Disclosure of Invention
According to a first aspect, the invention comprises compounds of general formula (I):
wherein:
represents a group selected from:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6Alkyl halidesradical-C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -alkyl-S-, -S-S(＝O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R"; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl optionally substituted one or more times by R substituents, heteroaryl optionally substituted one or more times by R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group;
when in useRepresents:
when the radicals are used, n represents an integer of 0, 1, 2, 3, 4 or 5;
or
When in useRepresents a group selected from:
when the radicals are used, n represents an integer of 0, 1, 2, 3 or 4;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
Definition of
Unless otherwise indicated, components optionally substituted as described herein may be substituted one or more times independently of each other at any possible position. When any variable occurs more than one time in any constituent, each definition is independent. For example, each definition of R, R 'and R "is independent whenever R, R' and/or R" occurs more than one time in any compound of formula (I).
In the case where the component contains more than one moiety, e.g. C1-C6-alkoxy-C2-C6-alkyl-, the position of possible substituents may be at any suitable position of any of these moieties. The hyphen at the beginning or end of a component marks the point of attachment to the rest of the molecule. In the case of substituted rings, the substituents can be in any suitable position of the ring, also on the ring nitrogen atom, if appropriate.
The terms mentioned herein preferably have the following meanings:
the term "halogen atom", "halo" or "halogen" is to be understood as meaning a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably a fluorine atom, chlorine atom, bromine atom or iodine atom.
The term "C1-C6Alkyl "is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical 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, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or isomers thereof. In particular, the radicals have 1, 2, 3 or 4 carbon atoms ("C)1-C4Alkyl radicals ") such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly having 1, 2 or 3 carbon atoms (" C)1-C3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C1-C6Haloalkyl "is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon radical (where the term" C "is used)1-C6Alkyl "as defined above) and wherein one or more hydrogen atoms are substituted with the same or different halogen atoms (i.e., one halogen atom is independent of another). In particular, the halogen atom is F. Said C is1-C6Haloalkyl is, for example, -CF3、-CHF2、-CH2F、-CF2CF3Or CH2CF3。
The term "C1-C6Alkoxy "is to be understood as meaning a straight-chain or branched saturated monovalent hydrocarbon radical of the preferred 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. In particular, the said "C1-C6Alkoxy "may contain 1, 2, 3, 4 or 5 carbon atoms (" C)1-C5Alkoxy ").
The term "C1-C6Haloalkoxy "is understood to mean preferably a straight-chain or branched saturated monovalent C1-C6Alkoxy (as defined above) in which one or more hydrogen atoms are replaced by the same or different halogen atoms. In particular, the halogen atom is F. Said C1-C6Haloalkoxy is, for example, -OCF3、-OCHF2、-OCH2F、-OCF2CF3or-OCH2CF3。
The term "C1-C6alkoxy-C1-C6Alkyl "is understood to mean preferably a linear or branched, saturated monovalent alkyl radical (as defined above) in which one or more hydrogen atoms are replaced by identical or different C1-C６Alkoxy (as defined above) is substituted, e.g. methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentoxyalkyl, isopentoxyalkyl, hexyloxyalkyl (wherein the term "C" is used)1-C6Alkyl "as defined above), or isomers thereof.
The term "C1-C6halogenoalkoxy-C1-C6Alkyl "is understood to mean preferably a straight-chain or branched saturated monovalent C1-C6alkoxy-C1-C6Alkyl (as defined above) in which one or more hydrogen atoms are replaced by the same or different halogen atoms. In particular, the halogen atom is F. Said C is1-C6halogenoalkoxy-C1-C6Alkyl is, for example, -CH2CH2OCF3、-CH2CH2OCHF2、-CH2CH2OCH2F、-CH2CH2OCF2CF3or-CH2CH2OCH2CF3。
The term "C2-C6Alkenyl "is to be understood as meaning preferably straight-chain or branched monovalent hydrocarbon radicals which contain one or more double bonds and which have 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (" C)2-C3Alkenyl "), it being understood that when the alkenyl group contains more than one double bond, then the double bonds may be isolated from each other or conjugated to each other. Such as vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, higher alkenylPropyl, (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, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, m-n-1-enyl, m-n-5-enyl, m-4-enyl, m-n-2-, (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, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3-methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2-methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -1-methylpent-3-enyl, (Z) -1-methylpent-3-enyl, (E) -4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, methyl-4-pentenyl, methyl-3-enyl, methyl-4-pentenyl, methyl-4-, (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, methyl-2-penten-2-enyl, methyl-2-methylpent-2-enyl, methyl-2-penten-2-enyl, methyl-1-enyl, methyl-2-penten-2-enyl, methyl, (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, and mixtures thereof, (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 group is vinyl or allyl.
The term "C2-C6Alkynyl "is to be understood as meaning preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and which contains 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (" C)2-C3Alkynyl "). Said C is2-C6Alkynyl 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, 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 a saturated, monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (" C)3-C10CycloalkanesBase "). Said C is3-C10Cycloalkyl is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, such as a perhydropentalene or decalin ring. In particular, the ring contains 3, 4, 5 or 6 carbon atoms ("C)3-C6Cycloalkyl ").
The term "C3-C6Cycloalkoxy "is to be understood as meaning a saturated monovalent hydrocarbon ring, preferably of the formula-O-cycloalkyl, which contains 3, 4, 5 or 6 carbon atoms (where the term" cycloalkyl "is as defined above), for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
The term "C3-C6-cycloalkyl-C1-C6Alkyl is understood to mean a saturated monovalent alkyl radical, preferably as defined above, in which one hydrogen atom is replaced by C as defined above3-C6-cycloalkyl substitutions, such as cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl (wherein the term "alkyl" is as defined above), or isomers thereof.
The term "C3-C6cycloalkyl-C1-C6Alkoxy "is to be understood as meaning preferably saturated monovalent alkoxy radicals (as defined above) in which one hydrogen atom is replaced by C3-C6Cycloalkyl (as defined above) is substituted, for example cyclopropylalkoxy, cyclobutylalkoxy, cyclopentylalkoxy, cyclohexylalkoxy (wherein the term "alkoxy" is as defined above), or isomers thereof.
The term "C4-C10Cycloalkenyl is understood as meaning preferably monovalent monocyclic or bicyclic hydrocarbon rings which contain 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one, two, three or four conjugated or unconjugated double bonds, where the size of the cycloalkenyl ring allows. Said C is4-C10Cycloalkenyl is, for example, a monocyclic hydrocarbon ring, such as cyclobutenyl, cyclopentenyl or cyclohexenyl, or a bicyclic hydrocarbon, such as:
the term "4 to 10 membered heterocycloalkyl" may be understood as a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more selected from C (═ O), O, S, S (═ O), S (═ O)2And NRaWherein Ra represents a hydrogen atom or C1-C6Alkyl or C1-C6A haloalkyl group; the heterocycloalkyl group may be attached to the remainder of the molecule through any carbon or nitrogen atom, if present.
In particular, the 4-to 10-membered heterocycloalkyl group may comprise 3, 4 or 5 carbon atoms, and one or more of the above-described heteroatom-containing groups ("4-to 6-membered heterocycloalkyl"), more particularly the heterocycloalkyl group may comprise 4 or 5 carbon atoms, and one or more of the above-described heteroatom-containing groups ("5-to 6-membered heterocycloalkyl").
In particular, without limitation thereto, the heterocycloalkyl group may be, for example, a 4-membered ring (e.g., azetidinyl, oxetanyl) or a 5-membered ring (e.g., tetrahydrofuryl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl) or a 6-membered ring (e.g., tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl) or a 7-membered ring (e.g., diazepanyl ring). Optionally, the heterocycloalkyl group can be benzofused.
The heterocyclyl group may be a bicyclic heterocyclyl group, without limitation thereto, such as a 5, 5-membered ring (e.g., hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring) or a 5, 6-membered bicyclic ring (e.g., hexahydropyrrolo [1, 2-a ] pyrazin-2 (1H) -yl ring).
As mentioned above, the nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, for example, without limitation, a 2, 5-dihydro-1H-pyrrolyl, 4H- [1, 3, 4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1, 4] thiazinyl ring, or it may for example be a benzo-fused, for example, without limitation, dihydroisoquinolinyl ring.
The term "4 to 10 membered heterocycloalkenyl" may be understood as an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 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)2And NRaWherein R isaRepresents a hydrogen atom or C1-C6Alkyl-or C1-C6Haloalkyl-; the heterocycloalkenyl group may be attached to the remainder of the molecule through any carbon or nitrogen atom, if present. Examples of said heterocycloalkenyl may comprise one or more double bonds, such as 4H-pyranyl, 2H-pyranyl, 3H-diazacyclopropenyl, 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 [ ]]Thiazinyl, or it may be benzo-fused.
The term "aryl" is to be understood as meaning preferably monovalent aromatic or partially aromatic monocyclic or bicyclic or tricyclic hydrocarbon rings which contain 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C)6-C14Aryl group "), in particular a ring having 6 carbon atoms (" C6-aryl "), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C)9-aryl "), such as indanyl or indenyl, or a ring having 10 carbon atoms (" C10Aryl radicals), such as tetralinyl, dihydronaphthyl, or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or the ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "aryl-C1-C6Alkyl "is understood to mean a monovalent, preferably saturated, alkyl radical (as defined above) in which one hydrogen atom is replaced by an aryl radical (as defined above).
The term "heteroaryl" is understood as preferably meaning a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 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 (the heteroatom being, for example, oxygen, nitrogen or sulfur), and which, in addition, may be benzo-fused in each case. Specifically, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl (thia-4H-pyrazoyl), and the like, and benzo derivatives thereof, 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 oxepinyl (oxypyridinyl) and the like.
Typically, unless otherwise specified, heteroaryl or heteroarylene includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for certain illustrative, non-limiting examples, the term pyridyl or pyridinylidene includes pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl, and pyridin-4-ylidene; or the term thienyl or thienylene includes thien-2-yl, thien-3-yl, and thien-3-yl.
As used throughout this document, for example at "C1-C6Alkyl group "," C1-C6Haloalkyl "," C1-C6Alkoxy "or" C1-C6Haloalkoxy "The term "C" as used in the context of the definition of1-C6"is to be understood as meaning alkyl having from 1 to 6 carbon atoms in a defined number, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to1-C6"should be interpreted as including any subrange therein, e.g. C1-C6、C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5(ii) a In particular C1-C2、C1-C3、C1-C4、C1-C5、C1-C6(ii) a More particularly C1-C4(ii) a In "C1-C6Haloalkyl "or" C1-C6In the case of haloalkoxy ", even more particularly C1-C2。
Similarly, as used herein, throughout this document, for example at "C2-C6Alkenyl "and" C2-C6The term "C" as used in the context of the definition of alkynyl2-C6"is to be understood as meaning alkenyl or alkynyl groups having 2 to 6 carbon atoms in a defined number, i.e. 2, 3, 4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to2-C6"should be interpreted as including any subrange therein, e.g. C2-C6、C3-C5、C3-C4、C2-C3、C2-C4、C2-C5(ii) a In particular C2-C3。
Further, as used herein, throughout this document, for example at "C3-C6The term "C" as used in the context of the definition of-cycloalkyl3-C6"is understood to mean cycloalkyl having 3 to 6 defined number of carbon atoms, i.e. 3, 4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to3-C6"should be interpreted as including any subrange therein, e.g. C3-C6、C4-C5、C3-C5、C3-C4、C4-C6，C5-C6(ii) a In particular C3-C6。
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a designation group option, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" means optionally substituted with a specified group, radical or moiety.
A substituent of a ring system refers to a substituent attached to an aromatic or non-aromatic ring system, e.g. replacing an available hydrogen on the ring system.
The term "one or more", as used herein, for example in the definition of a substituent of a compound of the general formula in accordance with the invention, is understood to mean "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".
The invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variations of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I and131I. book (I)Some isotopic variations of the compounds of the invention, e.g. wherein one or more are introduced, e.g.3H or14Those of the radioactive isotopes of C are useful for drug and/or substrate tissue distribution studies. Tritiated and carbon-14 (i.e., tritiated) are particularly preferred due to ease of preparation and detectability14C) An isotope. Furthermore, substitution with isotopes such as deuterium may afford some therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, for example by the exemplary procedures or preparative procedures described in the examples below, using appropriate isotopic variations of appropriate reagents.
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.
"stable compound" or "stable structure" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.
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 compounds of the invention may contain a sulfur atom, which may be asymmetric, such as an asymmetric sulfoxide or sulfoximine group of the structure:
wherein denotes an atom which may be bonded to the rest of the molecule.
The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention.
Preferred compounds are those that produce a more desirable biological activity. Isolated, purified 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 separated 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 manufactured by Daicel, e.g., 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 Rules Section 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 stereoisomers (e.g. R-or S-isomers, or E-or Z-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 prior art method, such as 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 in the form of a 1H tautomer or a 2H tautomer, or even in the form of 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 in the form of a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even in the form of a mixture of any amount of the 1H, 2H, and 4H tautomers, i.e.:
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, for example, as structural element of the crystal lattice of the compound, a polar solvent, 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-or hemi-) solvates or hydrates, mono-solvates or hydrates, sesquisolvates or hydrates, di-solvates or hydrates, tri-solvates or hydrates, tetra-solvates or hydrates, pentasolvates or hydrates, etc., respectively. The present invention includes all such hydrates or solvates.
In addition, the compounds of the invention may exist in free form, e.g. as a free base, or as a free acid or zwitterion, or may exist in the form of a salt. The salt may be any salt, which may be an 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 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, pyrosulfuric acid (disufuric 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, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric 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, 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 bromide, 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.
In this context, in particular in the experimental section for the synthesis of intermediates and examples of the invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form obtained by the corresponding preparation and/or purification method is in most cases unknown.
Suffixes of chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF", unless otherwise specified3COOH "," x Na + "should be understood not as a stoichiometric specification, but only in salt form.
This similarly applies to the following cases: wherein the synthetic intermediates or the compounds of the examples or salts thereof are obtained as solvates, if defined, with unknown stoichiometric composition, by the described preparation and/or purification methods, as hydrates.
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 ester (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) and [ alpha ] -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 (acetoxymethyl) and 2, 2-dimethylpropionyloxymethyl ether (2, 2-dimethylpropionyloxymethyl). 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 embodiment of the first aspect, the present invention comprises 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:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
R3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl optionally substituted one or more times by R substituents, heteroaryl optionally substituted one or more times by R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", a group S (═ O) (═ NR') R";
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝0)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-a haloalkyl group;
n represents an integer of 0, 1, 2, 3, 4 or 5.
According to a third embodiment of the first aspect, the invention comprises the compounds of the preceding general formula (I), wherein:
Represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-a haloalkyl group;
n represents an integer of 0, 1, 2, 3, 4 or 5;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a fourth embodiment of the first aspect, the invention comprises the compounds of the preceding general formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ o)O)R’、-OC(＝O)NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NHR', -OH, C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-a haloalkoxy group;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times independently of each other by R substituents-, aryl optionally substituted one times independently of each other by R substituentsOr multiple heteroaryl-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R'; and,-S(＝O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-a haloalkyl group;
n represents an integer of 0 or 1;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a fifth embodiment of the first aspect, the present invention includes the compounds of the preceding general formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
R1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one OR more times independently of each other by R substituents-, -C (═ O) NH2, -C (═ O) N (h) R ', -C (═ O) N (R ') R ", -C (═ O) OH, -C (═ O) OR ', -NH2、-NHR'、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR'、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NHR', -OH, C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-a haloalkoxy group;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-a haloalkyl group;
n represents an integer of 0 or 1;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a sixth embodiment of the first aspect, the invention comprises the compounds of the preceding general formula (I), wherein:
Represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-or branched C3-C6-an alkyl-group, optionally substituted one or more times independently from each other with a substituent selected from:
phenyl, -N (R') R ", -OH or C1-C6-an alkoxy-group;
r2 represents a hydrogen atom;
r4 represents a hydrogen atom;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
r' and R "independently of each other represent a substituent selected from:
C1-C6-an alkyl-group;
n represents 0;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a seventh embodiment of the first aspect, the invention comprises the compounds of general formula (I) above, selected from:
3- (1-benzofuran-2-yl) -N- [3- (dimethylamino) propyl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N- [ (2R) -1-hydroxypropan-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N- (3-methoxypropyl) imidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N- [ (2R) -1-hydroxy-3-methylbut-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N-benzylimidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N- (2-methoxyethyl) imidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N-benzyl-N-methylimidazo [1, 2-b ] pyridazine-6-carboxamide;
3- (1-benzofuran-2-yl) -N- [2- (dimethylamino) ethyl ] imidazo [1, 2-b ] pyridazine-6-carboxamide; and
3- (1-benzofuran-2-yl) -N- [ (2S) -1-hydroxy-3-methylbut-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
R1-CH2-CH2-*a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R' group.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ C)O)NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-groups.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-or branched C3-C6-an alkyl-group, optionally substituted one or more times independently from each other with a substituent selected from:
phenyl, -N (R') R ", -OH or C1-C6-alkoxy-.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r2 represents a hydrogen atom.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R".
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
R3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NHR', -OH, C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl optionally substituted one or more times by R substituents, heteroaryl optionally substituted one or more times by R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R".
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents independently of each other-.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a hydrogen atom.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom、-CN、C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2C (═ O) N (h) R ', -C (═ O) N (R ') R ", -C (═ O) OH, -C (═ O) OR ', NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
R5 represents a hydrogen atom or C1-C6-alkyl-substituents.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynesradical-C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl, -S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2C (═ O) N (h) R ', C (═ O) N (R ') R ", -C (═ O) OH, -C (═ O) OR ', -NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
The 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R".
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0, 1, 2, 3, 4 or 5.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 1.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 2.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 3.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 4.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 5.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0 or 1.
According to an eighth embodiment of the first aspect, the invention comprises the compounds of the general formula (I):
wherein:
represents a group selected from:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R"; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group, which is optionallyContaining a further heteroatom selected from O, N and S;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl optionally substituted one or more times by R substituents, heteroaryl optionally substituted one or more times by R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl radical-、C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
R represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group;
n represents an integer of 0, 1, 2, 3 or 4;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. According to a ninth embodiment of the first aspect, the present invention comprises the compounds of the preceding general formula (I), wherein:
represents a group selected from:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R"; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
R5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
R' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group;
n represents an integer of 0, 1, 2, 3 or 4;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a tenth embodiment of the first aspect, the invention comprises the compounds of the preceding general formula (I), wherein:
represents a group selected from:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents a group selected from:
R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl, -S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NH2、-NHR’、-N(R’)R”、-OH，C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-a haloalkoxy-group; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S;
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group;
n represents an integer of 0 or 1;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to an eleventh embodiment of the first aspect, the present invention includes the compounds of the preceding general formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally selected fromThe following substituents are substituted one or more times independently of each other:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR'、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR'、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NH2、-NHR'、-N(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-a haloalkoxy-group; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S;
R4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents;
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
said 6-or 7-membered heterocycloalkyl optionally containing another heteroatom selected from O, N and S;
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R";
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group;
n represents an integer of 0 or 1;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a twelfth embodiment of the first aspect, the present invention includes the compounds of the preceding general formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule; and
r1 represents straight chain C1-C6Alkyl-or branched C3-C6-an alkyl-group, optionally substituted one or more times independently from each other with a substituent selected from:
phenyl-, -N (R') R ", -OH or C1-C6-an alkoxy-group;
r2 represents a hydrogen atom;
r3 represents a substituent selected from:
6-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-substituted one or more times independently of each other, said heterocycloalkyl being linked to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-membered cyclic amine group further contains a heteroatom selected from O;
R4 represents a substituent selected from:
a hydrogen atom, and a nitrogen atom,
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5, together with the nitrogen atom to which they are attached, form a 6-membered heterocycloalkyl group, optionally substituted with C1-C6-an alkyl-group;
said 6-membered heterocycloalkyl optionally containing another heteroatom selected from N;
r' and R "independently of each other represent a substituent selected from:
C1-C6-an alkyl-group;
n represents an integer of 1;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
According to a thirteenth embodiment of the first aspect, the invention comprises the compounds of the general formula (I) above, selected from:
n-benzyl-3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
n- (3-methoxypropyl) -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
n- [2- (dimethylamino) ethyl ] -N-methyl-3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
(4-methylpiperazin-1-yl) {3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazin-6-yl } methanone;
N- (2-methoxyethyl) -N-methyl-3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
n- (2-methoxyethyl) -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
n- [ (2R) -1-hydroxypropan-2-yl ] -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide;
n- [ (2S) -1-hydroxypropan-2-yl ] -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide; and
n- [3- (dimethylamino) propyl ] -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents a group selected from:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein: Represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents a group selected from:
R1-C≡C-*、R1-CH＝CH-*、R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents a group selected from:
R1-CH2-CH2-*orA group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
represents:
R1-CH2-CH2-*a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
Represents:
a group;
wherein denotes the point of attachment of the group to the rest of the molecule.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times by R substituents-, -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R' group.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-, branched C3-C6-alkyl-or C3-C6-cycloalkyl, optionally substituted one or more times independently from each other by a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one OR more times independently of each other by R substituents-, -C (═ O) NH2, -C (═ O) N (h) R ', -C (═ O) N (R ') R ", -C (═ O) OH, -C (═ O) OR '; optionally substituted one OR more times with R substituents, -NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-groups.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 represents straight chain C1-C6Alkyl-or branched C3-C6-an alkyl-group, optionally substituted one or more times independently from each other with a substituent selected from:
phenyl-, -N (R') R ", -OH or C1-C6-alkoxy-groups.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r2 represents a hydrogen atom.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -SH, C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R"; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C６-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r3 represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -NH2、-NHR’、-N(R’)R”、-OH，C1-C6-alkoxy-, C3-C6-cycloalkyl-C1-C6-alkoxy-, C1-C6-a haloalkoxy-group; or 4-to 7-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-groups are substituted one or more times independently of each other, said heterocycloalkyl being connected to the rest of the molecule via the nitrogen ring atom of the heterocycloalkyl; and said 6-to 10-membered cyclic amine group optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r3 represents a substituent selected from:
6-membered nitrogen atom-containing heterocycloalkyl group optionally substituted by C1-C6-alkyl-substituted independently of each other one or more timesThe heterocycloalkyl group being attached to the remainder of the molecule via the nitrogen ring atom of the heterocycloalkyl group; and said 6-membered cyclic amine group further contains a heteroatom selected from O.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a substituent selected from:
Hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl optionally substituted one or more times by R substituents, heteroaryl optionally substituted one or more times by R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', one S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R".
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a substituent selected from:
hydrogen atom, halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents independently of each other-.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r4 represents a substituent selected from:
a hydrogen atom.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-alkyl-substituents.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
Halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2A N (R ') R' group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocycloalkyl group, which is optionally substituted one or more times independently of each other by a substituent selected from the group consisting of:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C3-C10-cycloalkyl-, aryl optionally substituted one or more times with R substituents, heteroaryl optionally substituted one or more times with R substituents, C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-an alkyl-S-group;
the 6-or 7-membered heterocycloalkyl optionally contains another heteroatom selected from O, N and S.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r5 represents a hydrogen atom or C1-C6-a substituent of an alkyl group;
or:
r1 and R5, together with the nitrogen atom to which they are attached, form a 6-membered heterocycloalkyl group, optionally substituted with C1-C6-an alkyl-group;
the 6-membered heterocycloalkyl optionally contains one heteroatom selected from N.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r1 and R5, together with the nitrogen atom to which they are attached, form a 6-membered heterocycloalkyl group, optionally substituted with C1-C6-an alkyl-group;
the 6-membered heterocycloalkyl optionally contains another heteroatom selected from N.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r represents a substituent selected from:
halogen atom, -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C10-cycloalkyl-, 4-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH2、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH2、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH2、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH2、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO2、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)2R’、-N(R’)S(＝O)2R’、-N＝S(＝O)(R’)R”、-OH、C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH2、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C1-C6-alkyl-S-, -S (═ O) R', -S (═ O)2R’、-S(＝O)2NH2、-S(＝O)2NHR’、-S(＝O)2N (R ') R ", -S (═ O) (═ NR') R".
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r' and R "independently of each other represent a substituent selected from:
C1-C6-alkyl-, C3-C10-cycloalkyl-, C1-C6-haloalkyl-, C1-C3-alkoxy-C2-C6-an alkyl-group.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
r' and R "independently of each other represent a substituent selected from:
C1-C6-an alkyl-group.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0, 1, 2, 3 or 4.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 1.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 2.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 3.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 4.
In another embodiment of the above aspects, the present invention relates to a compound of formula (I), wherein:
n represents an integer of 0 or 1.
In another embodiment of the above aspect, the present invention relates to a compound of formula (I) according to any of the above embodiments in the form of a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt, or a mixture thereof.
It is to be understood that the present invention relates to any subcombination within any embodiment or aspect of the invention of a compound of formula (I) above.
More specifically, the present invention includes compounds of the general formula (I) disclosed in the examples section herein below.
According to another aspect, the invention includes a method of making a compound of the invention, the method comprising the steps described in the experimental section herein.
According to another aspect, the present invention encompasses intermediate compounds useful in the preparation of the compounds of the present invention of general formula (I), in particular for the processes described herein. In particular, the invention encompasses compounds of general formula (F):
wherein A, R2, R3, R4 and n are as defined for the compounds of formula (I) above, and Y represents C1-C6-an alkyl group.
According to another aspect, the invention includes intermediate compounds which are useful in the preparation of the compounds of general formula (I) of the invention, in particular in the processes described herein. Specifically, the present invention includes compounds of general formula (G):
wherein A, R2, R3, R4 and n are as defined for the compounds of general formula (I) above.
According to another aspect, the invention comprises the use of an intermediate compound of general formula (E) for the preparation of a compound of general formula (I) as defined above:
wherein A, R2, R3, R4 and n are as defined for the compounds of general formula (I) above, and wherein X represents a leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group.
According to another aspect, the invention comprises the use of an intermediate compound of formula (F) for the preparation of a compound of formula (I) as defined above:
wherein A, R2, R3, R4 and n are as defined for the compounds of formula (I) above, and Y represents C1-C6-an alkyl group.
According to another aspect, the invention comprises the use of an intermediate compound of formula (G) for the preparation of a compound of formula (I) as defined above:
wherein A, R2, R3, R4 and n are as defined for the compounds of general formula (I) above.
Intermediates useful in the synthesis of compounds of formula (I) as described herein and their use in the synthesis of compounds of formula (I) are further aspects of the invention. Preferred intermediates are the examples of intermediates disclosed below.
Experimental part
The following table lists the abbreviations used in this section and in the examples section.
Synthesis of compounds (overview):
the compounds of the invention can be prepared as described in the section below. Scheme 1 and the following procedures illustrate the general synthetic route for the compounds of general formula (I) of the present invention and are not limiting. It is clear to the person skilled in the art that the switching order illustrated in scheme 1 can be modified in various ways. Thus, the order of conversion illustrated in scheme 1 is not limiting. Further, interconversion of any substituents (R1, R2, R3, R4, a and Y) may be achieved before and/or after the exemplified transformations. These modifications may be, for example, the introduction of protecting groups, the cleavage of protecting groups, the exchange of functional groups, reduction or oxidation, halogenation, metallation, substitution or other reactions known to those skilled in the art. These transformations include transformations that introduce functional groups that allow further interconversion of substituents. Suitable protecting Groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., p.g.m.wuts and t.w.greene in "Protective Groups in Organic Synthesis", 4th edition, Wiley 2006). Specific examples are described in subsequent paragraphs. Furthermore, it is possible that two or more consecutive steps may be carried out without carrying out work-up between said steps, for example a "one-pot" reaction as known to the person skilled in the art.
Scheme 1:
wherein A, R1, R2, R3, R4 and n are as defined above, and X' represent a leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group, a nonafluorobutylsulfonate group, Y represents C1-C6Alkyl radicals such as methyl or ethyl.
In a first step, a compound of formula A (i.e., dichloropyridazine with a suitable X substituent) may be reacted with ammonia at elevated temperature and pressure to provide a compound of formula B. [ similar to WO200733080, the entire contents of which are incorporated herein by reference ]
In a second step, the compound of the general formula B is reacted with, for example, chloroacetaldehyde diacetal (chloroacetaldehyde diacetal) or bromoacetaldehyde diacetal (bromoaldehyde diacetal) to give a bicyclic ring system C [ analogously to DE102006029447, the entire content of which is incorporated herein by reference ].
Activation of the 3-position of the bicyclic system to give compounds of general formula D can be accomplished, for example, by: the compound of formula C is brominated or iodinated using N-bromo-succinimide or N-iodo-succinimide, respectively.
In the fourth step, the residue A- [ R3]nThe introduction of (a) can be effected using a suitably catalysed cross-coupling reaction, using, for example, boric acid or stannane, which gives compounds of the general formula E.
In the fifth step, introduction of the ester moiety YO (O ═ C) can be achieved using carbon monoxide and an alcohol (e.g., methanol) with a suitable catalyst such as 1, 1-bis- (diphenylphosphino) ferrocene dichloropalladium (II), which gives the compound of general formula F.
In a sixth step, the compound of formula F is saponified, for example, by reaction with a suitable base (e.g., lithium hydroxide or sodium hydroxide) in water, which gives the compound of formula G.
The preparation of embodiments of the invention from compounds of the general formulae E and G can be effected in various ways, for example by the methods described below.
For example, the synthesis examples starting from compounds of general formula G can be achieved as outlined in scheme 2.
Scheme 2:
compounds of formula G are useful as central intermediates for introducing various amide side chains, which give imidazopyridazinyl-amides of formula (Ia). The introduction of the side chain can be effected, for example, using an amine of the formula J by applying standard amide coupling methods, for example using suitable coupling reagents such as HATU or 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriophosphate-2, 4, 6-trioxides and a suitable base such as Hunig's base. Depending on the nature of the side chains, it may be necessary to run these reactions at elevated temperatures. It may also be desirable to introduce side chains modified with suitable protecting groups on functional groups that may interfere with the desired reaction.
Alternatively, an acid chloride or anhydride (which may be obtained from a compound of formula G using standard methods) may be used in the presence of a base to produce a compound of formula (Ia).
For example, the synthesis examples starting from compounds of general formula E can be achieved as outlined in scheme 3.
Scheme 3:
compounds of formula E as central intermediates for the introduction of compounds containing C2-alkynylene moiety (C ≡ C), C2-alkenylene moiety (HC ═ CH) or C2Alkylene moieties (H)2C-CH2) To give the corresponding imidazopyridazinyl compounds of the general formulae (Ib), (Ic) and (Id).
The introduction of the side chain can be achieved, for example, by the following method: coupling of the compound of the general formula E with acetylene of the general formula K using a coupling method, for example using a suitable coupling reagent such as bis (triphenylphosphine) palladium (II) chloride and a suitable base such as triethylamine, in the presence of copper (I) iodide using elevated temperatures gives the compound of the general formula (Ib). It may be desirable to introduce side chains modified with suitable protecting groups on functional groups that may interfere with the desired reaction.
Alternatively, the introduction of the side chain can be achieved, for example, by: coupling of a compound of formula E with a boronic acid of formula L using a coupling procedure, for example using a suitable coupling reagent such as bis (triphenylphosphine) palladium (II) chloride and triphenylphosphine and a suitable base such as potassium carbonate, using elevated temperatures gives a compound of formula (Ic). It may be desirable to introduce side chains modified with suitable protecting groups on functional groups that may interfere with the desired reaction.
The compounds of formula (Ib) can be converted to compounds of formula (Ic) by partial hydrogenation or to compounds of formula (Id) by complete hydrogenation using hydrogenation catalysts and reaction conditions well known to those skilled in the art. The compounds of formula (Ic) can be converted to compounds of formula (Id) by hydrogenation using hydrogenation catalysts and reaction conditions well known to those skilled in the art.
According to one embodiment, the present invention also relates to a process for the preparation of the aforementioned compound of general formula (Ia), said process comprising the steps of: reacting the intermediate compound of formula (G) with a compound of formula (J) to thereby obtain a compound of formula (Ia),
the general formula (G) is:
wherein A, R2, R3, R4 and n are as defined for the compounds of the general formula (I),
the general formula (J) is:
wherein R1 and R5 are as defined for the compounds of the general formula (I),
the general formula (Ia) is:
wherein A, R1, R2, R3, R4, R5 and n are as defined for the compounds of general formula (I) hereinbefore.
According to one embodiment, the present invention also relates to a process for the preparation of the aforementioned compound of general formula (Ib), said process comprising the steps of: reacting the intermediate compound of formula (E) with a compound of formula (K) thereby obtaining a compound of formula (Ib),
The general formula (E) is:
wherein A, R2, R3, R4 and n are as defined for the compounds of general formula (I) above, X represents a leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group, a nonafluorobutylsulfonate group,
the general formula (K) is:
wherein R1 is as defined for the compounds of formula (I) above,
the general formula (Ib) is:
wherein A, R1, R2, R3, R4 and n are as defined for the compounds of the general formula (I) above.
According to one embodiment, the present invention also relates to a process for the preparation of the aforementioned compound of general formula (Ic), said process comprising the steps of: reacting the intermediate compound of formula (E) with a compound of formula (L) to thereby obtain a compound of formula (Ic),
the general formula (E) is:
wherein A, R2, R3, R4 and n are as defined for the compounds of general formula (I) above, X represents a leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group, a nonafluorobutylsulfonate group,
the general formula (L) is:
wherein R1 is as defined for the compounds of formula (I) above,
the general formula (Ic) is:
wherein A, R1, R2, R3, R4 and n are as defined for the compounds of the general formula (I) above.
According to one embodiment, the invention also relates to a process for the preparation of the aforementioned compound of general formula (Id), comprising the following steps: reacting the intermediate compound of formula (Ib) with hydrogen in the presence of a hydrogenation catalyst, thereby obtaining a compound of formula (Id),
the general formula (Ib) is:
wherein A, R2, R3, R4 and n are as defined for the compounds of the general formula (I),
the general formula (Id) is:
wherein A, R1, R2, R3, R4 and n are as defined for the compounds of the general formula (I) above.
General part
The ACD/Name Batch version 12.01 is used to generate the chemical Name.
All reagents not described for synthesis in the experimental part are commercially available or synthesized as described in the literature.
HPLC method:
the method comprises the following steps:
the instrument comprises the following steps: waters Acquity UPLCMS ZQ 4000; column: acquity UPLC BEH C181.7 μm, 50 × 2.1mm; eluent A: water +0.05 vol% formic acid, eluent B: acetonitrile +0.05 vol% formic acid; gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD
The method 2 comprises the following steps:
the instrument comprises the following steps: waters Acquity uplmcs SQD 3001; column: acquity UPLC BEH C181.7 μm, 50 × 2.1mm; eluent A: water +0.1 vol% formic acid (95%), eluent B: acetonitrile, gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD
The method 3 comprises the following steps:
the instrument comprises the following steps: waters Acquity UPLCMS SQD; column: acquity UPLC BEH C181.7 μm, 50 × 2.1mm; eluent A: water +0.05 vol% formic acid (95%), eluent B: acetonitrile +0.05 vol% formic acid (95%), gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD
Method 4
The instrument comprises the following steps: waters Acquity UPLC-MS SQD; column: acquity UPLC BEH C181.750x2.1mm; eluent A: water +0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD.
Method 4'
And (4) an instrument MS: waters ZQ; HPLC (high Performance liquid chromatography) of an instrument: waters UPLC Acquity; column: acquity BEH C18(Waters), 50mmx2.1mm, 1.7 μm; eluent A: water +0.1 vol% formic acid, eluent B: acetonitrile (lichrosolvmmerck); gradient: 0.0min 99% vol A-1.6min 1 vol% A-1.8min 1 vol% A-1.81min 99v0 l% A-2.0min 99 vol% A; temperature: 60 ℃; flow rate: 0.8 mL/min; UV-detection of PDA 210 ion 400nm
Method 5
The instrument comprises the following steps: waters Acquity uplmcs SQD 3001; column: acquity UPLC BEH C181.7 μm, 50 × 2.1mm; eluent A: water +0.2 vol.% ammonia (32%), eluent B: acetonitrile, gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD.
Method 6
The instrument comprises the following steps: waters Acquity UPLC-MS SQD; column: acquity UPLC BEH C181.750x2.1mm; eluent A: water +0.2 vol.% ammonia (32%), eluent B: acetonitrile, gradient: 0-1.6min 1-99% B, 1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; and (3) injection: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD. Intermediates
Intermediate 1
3-bromo-6-chloro-imidazo [1, 2-b ] pyridazine
3-bromo-6-chloro-imidazo [1, 2-b ] pyridazine is synthesized as described, for example, in WO 2007/147646 or DE 102006029447, for example, as follows:
step 1: preparation of 6-chloroimidazo [1, 2-b ] pyridazine:
5.0g (38.6mmol) of 3-amino-6-chloropyridazine were heated together with 4.7mL (40mmol) of chloroacetaldehyde (55% strength in water) in 15mL of n-butanol at 120 ℃ for 5 days. After the reaction was completed, the reaction mixture was added to a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed in vacuo. In the final purification by chromatography on silica gel, 4.17g (70%) of the desired product are isolated in the form of an amorphous white solid.
1H-NMR (chloroform-d): [ ppm of]＝7.06(d，1H)；7.79(d，1H)；7.92，(d，1H)；7.96(d，1H)。
Step 2: preparation of 3-bromo-6-chloroimidazo [1, 2-b ] pyridazine
478mg (3.11mmol) of 6-chloroimidazo [1, 2-b ] pyridazine is introduced into 10mL of chloroform under argon and 664mg (3.73mmol) of N-bromo-succinimide are added while cooling in ice. After the end of the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate, and the phases were separated after addition of saturated sodium bicarbonate solution. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield as an amorphous white solid, which was used in the subsequent reaction without further chromatographic purification.
1H-NMR (chloroform-d): [ ppm of]＝7.12(d，1H)；7.79(s，1H)；7.90，(d，1H)。
Intermediate 2
4- (morpholin-4-yl) furo [3, 2-c ] pyridines
A mixture of 4-chlorofuro [3, 2-c ] pyridine (12.0g) and morpholine (34g) was heated to 180 ℃ in a microwave oven and held for 2 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent removed in vacuo. Amino phase silica gel chromatography gave 13.4g of the title compound.
LCMS (method 5): rt＝0.88min；MS(ESIpos)m/z＝205[M+H]+。
Intermediate 3
[4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] boronic acid
To a stirred solution of 4- (morpholin-4-yl) furo [3, 2-c ] pyridine (15.8g) in anhydrous THF (190mL) at-78 ℃ was added a solution of n-butyllithium in hexane (46.5 mL; c ═ 2.5M). The solution was stirred at-78 ℃ for 1.5 hours. Triisopropyl borate (23.8g) was added at-78 deg.C, the mixture was stirred at-78 deg.C for 0.5 hour and allowed to warm to room temperature over 16 hours. Water was added, the reaction mixture was stirred for 15 minutes, and the solvent was removed in vacuo. Water was again added and the mixture was lyophilized to give 24.3g of the title compound as a crude product (calculated purity: 78%), which was used without further purification.
Intermediate 4
6-chloro-3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine
To a stirred solution of 3-bromo-6-chloro-imidazo [1, 2-b ] pyridazine (5.52g) in 1-propanol (170mL) was added potassium carbonate solution (36 mL; c ═ 2M), crude [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] boronic acid (72% w/w; 9.0g), triphenylphosphine (623mg) and bis (triphenylphosphine) palladium (II) dichloride (1.70 g). The mixture was heated to reflux and held for 1 hour. The warm mixture was filtered through Celite and the solvent removed in vacuo. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with a mixture of dichloromethane and methanol. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent removed in vacuo. Silica gel chromatography gave 4.28g of the title compound.
LCMS (method 5): rt＝1.11min；MS(ESIpos)m/z＝356[M+H]+。
Intermediate 5
3- [4- (Morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxylic acid methyl ester
To a suspension of 6-chloro-3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine in a mixture of methanol (50mL) and THF (5mL) in a 90mL autoclave vessel were added 1, 1-bis- (diphenylphosphino) ferrocene-palladium (II) dichloride (1.9g) and triethylamine (1.8 mL). The mixture was purged three times with carbon monoxide gas and carbon monoxide gas was added until a pressure of 11.88 bar was reached. The mixture was stirred at room temperature for 0.5 h (pressure reduced to 8.87 bar). The overpressure was released and the mixture was evacuated and backfilled with carbon monoxide gas until a pressure of 12.11 bar was reached. The mixture was heated to 80 ℃ overnight and cooled to room temperature (pressure reduced to 6.67 bar). The overpressure was released and the mixture was evacuated and backfilled with argon. The solution was filtered and the solid collected to give 2.3g of the title compound, which was used in the next reaction without further purification.
1H-NMR (300MHz, chloroform-d), [ ppm [ (] ppm ]]＝3.83(4H)，3.93-4.00(4H)，4.10(3H)，7.04(1H)，7.88(1H)，7.96(1H)，8.11(1H)，8.18(1H)，8.44(1H)。
LC-MS (method 5): rt＝1.06min；MS(ESIpos)m/z＝380[M+H]+。
Intermediate 6
3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxylic acid
To a stirred solution of methyl 3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxylate (2.2g) in tetrahydrofuran (26mL), methanol (7mL) and water (7mL) was added a solution of lithium hydroxide (0.42g) dissolved in water (17 mL). The mixture was stirred at room temperature for 2 hours. Water was added and aqueous hydrochloric acid (c ═ 4N) was added until an acidic pH was reached and a yellow solid precipitated. The solid was collected by filtration, washed with water and ethanol and dried in a vacuum oven at 60 ℃ to give 1.8g of the title compound, which was used for the next reaction without further purification.
1H-NMR(400MHz，DMSO-d6Detected signal), [ ppm ] of]＝3.66(4H)，3.76(4H)，7.14(1H)，7.82(1H)，7.95(1H)，8.03(1H)，8.38(1H)，8.44(1H)。
LC-MS (Square-tube Mass Spectrometry)Method 5): rt＝0.53min；MS(ESIpos)m/z＝366[M+H]+。
Intermediate 7
(2R) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine
To a stirred solution of tert-butyl (chloro) diphenylsilane (1.25mL) in DMF (30mL) was added imidazole (680mg) and (2R) -2-aminopropan-1-ol (300mg) slowly at room temperature. The mixture was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent removed in vacuo. Silica gel chromatography was performed to give 690mg of the title compound.
LC-MS (method 5): rt＝1.56min；MS(ESIpos)m/z＝314[M+H]+。
Intermediate 8
N- [ (2R) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-yl ] -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide
To a stirred suspension of 3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxylic acid (80mg) in ethyl acetate (2.5mL) were added Hunig's base (114. mu.L), (2R) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine (91mg) and 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriophosphate-2, 4, 6-trioxide (234. mu.L; 50% w/w in ethyl acetate). The mixture was heated to 100 ℃ in a microwave oven and held for 15 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent removed in vacuo. Amino phase-silica gel chromatography was performed to give 64mg of the title compound.
1H-NMR(300MHz，DMSO-d6)，[ppm]＝0.88-1.01(9H)，1.28(3H)，3.58-3.79(10H)，4.29(1H)，7.11(1H)，7.26-7.43(6H)，7.53-7.63(4H)，7.75(1H)，7.99(1H)，8.02(1H)，8.38(1H)，8.42(1H)，8.80(1H)。
LC-MS (method 5): rt＝1.68min；MS(ESIpos)m/z＝661[M+H]+。
Intermediate 9
(2S) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine
(2S) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine was prepared in analogy to the procedure used to prepare (2R) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine, starting with (2S) -2-aminopropan-1-ol.
Intermediate 10
N- [ (2S) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-yl ] -3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide
To a stirred suspension of 3- [4- (morpholin-4-yl) furo [3, 2-c ] pyridin-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxylic acid (120mg) in ethyl acetate (3.7mL) were added Hunig' S base (172. mu.L), (2S) -1- { [ tert-butyl (diphenyl) silyl ] oxy } propan-2-amine (330mg) and 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriene-2, 4, 6-trioxide (351. mu.L; 50% w/w in ethyl acetate). The mixture was heated to 100 ℃ in a microwave oven and held for 15 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent removed in vacuo. Silica gel chromatography was performed to give 130mg of the title compound.
1H-NMR(300MHz，DMSO-d6)，[ppm]＝0.94(9H)，1.28(3H)，3.57-3.79(10H)，4.19-4.37(1H)，7.11(1H)，7.29-7.43(6H)，7.55-7.63(4H)，7.74(1H)，7.99(1H)，8.02(1H)，8.38(1H)，8.42(1H)，8.84(1H)。
LC-MS (method 5): rt＝1.68min；MS(ESIpos)m/z＝661[M+H]+。
Intermediate 11
3- (1-benzofuran-2-yl) -6-chloroimidazo [1, 2-b ] pyridazine
13.9g (59.8mmol) of 3-bromo-6-chloro-imidazo [1, 2-b ] pyridazine are suspended in 508mL of 1, 4-dioxane. 10.1g (62.8mmol) of 2-benzofuranylboronic acid, 2.76g (2.29mmol) of tetrakis (triphenylphosphino) palladium- (0) and 19.0g (179mmol) of sodium carbonate are added. The resulting mixture was heated to 100 ℃ and held for 24 hours.
400mL of saturated aqueous ammonium chloride solution was added. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting solid material was digested in 40mL of a mixture of dichloromethane and methanol (8: 2), filtered and concentrated in vacuo to give 5.42g (44%) of the title compound as a solid material.
1H-NMR(300MHz，DMSO-d6)：[ppm]＝7.23-7.40(2H)，7.51(1H)，7.59-7.67(2H)，7.77(1H)，8.33-8.40(2H)。
LCMS (method 1): rt＝1.35min；MS(ESIpos)m/z＝270[M+H]+。
Intermediate 12
3- (1-benzofuran-2-yl) imidazo [1, 2-b ] pyridazine-6-carboxylic acid methyl ester
In a 1.2L autoclave vessel, to a suspension of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1, 2-b ] pyridazine in a mixture of methanol (210mL) and THF (21mL) were added 1, 1-bis- (diphenylphosphino) -ferrocene-palladium (II) dichloride (6.5g) and triethylamine (6.0 mL). The mixture was purged three times with carbon monoxide gas, and carbon monoxide gas was added until a pressure of 11.08 bar was reached. The mixture was stirred at room temperature for 0.5 h (pressure reduced to 10.15 bar). The overpressure was released and the mixture was evacuated and backfilled with carbon monoxide gas until a pressure of 11.66 bar was reached. The mixture was heated to 80 ℃ overnight and cooled to room temperature (pressure reduced to 10.73 bar). The overpressure was released and the mixture was evacuated and backfilled with argon. The solution was filtered through a membrane filter (0.45 μm), the solid was collected, dissolved in dichloromethane and filtered through an amino phase-silica gel column, and the solvent was removed in vacuo to give a yellow solid. The solid was triturated with warm ethanol to give 4.0g of the title compound.
1H-NMR (300MHz, chloroform-d), [ ppm [ (] ppm ]]＝4.13(3H)，7.24-7.31(1H)，7.31-7.38(1H)，7.56(1H)，7.66-7.72(1H)，7.81(1H)，7.84(1H)，8.14(1H)，8.46(1H)。
LC-MS (method 2): rt＝1.20min；MS(ESIpos)m/z＝294[M+H]+。
Intermediate 13
3- (1-benzofuran-2-yl) imidazo [1, 2-b ] pyridazine-6-carboxylic acid
To a stirred solution of methyl 3- (1-benzofuran-2-yl) imidazo [1, 2-b ] pyridazine-6-carboxylate (4.0g) in tetrahydrofuran (63mL), methanol (16mL) and water (16mL) was added a solution of lithium hydroxide (0.98g) dissolved in water (40 mL). The mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo. Water was added and aqueous hydrochloric acid (c ═ 4N) was added until an acidic pH was reached and a yellow solid precipitated. The solid was collected by filtration, washed with water and dried in a vacuum oven at 60 ℃ to give 3.7g of the title compound.
1H-NMR(500MHz，Pyr)，[ppm]＝7.26-7.32(1H)，7.37(1H)，7.61-7.65(1H)，7.68(1H)，8.11(1H)，8.29(1H)，8.33(1H)，8.66(1H)。
LC-MS (method 2): rt＝0.94min；MS(ESIpos)m/z＝280[M+H]+。
Example 18
3- (1-benzofuran-2-yl) -N- [ (2S) -1-hydroxy-3-methylbut-2-yl ] imidazo [1, 2-b ] pyridazine-6-carboxamide
To a stirred suspension of 3- (1-benzofuran-2-yl) imidazo [1, 2-b ] pyridazine-6-carboxylic acid (50mg) in ethyl acetate (2.0mL) were added Hunig' S base (94. mu.L), (2S) -2-amino-3-methylbutan-1-ol (41. mu.L) and 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriphosphate-2, 4, 6-trioxides (0.19 mL; 50% w/w in ethyl acetate). The mixture was heated to 100 ℃ in a microwave oven and held for 15 minutes. Additional (2S) -2-amino-3-methylbutan-1-ol (41. mu.L) and 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriophosphate-2, 4, 6-trioxide (0.19 mL; 50% w/w in ethyl acetate) were added and the mixture was heated to 100 ℃ in a microwave oven and held for an additional 15 minutes. The solvent was removed in vacuo. Preparative reverse phase HPLC was carried out to give 25mg of the title compound.
1H-NMR(300MHz，DMSO-d6)，[ppm]＝0.91-1.03(6H)，2.03(1H)，3.53-3.70(2H)，3.78-3.91(1H)，4.82(1H)，7.33(2H)，7.62-7.71(2H)，7.78(1H)，7.84(1H)，8.41(2H)，8.47(1H)。
LC-MS (method 6): rt＝1.15min；MS(ESIpos)m/z＝365[M+H]+。
Furthermore, the compounds of general formula (I) of the present invention may be converted into any of the salts described herein by any method known to those skilled in the art. Likewise, any salt of a 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 the 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 pharmaceutically acceptable carriers known in the art 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 (opthalmologicaly), ocular (opthalcogly), sublingual, rectal, vaginal, and the like.
For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches (troche), lozenges (lozenge), melt gels (melt), 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 in combination with conventional tablet bases (e.g., lactose, sucrose and corn starch) and the following: binders such as acacia, corn starch or gelatin, disintegrating agents to aid disintegration and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia, lubricants to improve the flowability of the tablet particles and to prevent adhesion of the tablet material to the surfaces of the tablet die and punch, such as talc, stearic acid or magnesium stearate, calcium or zinc stearate, dyes, colorants and flavouring agents to improve the organoleptic properties of the tablet and make them more acceptable to the patient, such as peppermint, oil of wintergreen or cherry flavouring. 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 lecithin 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, in an injectable form of the compound, 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, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutically acceptable adjuvants.
Exemplary oils useful in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, 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) or ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quaternary ammonium salts, and mixtures thereof.
The parenteral compositions of the invention will typically comprise 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 polyoxyethylene 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 bland fixed oil may be employed 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 issued on 6/11 of 1991, 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. One such implantable delivery system for delivering agents to specific anatomical locations of the body is described in U.S. patent No. 5,011,472 issued on 30/4 1991.
The compositions of the present invention may also contain, as necessary or desired, other conventional pharmaceutically acceptable formulation ingredients, which are commonly 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 particulate Formulations" 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-1," PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and therir Use in Injectable Products" PDAjournal of 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, aqueous 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 propellant (powder)Examples include, but are not limited to, carbon dioxide, CCl2F2、F2ClC-CClF2And CClF3)；
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 to FD & C Red No.3, FD & C Red No.20, FD & C Yellow No.6, FD & C Blue No.2, D & C Green No.5, D & C Orange No.5, D & C 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, glyceryl 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 (arachis oil), mineral oil, olive oil, peanut oil (parautoil), sesame oil, and vegetable oils);
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, mono-or polyvalent 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, glucose and sodium chloride);
viscosity increasing agents (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 intravenous 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 to 1-2mg/mL with sterile 5% glucose for administration and administered as an intravenous infusion over about 60 minutes.
Lyophilized powder for intravenous administration: can be used(i) 100-. The formulation is reconstituted to a concentration of 10-20mg/mL with sterile saline for injection or 5% glucose, then further diluted to 0.2-0.4mg/mL with saline or 5% glucose and administered as an intravenous bolus or intravenous 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 capsules: a large number of unit capsules were prepared by filling standard two-piece hard capsules with 100mg of the powdered active ingredient, 150mg of lactose, 50mg of cellulose and 6mg of magnesium stearate, respectively.
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 a 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 solids prepared by conventional and novel processesAn oral dosage form. These unit dosage forms are administered orally without the need for water for immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid 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.
According to one embodiment, the present invention relates to a pharmaceutical combination comprising:
-one or more first active ingredients selected from compounds of general formula (I) as defined above, and
-one or more second active ingredients selected from chemotherapeutic anti-cancer agents.
The term "chemotherapeutic anti-cancer agent" includes, but is not limited to:
131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinol, altretamine, aminoglutethimide, amsacrine, anastrozole, Arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel (cabazitaxel), calcium folinate, levofolinate, capecitabine, carboplatin, carmofur, carmustine, cetuximab (catumaxob), celecoxib, simox interleukin, cetuximab, chlorambucil, chlormadinone, mechlorethamine, cisplatin, cladribine, clodronic acid, clofarabine, cobicis (BAlisib 80), ciprofloxacin, cyclophosphamide (6946), cyclophosphamide, ciprofloxacin, cyclophosphamide, and cyclophosphamide, Cytarabine, dacarbazine, dactinomycin, daltepatin alpha, dasatinib, daunorubicin, decitabine, degarelix, dinil interleukin 2, dinolizumab, deslorelin, dibromospiro-ammonium chloride, docetaxel, doxifluridine, doxorubicin + estrone, eculizumab (eculizumab), eculizumab, etiracetam, etiridium, eltrombopag (eltrompag), endostatin, enocitabine, enzutamide, epirubicin, epithisterol, alfafurtiptin, betanepetin, etaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, fulvestramustine, fulvestrant, gemcitabine, valnemulin, gefitinib, glutethimide, gefitinib, glutethimide, geucine, geucin, glutathione, geucirumicin, geucin, glutathione, geucin, ge, Goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I-125 radioactive particles, ibandronic acid, temomamab, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, eprinimumab (ipilimumab), irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenastin, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxolone, medroxyprogesterone, megestrol, melphalan, melandroxane, mercaptopurine, methotrexate, methoxsalen, aminolevulinic acid methyl ester, methyltestosterone, valamustine (mifamurtide), miltefosine, miriplatin, dibromomannitol, mitoguazatione, mitoxantrone, nespitin, platinum, and its, Nelarabine, nilotinib, nilutamide, nimotuzumab (nimotuzumab), nimustine, nitraminoacridan, ofatumumab (ofatumumab), omeprazole, ompreinterleukin, oxaliplatin, p53 gene therapy, paclitaxel, palivumin, palladium-103 radioactive particles, pamidronic acid, pamitumomab, pazopanib (pazopanib), pemetrexed, PEG-betaepoetin (methoxy PEG-betaepoetin), pegylated filgrastim, pegylated interferon alpha-2 b, pemetrexed, pentazocine, pentostatin, pellomycin, phosphoramide, streptolysin (picibanil), pirarubicin, plerixafor (plerixaporin), plicamycin, chitosan, estradiol polyphosphate, proteoglycan-k, sodium humamurate, prasugrexate (predryxate), predryzine, quinacre, gazepine, fluazure, fludarabine, gazepine, fludara, Radium-223 chloride, raloxifene, raltitrexed, ramosestin, razoxane, refametinib BAY 86-9766(RDEA 119), regorafenib, risedronic acid, rituximab, romidepsin, ronitrilib (romiplosmist), roniclib (BAY 1000394), sargrastim, sipuleucel-T, cilazalolan, sobuzosin, sodium bisoxazole (sodium glydidazole), sorafenib, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasosenib, taxofenadine, thiepindol, temustine, tegafur + trimethoprim + oxiracetam, temoporfin, temozololimumab, temustine, teniposide, testosterone, tipepin, triptorezine, triptoretinib, netorubine, valtretinomycin, valtretin, valtretinomycin, temustine, valtuzumab, valtretinomycin, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, homostat, homostastin esters, zoledronic acid, zorubicin, or combinations thereof.
The additional agent may be everolimus, aldesleukin, alendronic acid, alpha-interferon, alitretinoin, allopurinol, sodium allopurinol for injection (alprimem), palonosetron hydrochloride injection (aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasemet, alfa-bepotastine injection (aranesp), parthenolide derivative (arglabin), diarsenic trioxide, arnoxine, 5-azacitidine, azathioprine, BAY 80-6946, BCG or tide, BCG, amastatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, busulfan, calcitonin, argatron (caepath), capecitabine, platinum, pemetrexene, bicolone, bicuccine, daunorubicin, carmustine, doxycycline, and other, Cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin liposome citrate (DaunoXome), dexamethasone sodium phosphate, estradiol valerate, dinil interleukin 2, methylprednisolone, deslorelin, dexrazoxane, diethylstilbestrol, tolbutan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprolide acetate (eligard), labyrinase injection (elitek), epirubicin hydrochloride injection (ellence), aprepitant capsule (emide), epirubicin, alfa eptin alfa, alfa farabin (epogen), epta, levamisole, estradiol formulations (estratriol), estradiol, sodium phosphate estramustine, amifostine, etidronic acid, piridopipons (etophos), etoposide, posaconazole, fafavudine, favudine, dox, etoposide, doxepidopton, doxorfazole, doxepirubin, doxycycline, doxyc, Filgrastim, finasteride, filgrastim, floxuridine, tolbutamide, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosetabine, fotemustine, fulvestrant, gamma-globulin (gammagard), gemcitabine, gemumab, gleevec, carmine, carmustine capsules (gliadel), goserelin, granisetron hydrochloride, histrelin, and metin, hydrocortisone, erythrohydroxynonyladenine (eyrtho-hydroxyynyladenine), hydroxyurea, temomamab, idarubicin, ifosfamide, alpha interferon, alpha 2 interferon, a-2A interferon, a-2B interferon, a-n1 interferon, a-n3 interferon, p interferon, gamma-1 a interferon, interleukin 2A, alpha interferon (alpha-introne A), Iressa, irinotecan, Ketirel, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levamisole, calcium levofolinate, levothyroxine sodium (1evothroid), levothyroxine sodium preparation (1evoxyl), lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin acetate, megestrol acetate, melphalan, esterified estrogen preparation (menest), 6-mercaptopurine, mesna, methotrexate, mertevic, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trostan (Modrenal), doxorubicin liposomes (Myocet), nedaplatin, filgrastim injection (nenasta), recombinant human interleukin 11 (neuumamga), Youjin (neugen), nilutal, norvas, norvastus, OCT-8943, triptolide-631570, triptolide, OCT-D, leupeptin (leupeptin), leupeptin, leupept, Ondansetron hydrochloride, prednisolone oral rapidly disintegrating tablet (orapred), oxaliplatin, paclitaxel, prednisone sodium phosphate preparation (pediapared), pemetrexed, pyroxene, pentostatin, streptolysin preparation, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednisolone, prednisone, bemeili, procarbazine, recombinant human erythropoietin alpha, raltitrexed, RDEA 119, recombinant human interferon B1a injection (rebif), rhenium-186 hydroxyethylphosphonate, rituximab, roscovitine (roferon-A), romotein, pilocarpine hydrochloride tablet (salagen), shannin, sargrastim, semustine, Sizopyran, Sobuconazole, methylprednisolone, fosetyl, dry cell therapy, streptozocin, strontium 89, sunitinib, levo sodium, thyroxine, neotamicin, tamoxifen, and thelin, Tasolomine, testolactone, docetaxel injection (taxotere), teicoplanin, temozolomide, teniposide, testosterone propionate, mesterolone capsule (tetred), thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (trexal), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, vilulizine, dexrazol, dexrazoxane, setastine, pinocetin, abine, ABI-007, allophile (aclobirene), interferon gamma-1 b (actimmumole), finafiltrene, aminopterin, arzoxifene, progesterone receptor modulator (ioprisperidone), oxypetamol (9006-9006) and bafenib (oxypheniramine, oxyphenirane, ketonura-43) Avastin (Avastin), CCI-779, CDC-501, celecoxib, cetuximab, clinacator, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, efluoromidine, efaprotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, ibandronic acid, gamma interferon, pegylated interferon alpha-2 b (intron-PEG), ixabepilone, keyhole limpet hemocyanin (keyhol limpet hemocyanin), L-651582, lanreotide, lasofoxifene, libra, farnesol protein transferase inhibitors (lonarnib), mirepredfene, minophosphonate (minodronate), MS-209, liposome-PE, MX-6, nararelin, laniroxostat, nemorosa, neosloxostat, minostrobin, trimethoprim, celecoxib, medroxypterin, medroxypr S, merrimeric S, merremicade, neritin, nereid, doxylamine, and doxylamine, Paclitaxel, disodium pamidronate, PN-401, QS-21, quasipam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, Tarceva (tarceva), taxoprexin, alpha-1 thymosin, thiazolufrine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valcephrade, 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 edition (1996) (incorporated herein by reference), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levoasparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, epothilone derivatives, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, nitrogen mustard, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, meclizine, thioguanine, topotecan, 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 for use in The treatment of neoplastic diseases in Goodmanand Gilman's, The Pharmacological Basis of Therapeutics (9 th edition), edited by Molinoff et al, McGraw-Hill, pp.1225-1287 (1996) (incorporated herein by reference), e.g., aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrononyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorometholone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotanetan, medroxyprogesterone, medroxyprogen, medullone, medullol acetate, melphalan, 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 2, rituximab, alpha 1 thymosin, bevacizumab, mecamylamine Rifafibate (mecamylin Rifabite), Ompur interleukin, natalizumab, rhMBL, E-CPl + ZD-2767-P, ABT-828, ErbB 2-specific immunotoxins, SGN-35, MT-103, Rifame (rinabate), AS-1402, B43-genistein, L-19 series radioimmunotherapeutic, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r (m) CRP, MORAB-009, Avicumine (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, labetuzumab (1abetuzumab), alpha-emitting radioisotope cross-linked trastuzumab, Acem-1421, Hypertevudine vaccine, interleukin-7, HPV-3516, HPV-30625, and Abelituzumab (pertuzumab-3063), Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, agovacizumab (oregomab), ofatumumab (ofatumumab), zalmumab (zalmumab), bevacizumab (cindrekinbestudox), WX-G250, Albuferon, aflibercept (aflibercept), denomab (denosumab), vaccine, CTP-37, efungumab (efungumab), or 13 lI-chTNT-1/B. Monoclonal antibodies useful as protein therapeutics include, but are not limited to, molobuzumab-CD 3, abciximab, edrecolomab, daclizumab, gemtuzumab (gentuzumab), alemtuzumab, ibritumomab tiuxetan (ibritumomab), cetuximab, bevacizumab, efalizumab (efalizumab), adalimumab (adalimumab), omalizumab, moelimumab-CD 3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
The compounds of the invention may also be combined with biological therapeutic agents such as antibodies (e.g., avastin, B cell monoclonal antibodies, erbitux, herceptin) and recombinant proteins.
According to one embodiment, the present invention relates to a pharmaceutical combination comprising:
-one or more compounds of general formula (I) above, 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; and
-one or more drugs selected from: a taxane, such as docetaxel, paclitaxel, lapatinib, sunitinib, or taxol; epothilones, such as ixabepilone, paclitaxel, or salgopirone; mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; vincamine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2' -deoxyadenosine; thioguanine; antiandrogens, such as flutamide, cyproterone acetate, or bicalutamide; bortezomib; platinum derivatives, such as cisplatin, or carboplatin; chlorambucil; methotrexate; and rituximab.
The compounds of the invention may also be combined with an anti-angiogenic agent, for example with avastin, axitinib, DAST, recentin, sorafenib or sunitinib. It may also be combined with proteasome inhibitors or mTOR inhibitors or antihormone or steroid metabolic enzyme inhibitors.
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 wider range 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 or 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 useful 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 in the cell. 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 another aspect of the invention, the compounds of the invention are administered immediately after the initiation of irradiation or other induction that causes DNA damage to the 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 MKNK-1 and are therefore useful for 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 MKNK-1, e.g. hematological tumors, solid tumors and/or their metastases, such as leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, tumors, and/or metastases, in particular, in the treatment or prevention of diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response 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), stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, particularly pharmaceutically acceptable salts, or mixtures thereof, 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.
Another aspect of the present invention is the use of a compound of formula (I) as described above in the manufacture of a medicament for the prevention or treatment of a disease.
The diseases mentioned in the first three 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 MKNK-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 cellular immune response or inappropriate cellular inflammatory response" as used herein, the term "inappropriate" is to be understood as preferably meaning 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, or 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, for example, 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 distal metastases. Those 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 variation), 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 conditions 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.
The term "treating" as referred to throughout this document generally manages or cares for the patient, e.g., for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder such as sarcoma, etc.
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 any 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 the growth of new (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, sci, 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 amounts andadministration of drugs
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. The desired mode of treatment and the number of doses of a compound of the invention, or a pharmaceutically acceptable salt, or ester, or composition thereof, can be determined by one skilled in the art using routine therapeutic testing.
Preferably, the disease to which the method is directed is a hematological tumor, a solid tumor and/or metastases thereof.
The compounds of the invention are particularly useful in the treatment and prevention (i.e. prevention) of tumor growth and metastasis, particularly 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 exemplify the invention and the invention is not limited to the examples provided.
And (3) biological determination:
the examples were tested one or more times in selected bioassays. When tested more than once, the data is reported as a mean or median value, where:
The mean, also called arithmetic mean, represents the sum of the values obtained divided by the number of tests, and
the median value represents the number of the median position of the group of numerical values when arranged in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median value is the arithmetic mean of the two intermediate values.
The examples were synthesized one or more times. When synthesized more than once, the data from the bioassay represents mean or median values calculated using a data set obtained by testing one or more synthetic batches.
MKNK1 kinase assay
MKNK 1-inhibitory activity of the compounds of the invention was quantified using the MKNK1 TR-FRET assay as described in the following paragraphs.
Recombinant fusion proteins (product nos. 02-145) of glutathione-S-transferase (GST, N-terminally bound) and human full length MKNK1 (amino acids 1-424 and T344D of accession No. BAA 19885.1), expressed in insect cells using a baculovirus expression system and purified by glutathione agarose affinity chromatography, were purchased from Cama Biosciences and used as enzymes. The biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (SEQ ID NO.1) (C-terminus in amide form) was used as a substrate for kinase reactions, which are available, for example, from Biosyntan (Berlin-Buch, Germany).
For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ l of MKNK1 solution in aqueous assay buffer [50mM HEPES pH7.5, 5mM magnesium chloride, 1.0mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma) ] was added, and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. Then, the kinase reaction was started by adding a solution of 3 μ L of adenosine triphosphate (ATP, 16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (0.1 μ M ═ 0.06 μ M final concentration in 5 μ L assay volume) in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 45 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in the linear range, typical concentrations were in the range of 0.05 μ g/ml. The reaction was stopped by the addition of 5. mu.L of TR-FRET detection reagent solution (5nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France ] and lnM anti-ribosomal protein S6(pSer236) -antibody [ #44921G ] from Invitrogen and 1nM LANCE EU-W1024-labeled protein G [ Perkin-Elmer, product AD0071] in aqueous EDTA (100mM EDTA, 0.1% (W/v) bovine serum albumin in 50mM HEPES, pH 7.5).
The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm are measured using a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fitting50Values, the concentration range is 20. mu.M to 0.1nM (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series being prepared separately by serial dilution 1: 3.4 at 100-fold the level of concentrated DMSO solution prior to assay).
Table 1: MKNK1 IC50
MKNK1 kinase high ATP assay
MKNK 1-inhibitory activity at high ATP of the compounds of the invention after their pre-incubation with MKNK1 was quantified using the TR-FRET based MKNK1 high ATP assay as described in the following paragraphs.
Recombinant fusion proteins (product No. 02-145) of glutathione-S-transferase (GST, N-terminally bound) and human full-length MKNK1 (amino acids 1-424 and T344D of accession No. BAA 19885.1), expressed in insect cells using a baculovirus expression system and purified by glutathione agarose affinity chromatography, were purchased from Carna Biosciences and used as enzymes. The biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (SEQ ID NO.2) (C-terminus in amide form) was used as a substrate for kinase reactions, which are available, for example, from Biosyntan (Berlin-Buch, Germany).
For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ l of MKNK1 solution in aqueous assay buffer [50mM HEPES pH7.5, 5mM magnesium chloride, 1.0mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma) ] was added, and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. Then, the kinase reaction was started by adding 3 μ L of a solution of adenosine triphosphate (ATP, 3.3mM ═ 2mM final concentration in 5 μ L assay volume) and substrate (0.1 μ M ═ 0.06 μ M final concentration in 5 μ L assay volume) in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 30 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in the linear range, typical concentrations were in the range of 0.003 μ g/mL. The reaction was stopped by the addition of 5. mu.L of TR-FRET detection reagent solution (5nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France ] and 1nM anti-ribosomal protein S6(pSer236) -antibody [ #44921G ] from Invitrogen and 1nM LANCE EU-W1024-labeled protein G [ Perkin-Elmer, product AD0071] in aqueous EDTA (100mM EDTA, 0.1% (W/v) bovine serum albumin in 50mM HEPES, pH 7.5).
The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, measurements at 620nm and 665nm after excitation at 350nm were made using a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)Fluorescence emission at nm. The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fitting50Values in the range of 20. mu.M to 0.1nM (e.g., 20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series being prepared separately by serial dilution at 100-fold the level of concentrated DMSO solution prior to assay, the exact concentration being variable depending on the pipette used).
Table 2: MKNK1 high ATP IC50