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
4- [4- (butylamino) -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl ] -2-chloro-N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (2-hydroxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (8-fluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- [7, 8-difluoro-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
4- [4- (butylamino) -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [3- (1H-imidazol-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {4- [ (cyclopropylmethyl) amino ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- [4- (7, 8-difluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
1- (4- {7, 8-difluoro-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl } -2-chloro-N-cyclopropylbenzamide
N-cyclopropyl-4- [7, 8-dimethyl-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
N-cyclopropyl-4- {4- [ (cyclopropylmethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-dimethyl-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-3- (7, 8-dimethyl-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) -beta-alaninamide
1- [4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-N-cyclopropyl-4- {4- [ (4-hydroxybutyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
[3- ({1- [ 3-chloro-4- (cyclopropylcarbamoyl) phenyl ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-4-yl } amino) propyl ] carbamic acid tert-butyl ester
4- { 7-cyano-4- [ (2,2, 2-trifluoroethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
1- (4- { 7-cyano-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 7-cyano-4- [ (2, 3-dihydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-4- { 7-cyano-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (2-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
1- (4- {4- [ (2, 3-dihydroxypropyl) amino ] -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {4- [ (2, 3-dihydroxypropyl) amino ] -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- [4- (7, 8-difluoro-4- { [3- (1H-imidazol-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
1- (4- {4- [ (cyclopropylmethyl) amino ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- (4- {4- [ (3-fluorobenzyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- {4- [ (2-fluorobenzyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2- [ (7, 8-dimethyl-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) amino ] ethanesulfonamide
2-chloro-N-cyclopropyl-4- [7, 8-dimethyl-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
2-chloro-N-cyclopropyl-4- {4- [ (3-hydroxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- (4- { [2- (acetylamino) ethyl ] amino } -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
N- {2- [ (7-cyano-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) amino ] ethyl } acetamide
2-chloro-4- { 7-cyano-4- [ (2-hydroxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
2-chloro-4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (2, 3-dihydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (4-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (2, 3-dihydroxypropyl) amino ] -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (4- { 8-fluoro-4- [ (3-hydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 8-fluoro-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 8-fluoro-4- [ (furan-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2- [ (8-fluoro-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) amino ] ethanesulfonamide
2-chloro-N-cyclopropyl-4- (8-fluoro-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- (8-fluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
[3- ({1- [ 3-chloro-4- (cyclopropylcarbamoyl) phenyl ] -8-fluoroimidazo [1,2-a ] quinoxalin-4-yl } amino) propyl ] carbamic acid tert-butyl ester
N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-hydroxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-difluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (2,2, 2-trifluoroethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
N-cyclopropyl-4- {4- [ (2, 3-dihydroxypropyl) amino ] -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- {4- [4- (butylamino) -7, 8-difluoroimidazo [1,2-a ] quinoxalin-1-yl ] phenyl } -3-methylurea
2-chloro-N-cyclopropyl-4- [7, 8-difluoro-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (pyridin-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (4-hydroxybutyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (3-methoxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- (4- {4- [ (cyclopropylmethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- [4- (7, 8-dimethyl-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-N-cyclopropyl-4- {4- [ (2-methoxyethyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- { 7-cyano-4- [ (2-hydroxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (3-methoxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
1- (4- { 7-cyano-4- [ (2-hydroxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-4- (7-cyano-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
2-chloro-4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
N-cyclopropyl-4- (8-fluoro-4- { [3- (morpholin-4-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- { 8-fluoro-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (cyclopropylmethyl) amino ] -8-fluoroimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- (8-fluoro-4- { [ (1-methyl-1H-pyrazol-4-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
1- [4- (8-fluoro-4- { [3- (2-oxopyrrolidin-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
N- {2- [ (8-fluoro-1- {4- [ (methylcarbamoyl) amino ] phenyl } imidazo [1,2-a ] quinoxalin-4-yl) amino ] ethyl } acetamide
1- (4- { 8-fluoro-4- [ (pyridin-4-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- { 8-fluoro-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (8-fluoro-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (3-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-methylpropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-sulfamoylethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (2-methoxyethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (4-fluorobenzyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-difluoro-4- [ (4-hydroxybutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- (7, 8-difluoro-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) benzamide
N-cyclopropyl-4- {7, 8-dimethyl-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {4- [ (3-hydroxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
N-cyclopropyl-4- {7, 8-dimethyl-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
1- (4- {4- [ (4-fluorobenzyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- {4- [ (4-hydroxybutyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- {7, 8-dimethyl-4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- {7, 8-dimethyl-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
2-chloro-N-cyclopropyl-4- [4- (ethylamino) -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl ] benzamide
2-chloro-N-cyclopropyl-4- {4- [ (3-methoxypropyl) amino ] -7, 8-dimethylimidazo [1,2-a ] quinoxalin-1-yl } benzamide
2-chloro-N-cyclopropyl-4- {7, 8-dimethyl-4- [ (2-sulfamoylethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } benzamide
4- { 7-cyano-4- [ (pyridin-3-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (furan-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-3-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) -N-cyclopropylbenzamide
4- { 7-cyano-4- [ (2, 3-dihydroxypropyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
1- (4- { 7-cyano-4- [ (3-methylbutyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- (4- { 7-cyano-4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- [4- (7-cyano-4- { [3- (1H-imidazol-1-yl) propyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
1- (4- { 7-cyano-4- [ (furan-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } phenyl) -3-methylurea
1- [4- (7-cyano-4- { [ (1-methyl-1H-pyrazol-5-yl) methyl ] amino } imidazo [1,2-a ] quinoxalin-1-yl) phenyl ] -3-methylurea
2-chloro-4- [ 7-cyano-4- (propylamino) imidazo [1,2-a ] quinoxalin-1-yl ] -N-cyclopropylbenzamide
4- [4- (benzylamino) -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl ] -2-chloro-N-cyclopropylbenzamide
2-chloro-4- { 7-cyano-4- [ (thiophen-2-ylmethyl) amino ] imidazo [1,2-a ] quinoxalin-1-yl } -N-cyclopropylbenzamide
4- {4- [ (3-amino-3-oxopropyl) amino ] -7-cyanoimidazo [1,2-a ] quinoxalin-1-yl } -2-chloro-N-cyclopropylbenzamide.
5. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 3, in which process an intermediate compound of general formula (4) is reacted
Wherein R is1、R3、R4、R5、R6And R7A compound of the general formula (I) as defined in any one of claims 1 to 3 and Y represents a halogen atom,
with an intermediate compound of the general formula
R2-Z
Wherein R is2A compound of formula (I) as defined in any one of claims 1 to 3, and Z is a suitable functional group, R2R of the compound-Z2Can be coupled to the carbon atom carrying Y of compound (4) via said functional group, thereby using said R2A group is substituted for said Y group,
thereby providing a compound of formula (I):
wherein R is1、R2、R3、R4、R5、R6And R7A compound of formula (I) as defined in any one of claims 1 to 3.
6. A compound of general formula (I), a salt thereof or a mixture thereof according to any one of claims 1 to 4 for use in the treatment or prevention of a disease.
7. The compound of formula (I), a salt thereof, or a mixture thereof, according to claim 6, wherein the salt is a pharmaceutically acceptable salt.
8. A pharmaceutical composition comprising a compound of general formula (I), a salt thereof or a mixture thereof according to any one of claims 1 to 4, and a pharmaceutically acceptable diluent or carrier.
9. The pharmaceutical composition of claim 8, wherein the salt is a pharmaceutically acceptable salt.
10. A pharmaceutical composition comprising:
-one or more compounds of general formula (I), a salt thereof or a mixture thereof, according to any one of claims 1 to 5 or obtainable according to any one of claims 6 to 9; and
-one or more agents selected from: a taxane; an epothilone; mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2' -deoxyadenosine; thioguanine; an antiandrogen; bortezomib; cisplatin and carboplatin; chlorambucil; methotrexate and rituximab.
11. The pharmaceutical composition of claim 10, wherein the salt is a pharmaceutically acceptable salt.
12. The pharmaceutical composition of claim 10 or 11, wherein the taxane is selected from the group consisting of docetaxel, paclitaxel, and paclitaxel.
13. The pharmaceutical composition of claim 10 or 11 wherein the epothilone is selected from the group consisting of ixabepilone, Patupilone (Patupilone) and sargopilone (Sagopilone).
14. The pharmaceutical composition of claim 10 or 11, wherein the antiandrogen is selected from flutamide, cyproterone acetate and bicalutamide.
15. The pharmaceutical composition of claim 10 or 11, wherein the one or more agents are selected from cisplatin and carboplatin.
16. Use of a compound of general formula (I), a salt thereof or a mixture thereof according to any one of claims 1 to 4 for the preparation of a medicament for the prevention or treatment of a disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1.
17. The use of claim 16, wherein the salt is a pharmaceutically acceptable salt.
18. The use of claim 16 or 17, wherein the disease is a hematological tumor, a solid tumor and/or metastases thereof.
19. The use according to claim 18, wherein the disease is leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors, breast tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors, skin tumors and sarcomas, and/or metastases thereof.
20. The use according to claim 19, wherein the head and neck tumor is a brain tumor or brain metastasis.
21. The use of claim 19, wherein the breast tumor is a non-small cell lung tumor or a small cell lung tumor.
22. The use of claim 19, wherein the urinary system tumor is a kidney tumor, a bladder tumor, or a prostate tumor.
23. A compound of the general formula (4):
wherein R is1、R3、R4、R5、R6And R7A compound of formula (I) as defined in any one of claims 1 to 3, and Y represents a halogen atom.
24. Use of a compound of general formula (4) according to claim 23 for the preparation of a compound of general formula (I) according to any one of claims 1 to 3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09159045 | 2009-04-29 | ||
| EP09159045.5 | 2009-04-29 | ||
| PCT/EP2010/002543 WO2010124826A1 (en) | 2009-04-29 | 2010-04-24 | Substituted imidazoquinoxalines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1168791A1 HK1168791A1 (en) | 2013-01-11 |
| HK1168791B true HK1168791B (en) | 2015-03-27 |
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