The present application claims priority from chinese prior patent application No. 200910177355.7, filed 2009, 09/30. Accordingly, the present invention includes the full scope of the above application.
Summary of the invention
The present invention provides a novel class of compounds, pharmaceutical compositions comprising the same, and methods of using the same for treating or preventing diseases or disorders associated with abnormal or deregulated kinase activity.
The invention provides, firstly, at least one compound of the formula I, II or III,
or a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof or a prodrug thereof,
wherein,
x and Y are selected from N or CH, and at least one of them is N, wherein said N may or may not be suitably substituted by a hydrogen atom;
R2is selected from R7、OR7、NR7R8、S(O)qR7、SO2NR7R8、NR7SO2R8、C(O)R7、C(O)OR7、C(O)NR7R8、NR7C(O)R8Or NR7C(O)OR8(ii) a Q is independently selected from 0, 1 or 2; the R is7And R8Independently selected from:
(a)C1-6a linear, branched or cyclic alkyl group, wherein the alkyl group is further substituted with a 5-8 membered heterocyclic cycloalkyl group containing 1-4 heteroatoms selected from O, N or S, and the alkyl group is optionally substituted with one halogen or more halogens;
(b)C1-6a linear, branched or cyclic alkyl group, wherein the alkyl group is further substituted with an amido or sulfonamido group, and the alkyl group is optionally substituted with one halogen or more halogens;
(c)C1-10a linear, branched or cyclic chain containing multiple ether linkages, optionally substituted with one or more halogens;
(d)C1-10a linear, branched or cyclic chain containing a plurality of ether linkages, wherein the chain containing the plurality of ether linkages is further substituted with a 5-8 membered heterocyclic cycloalkyl group containing 1-4 heteroatoms selected from O, N or S, and the chain containing the plurality of ether linkages is optionally substituted with one or more halogens; or
(e)C1-10A linear, branched or cyclic chain containing a plurality of ether linkages, wherein said chain containing a plurality of ether linkages further comprisesOne step is substituted by amido or sulfonamido, and the chain containing multiple ether linkages can be selectively substituted by one halogen or multiple halogens;
R1and R3Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, arylalkenyl, alkynyl, aryl, arylalkyl, arylalkynyl, aryloxyalkyl, alkoxycarbonylalkynyl, aryloxkynyl, arylsulfonylalkyl, arylsulfonylalkynyl, arylsulfonylalkenyl, carboxyl, carboxyalkenyl, carboxyalkyl, cycloalkyl, carboxyalkynyl, cyano, cyanoalkenyl, cyanoalkyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, halogen, heterocycloarylalkenyl, heterocycloarylalkyl, heterocycloarylalkynyl, heterocycloarylcarbonyl, heterocycloarylcarbonylalkenyl, heterocycloarylcarbonylalkyl, heterocycloalkenyl, heterocycloalkylalkyl, heterocycloalkynyl, heterocycloalkylalkyl, heterocycloalkylcarbonyl, heterocycloalkynyl, heterocycloalkylalkyl, heterocyclic cycloalkyl carbonylalkenyl, cycloalkyl alkenyl, cycloalkyl alkynyl, formylalkenyl, formylalkyl, haloalkyl, heterocyclic aryl, heterocyclic cycloalkyl carbonylalkyl, heterocyclic cycloalkyl oxyalkenyl, hydroxyalkenyl, hydroxyalkyl, hydroxyalkynyl, NRaRb、(NRaRb) Alkenyl, (NR)aRb) Alkyl group, (NR)aRb) Alkynyl, (NR)aRb) Carbonyl group, (NR)aRb) Carbonylalkenyl, (NR)aRb) Carbonylalkyl, (NR)aRb) Carbonyl alkynyl, nitro, nitroalkenyl, nitroalkyl or nitroalkynyl; and
Raand RbIndependently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, aryl, alkylcarbonyl, alkylmethanesulfoalkyl, alkylsulfonyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylsulfonyl, heterocycloarylcarbonyl, heterocycloarylsulfonyl, heterocycloarylhydrocarbyl, heterocycloacycloalkylalkyl, heterocycloacycloalkylalkylcarbonyl, heterocyloalkylcarbonylCycloalkyl carbonyl, heterocycloalkyl sulfonyl, hydroxyalkoxyalkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, heterocycloaryl, heterocycloarylalkyl, (NR)cRd) Alkylcarbonyl group, (NR)cRd) Carbonyl group, (NR)cRd) Alkyl or (NR)cRd) A carbonylalkyl group; wherein the aryl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl and arylsulfonyl aryl moieties, cycloalkyl moieties of cycloalkylalkyl, heterocycloaryl moieties of heterocycloarylalkyl and heterocycloarylcarbonyl, heterocycloalkyl, and heterocycloalkyi moieties of heterocycloalkylalkyl and heterocycloalkylcarbonyl in turn may be further optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, halogen, haloalkoxy, haloalkyl, hydroxyl, nitro, NR, halogencRd、(NRcRd) Alkyl group, (NR)cRd) Alkylcarbonyl group, (NR)cRd) Carbonyl group, (NR)cRd) Carbonylalkyl, -O-, or spiroheterocycloalkyl, wherein the aryl portion of said aryl and arylalkyl groups can be optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, nitro, or-O-; and
wherein R iscAnd RdIndependently selected from hydrogen, alkoxy, alkyl, aryl, carboxyalkyl, cycloalkyl, haloalkyl, heterocycloaryl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkoxyalkyl, hydroxyalkyl or (NR)eRf) An alkyl group; wherein said aryl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from alkenyl, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy or nitro; and
Reand RfIndependently selected from hydrogen or alkyl;
R4is selected from 1 to 3 optionally independent halogen and halogenated C1-6Alkyl, halo C1-6Alkoxy radical, C5-10Heterocyclic aryl radicals-C0-4Alkyl or C3-8Heterocyclic cycloalkyl-C0-4C substituted by alkyl radicals6-10An aryl group; the R is4The heterocyclic aryl substituent or the heterocyclic cycloalkyl substituent of (a) may be optionally substituted by C1-6Alkyl or N-oxide derivatives;
R5and R6Independently selected from hydrogen or C1-6An alkyl group;
R5and R6And with R5And R6The linked phenyl radicals together forming a C6-10Aryl or C5-10A heterocyclic aryl group.
In some embodiments, X is N.
In some embodiments, Y is N. In some embodiments, R2Is selected from R7、OR7、NR7R8、SO2NR7R8、C(O)R7、C(O)OR7、C(O)NR7R8、NR7C(O)R8Or NR7C(O)OR8。
In some embodiments, R7And R8At least one of which is independently selected from:
(a)C1-5a linear, branched or cyclic alkyl group, wherein the alkyl group is further substituted with a 5-8 membered heterocyclic cycloalkyl group containing 1-3 heteroatoms selected from O, N or S, and the alkyl group is optionally substituted with one halogen or more halogens;
(b)C1-5a linear, branched or cyclic alkyl group, wherein the alkyl group is further substituted with an amido or sulfonamido group, and the alkyl group is optionally substituted with one halogen or more halogens;
(c)C1-8straight-chain, branched-chain, or cyclicA chain containing a plurality of ether linkages and optionally substituted with one halogen or a plurality of halogens;
(d)C1-8a linear, branched or cyclic chain containing a plurality of ether linkages, wherein the chain containing the plurality of ether linkages is further substituted with a 5-8 membered heterocyclic cyclic hydrocarbon group containing 1-3 heteroatoms selected from O, N and S, and the chain containing the plurality of ether linkages may be optionally substituted with one halogen or more halogens; or
(e)C1-8A linear, branched or cyclic chain containing a plurality of ether linkages, wherein the chain containing the plurality of ether linkages is further substituted with an amide group or a sulfonamide group, and the chain containing the plurality of ether linkages may be optionally substituted with one halogen or more halogens.
In some embodiments, R7And R8At least one of which is independently selected from:
(a)C1-6a linear, branched or cyclic chain containing multiple ether linkages, optionally substituted with one or more halogens;
(b)C1-6a linear, branched or cyclic chain containing a plurality of ether linkages, wherein the chain containing the plurality of ether linkages is further substituted with a 5-8 membered heterocyclic cycloalkyl group containing 1-2 heteroatoms selected from O, N or S, and the chain containing the plurality of ether linkages may be optionally substituted with one halogen or more halogens; or
(c)C1-6A linear, branched or cyclic chain containing a plurality of ether linkages, wherein the chain containing the plurality of ether linkages is further substituted with an amide group or a sulfonamide group, and the chain containing the plurality of ether linkages may be optionally substituted with one halogen or more halogens.
In some embodiments, R7And R8At least one of which is independently selected from C1-4A linear, branched or cyclic alkyl group, wherein the alkyl group is further substituted with a 5-8 membered heterocyclic cycloalkyl group containing 1-2 heteroatoms selected from O, N or S, and the alkyl group may be optionally substituted with one halogen or more halogens.
In some embodiments, R7And R8At least one of which is independently selected from C1-4A linear, branched or cyclic alkyl group, and the alkyl group is further substituted with an amido or sulfonamido group, and the alkyl group may be optionally substituted with one halogen or more halogens.
In some embodiments, R1And R3Is independently selected from hydrogen, halogen or alkyl.
In some embodiments, R1And R3At least one of (A) is independently selected from hydrogen or C1-6An alkyl group.
In some embodiments, R1And R3At least one of which is independently selected from hydrogen or halogen.
In some embodiments, R1And R3Are all hydrogen.
In some embodiments, R4Is selected from 1 to 2 optionally independent halogen and halogenated C1-4Alkyl, halo C1-4Alkoxy radical, C5-8Heterocyclic aryl radicals-C0-4Alkyl or C3-6Heterocyclic cycloalkyl-C0-4C substituted by alkyl radicals6-10An aryl group; and said R4The heterocyclic aryl substituent or the heterocyclic cycloalkyl substituent of (a) may be optionally substituted by C1-4Alkyl or N-oxide derivatives.
In some embodiments, R4Is selected from 1 to 3 optionally independent halogen and halogenated C1-4Alkyl, halo C1-4Alkoxy radical, C5-8Heterocyclic aryl radicals-C0-4Alkyl or C3-6Heterocyclic cycloalkyl-C0-4C substituted by alkyl radicals6-8An aryl group; and said R4Optionally substituted by C1-4Alkyl or N-oxide derivatives.
In some embodiments, R4Is selected from 1 to 2 optionally independent halogen and halogenated C1-4Alkyl or halo C1-4C substituted by radicals of alkoxy6-8And (4) an aryl group.
In some embodiments, R4Is selected from 1 to 3 optionally independent halogen and halogenated C1-6Alkyl, halo C1-6Alkoxy radical, C5-10Heterocyclic aryl radicals-C0-4Alkyl or C3-8Heterocyclic cycloalkyl-C0-4C substituted by alkyl radicals6-10An aryl group; and said R4The heterocyclic aryl substituent or the heterocyclic cycloalkyl substituent of (a) may be optionally substituted by C1-6Alkyl or N-oxide derivatives.
In some embodiments, R5And R6At least one of (A) is independently selected from hydrogen or C1-4An alkyl group.
In some embodiments, R5And R6Are all hydrogen.
In some embodiments, R5And R6And with R5And R6The attached phenyl rings together form a quinolinyl or naphthyl group.
In some embodiments, R1、R3、R5And R6Independently selected from hydrogen, halogen or lower alkyl; and R4Is selected from 1 to 3 optionally independent halogen and halogenated C1-6Alkyl, halo C1-6Alkoxy radical, C5-10Heterocyclic aryl radicals-C0-4Alkyl or C3-8Heterocyclic aryl radicals-C0-4Alkyl groups substituted phenyl.
In some embodiments, R1、R3、R5And R6All are hydrogen; and R4Is selected from 1 to 3 optionally independent halogen and halogenated C1-6Alkyl, halo C1-6Alkoxy radical, C5-10Heterocyclic aryl radicals-C0-4Alkyl or C3-8Heterocyclic aryl radicals-C0-4Alkyl groups substituted phenyl.
In some embodiments, the compounds of the present invention are selected from at least one compound:
1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (piperidin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (piperazin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (tetrahydropyrrole-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (2-methoxyethoxy) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (piperidin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (piperazin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (tetrahydropyrrole-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4- (6- (2- (2-methoxyethoxy) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (1- (2-methoxyethoxy) methyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperidin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperazin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
11- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (tetrahydropyrrolyl-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (2-methoxyethoxy) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (pyridin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperidin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperazin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (tetrahydropyrrolyl-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
In a second aspect, the present invention also provides a pharmaceutical composition comprising: at least one compound of formulae I, II and III, or an N-oxide derivative thereof, or a single isomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.
In some embodiments, the pharmaceutical composition may also be combined with one or more other compounds.
In a third aspect, the invention provides the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of a disease or condition associated with kinase activity selected from Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl-T315I, FGFR1, FGFR3, Aurora-A, AxI, BMX, CHK2, cSRC, Fes, IKKA, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rsk1, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB.
In a fourth aspect, the invention provides a method of treatment of a disease associated with inhibition of kinase activity, in particular a disease associated with kinase activity selected from Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, AbI, Bcr-Abl, Aurora-A, AxI, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKK, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rsk1, SAPK2a, SAPK2ss, SAPK3SAPK4, Syk, Tie2, TrkA and/or TrkB, whereby the pathological state and/or condition of said disease may be prevented, inhibited or ameliorated. The method comprises administering to the animal a therapeutically effective amount of at least one compound of structural formula I, II or III, an N-oxide derivative thereof, a single isomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
In a fifth aspect, the present invention further provides the use of a compound of formula I, II or III or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with kinase activity, in particular for the manufacture of a medicament for the treatment of a disease and/or condition associated with kinase activity selected from Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, AbI, Bcr-Abl, Aurora-A, AxI, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKK, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rsk1, SAPK2a, SAPK2ss, SAPK3SAPK4, Syk, Tie2, TrkA and/or TrkB.
In a sixth aspect, the present invention still further provides a process for preparing a compound of formula I, II or III, N-oxide derivatives thereof, prodrug derivatives thereof, protecting group-containing derivatives thereof, single isomers and mixtures of isomers thereof, or a pharmaceutically acceptable salt thereof.
Definition of terms
"alkyl" means a saturated, branched, or straight chain monovalent hydrocarbon radical formed by the removal of one hydrogen atom from a carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to: a methyl group; an ethyl group; propyl groups such as prop-1-yl, prop-2-yl, prop-1-yl; butyl groups such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, cyclobut-1-yl, t-butyl; and the like. In certain embodiments, the alkyl group contains 1 to 20 carbon atoms. The term "lower alkyl" as used herein refers to an alkyl group containing 1 to 6 carbon atoms.
"alkenyl" refers to an unsaturated, branched or straight chain or cyclic hydrocarbyl group containing at least one C ═ C bond formed by the removal of a hydrogen atom from a carbon atom of a parent olefin. The C ═ C bonds of these groups can be present in either the Z-or E-configuration (or in both the cis and trans conformations). Typical alkenyl groups include, but are not limited to: a vinyl group; propenes, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl, prop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl; and the like alkenyl groups. In certain embodiments, the alkenyl group contains 2 to 20 carbon atoms. In another embodiment, the alkenyl group contains 2 to 6 carbon atoms, such as the term "lower alkenyl".
"alkynyl" refers to an unsaturated, branched, or straight chain hydrocarbyl group containing at least one C.ident.C bond formed by the removal of a hydrogen atom from a carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, and the like. In certain embodiments, the alkynyl group contains 2 to 20 carbon atoms. In another embodiment, the alkynyl group contains 2 to 6 carbon atoms, such as the term "lower alkynyl".
As used herein, "alkoxy" refers to a-OR radical, wherein R represents an alkyl group. Typical examples of such groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, and the like, to resemble alkoxy.
"alkoxycarbonyl" means a radical-C (O) -OR, wherein R is as defined above for alkyl.
"aryl" means a monocyclic or fused bicyclic aromatic ring containing 6 to 10 ring carbon atoms as shown. For example, the aryl group may be phenyl or naphthyl, preferably phenyl. "arylene" refers to a divalent group derived from an aryl group.
"Heterocyclaryl" means an aryl group as defined above in which one or more ring atoms are heteroatoms. For example, the heterocyclic aryl group includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo [1, 3] difuran, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophene, and the like.
"cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or fused bicyclic or bridged polycyclic hydrocarbon ring-forming group containing the indicated number of atoms. For example, wherein C3-10Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"heterocyclic cycloalkyl" means a cycloalkyl group as defined herein wherein one or more of the indicated number of ring carbon atoms is selected from-O-, -N ═ -NR-, -C (O) -, -S (O) -or-S (O)2-wherein R is selected from hydrogen, C1-4Alkyl or nitrogen protecting groups. For example, C is used in this application3-8Description of the Compounds of the invention comprising morpholino, tetrahydropyrrolyl-2-one, ethylpiperazinyl-diketone, pyridylalkyl-2-one, piperazinyl, piperidinyl, piperidyl ketone, 1, 4-dioxa-8-aza-spiro [4.5 ] group]A heterocyclic cycloalkyl group such as dodecyl-8-yl.
The "halogen" (or halogen) is preferably chlorine or fluorine, but may also be bromine or iodine.
"kinase List" is a kinase list including Abl (human), Abl (T3151), JAK, ALK, JNK1a, ALK, KDR, Aurora-A, Lck, Blk, MAPK, Bmx, MAPAPK, BRK, MEK, CaMKII (rat), Met, CDK/cyclinB, p70S6K7CHK, PAK, CK, PDGFRa, CK, PDK, c-kit, Pim-2, c-RAF, PKA (h), CSK, PKBa, cSrc, PKCa, DYRK, Plk, EGFR, Fes, Ron, FGFR, Ros, SAPK2, Fms, SGK, FIyn, SIK, GSK/3, Syk, IGF-1-2, WJ, TrKB, IRAK, WK, WN, BRK-70, SAPK, SAKK, SANKK, SAMKIK, SARK, SANKK, SACKK, SARK, SA, CDK6lcyclin D3, MLCK, TrkA, CDK7icyclin WMAT1, MRCKJ3, TSSK1, CHK, es, CK 1D, MST 1, ZIPK, c-Kit (D816 1), MUSK, DAPK 1, NEK 1, DDR 1, NEK 1, DMPK, PAK 1, DRAK1, PAR-1Ba, EphA1, PDGFRP, EphA1, Pim-1, EphA1, PKBP, EphB 1, PKCPI, EphB 1, PKCG, FGFRI, PKq, FGFR1, PKCB, FGFR1, PKD 1, Fgr, PKGlP, Flt1, PRK 1, Hck, PYK 1, HIPK 1, Rept, KaIRCsk 1, RIPK, KARSKK 1, JNK1, JNP, and RKP 1, human RKP 1, and RKP-36. The compounds of the invention are screened against kinases from the kinase repertoire (wild type and/or mutant) and are capable of inhibiting the activity of at least one of the kinases. As used herein, "BCR-Abl mutant" refers to a change in one amino acid or a plurality of amino acids from the amino acid sequence of a wild-type BCR-Abl. The BCR-ABL mutants act through a core junction between an interruptor protein and an inhibitor (e.g., Gleevec or the like), more typically by inducing its transition from a ground state to an excited state, such as a conformation to which BCR-ABL and Gleevec cannot bind. From clinical sample analysis, the discovered mutant forms of reporters, which accompany the resistant phenotype, continue to slowly but inevitably rise over time. The mutants appear to be clusters of four major regions. The first set of mutants (G250E, Q252R, Y253F/H, E255 5 255WV) includes amino acids that form an ATP phosphate group-binding loop (commonly referred to as the P-loop). The second group (V289A, F311L, T3151, F317L) can be found in the gleevec binding site and act directly with the inhibitor through hydrogen bonding or van der waals forces. The third set of mutants (M351T, E355G) clustered in the near field of their catalytic regions. The fourth mutant (H396R1P) is located in an activation loop, and its conformation is a molecular switch that controls the excited or ground state of the kinase. BCR-ABL point mutations associated with gleevec resistance can be detected in CML and ALL patients, including: M224V, L248V, G250E, G250R, Q252R, Q252H, Y253H, Y253F, E255K, E255V, D276G, T277A, V289A, F311L, T3151, T315N, F317L, M343T, M315T, E355G, F359V, F359A, V3791, F382L, L387M, L387F, H396P, H396R, A397P, S417Y, E459K and F486S (amino acid positions, index by the single cutter, area those to the bank sequence, Genace AAB 394, 6017 type, and J6090; Journal of Maralogue/Al 2005; Journal of Maralogue 2005/Biotechnology, et al).
"treatment" refers to a method of alleviating or ameliorating a disease and/or its symptoms.
By "pharmaceutically acceptable" is meant generally known for use in animals, particularly humans.
"pharmaceutically acceptable salts" which are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts with inorganic acids such as acids like hydrochloric, bromic, sulfuric, nitric, phosphoric, and the like, or with organic acids such as acetic, propionic, caproic, cyclopentylpropionic, glycolic, pyruvic, lactic, malonic succinic, malic, maleic, fumaric, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic, cinnamic, mandelic, methanesulfonic, and the like; or (2) salts may be formed when the acidic proton in the parent compound is substituted with a metal ion such as an alkali metal ion, alkaline earth metal ion, ammonium ion or the like, or chelated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine or the like, and the like.
In another aspect, the invention relates to a pharmaceutical composition comprising: at least one compound and one pharmaceutically acceptable auxiliary material. The term "pharmaceutically acceptable adjuvant" refers to any diluent, adjuvant, or carrier, with which at least one compound of the invention is administered.
By "therapeutically effective dose" is meant a dose of a compound that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to effect treatment of the disease, disorder, or symptom. The specific "therapeutically effective amount" may vary depending on the compound, the disease, disorder and/or the type, severity and/or symptoms of the disease or disorder being treated, the age and/or weight of the subject being treated. An appropriate dosage, where possible, will be readily apparent to those skilled in the art and may be determined by routine experimentation.
All numbers expressing quantities of ingredients, reaction conditions, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about" unless otherwise indicated. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that vary depending upon the standard deviation found in the respective test measurements.
Herein, when any variable occurs more than one time in a chemical structural formula, each definition thereof is independent of the other definitions. The compounds of the present invention may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (e.g., geometric isomers), optical enantiomers or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the present disclosure, whether partial or complete, which contains similar structures as described above, includes all possible enantiomers and stereoisomers of the compound, including any single stereoisomer (e.g., single geometric isomers, single enantiomers or single diastereomers) and any mixture of such stereoisomers. These enantiomers and stereoisomeric mixtures can be further resolved into their constituent enantiomers or stereoisomers by separation techniques or chiral molecular synthesis methods well known to those skilled in the art.
These compounds of formula I, II or III include, but are not limited to, optical isomers, racemic isomers, or other mixtures thereof. In these cases, these single enantiomers or diastereomers, e.g., optically active configurations, can be prepared by chiral synthesis or chiral resolution. Chiral resolution can be achieved by different methods, for example by recrystallization using conventional resolution-assisting reagents, or by chromatographic methods such as chiral high-pressure liquid chromatography (HPLC). In addition, the compounds of formula I, II or III may contain double bonds in either the Z-or E-configuration (or cis-or trans-configuration). When the compounds of structural formula I, II or III are in multiple tautomers, all such tautomers are also included in the chemical compounds of the present invention.
The compounds of the present invention include, but are not limited to, compounds of structural formula I, II or III and all their pharmaceutically acceptable forms. Pharmaceutically acceptable forms of these compounds described herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs or clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds of the present invention are pharmaceutically acceptable salts. In this context, the term "compound" includes not only the compound itself, but also a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, prodrug or mixture of any of the above.
As mentioned previously, ester or amide derivatives of prodrugs such as those of formulae I, II and III are also included in the scope of the above-mentioned chemicals. The term "prodrug" includes any compound that is converted to a compound of formula I, II or III upon administration to a patient, for example by metabolism of the prodrug. Examples of such prodrugs include, but are not limited to, acetyl derivatives, formyl derivatives, benzoyl derivatives, and other similar derivatives of various functional groups (e.g., alcohol or amino groups) of formula I, II or III.
In various places throughout the description of the invention, substituents of the compounds of the invention are represented as various groups or ranges. It is specifically contemplated that each and every subcombination of the groups and ranges encompassed by the present invention is encompassed therein. For example, the term "C1-3Alkyl "may particularly denote methyl, ethyl and C as described3Alkyl groups (including n-propyl and isopropyl).
The term "n-membered," wherein n is an integer, is commonly used to describe the number of ring-forming atoms in a chemical structure and indicates that the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heterocyclic aryl ring, and thiophene is an example of a 5-membered heterocyclic aryl ring.
The present invention provides a class of compounds, compositions and methods for treating kinase-associated diseases, particularly diseases associated with kinases selected from Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, AbI, Bcr-Abl, Aurora-A, Axi, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKK, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rsk1, SAPK2a, SAPK2ss, SAPK3SAPK4, Syk, Tie2, TrkA and/or TrkB. For example, leukemia and other BCR-Abl related cell proliferative disorders can be treated by inhibiting wild type and/or variant Bcr-Abl.
In some embodiments, R in the compounds of structural formulae I, II and II5And R6Are all hydrogen.
In other embodiments, R5And R6And with R5And R6The attached phenyl rings together form a quinolinyl or naphthol group.
In other embodiments, R1And R3Is selected from phenyl optionally substituted with 1-3 groups independently selected from chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, imidazolyl or piperazinyl, wherein R is1And R3The imidazolyl substituent or the piperazinyl substituent of (a) may be optionally substituted with methyl or ethyl.
Preferably, the compounds of the invention are selected from:
1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (tetrahydropyrrol-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (tetrahydropyrrol-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (piperidin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (piperazin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (tetrahydropyrrol-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (2-methoxyethoxy) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (piperidin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (piperazin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (tetrahydropyrrol-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4- (6- (2- (2-methoxyethoxy) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (tetrahydropyrrol-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- (1- (2-methoxyethoxy) methyl) aminosulfonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperidin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperazin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (tetrahydropyrrol-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (2-methoxyethoxy) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (pyridin-1-yl) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperidin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperazin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (tetrahydropyrrol-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea;
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea; or
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea.
Detailed embodiments of the present invention can be seen as follows. While certain embodiments of the invention have been described, it is to be understood that the embodiments of the invention are not to be limited in scope by these described embodiments. On the contrary, the embodiments of the invention are intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the embodiments of the invention as defined by the appended claims.
Further preferred compounds of the present invention are detailed in the following embodiments.
Pharmaceutical compositions and their administration
In general, the compounds of the present invention will be administered in therapeutically effective amounts by any of the usual and art-accepted models, either alone or in combination with one or more other therapeutic agents. The effective therapeutic dose depends on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. In general, studies have shown that satisfactory results can be obtained from a systemic study with a daily dose of about 0.03-2.5 mg/kg body weight. The exact daily dosage range for large mammals, such as humans, is from about 0.5 to about 1000mg and may be administered in a convenient form of administration, such as divided into up to 4 doses per day (subvided doses) or in a sustained release form. Suitable oral unit doses contain about 1-300 mg of active ingredient.
The compounds of the invention may be administered as pharmaceutical compositions by any conventional route of administration, in particular: the digestive tract, e.g., orally, e.g., in the form of tablets or capsules; alternatively, parenteral routes, such as in the form of injections or suspensions, and topical administration, such as in the form of lotions, gels, ointments or salves, or nasal or suppository forms. The pharmaceutical composition contains the compound of the invention in any form or pharmaceutically acceptable salt thereof, and is prepared by mixing, granulating or coating methods and other conventional methods together with at least one pharmaceutically acceptable auxiliary material or diluent. For example, the oral dosage form may be a tablet or gelatin capsule containing, in combination with the active ingredient: (1) diluents such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycine and the like; (2) lubricants, such as silica gel, talc, stearic acid or its magnesium or calcium salt and/or polyethylene glycol, and the like; also included for tablets are (3) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxy methyl cellulose, polyvinylpyrrolidone, and the like; if necessary, (4) disintegrating agent such as starch, agar, alginic acid or alginate, or effervescent mixture, etc.; and/or (e) absorbents, colorants, flavors, and sweeteners. The injection can be aqueous isotonic solution or suspension, and the suppository can be prepared by fat emulsion or suspension. These pharmaceutical compositions can be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, cosolvents, salts for regulating the osmotic pressure and/or buffers. In addition, they may also comprise other therapeutically active substances. Suitable transdermal administration forms contain a therapeutically effective amount of a compound of the invention, with the aid of adjuvants. The pharmaceutical carrier includes an easily absorbable pharmaceutically acceptable solvent to assist in release action on the skin of the host. For example, transdermal drug delivery devices may be in the form of an adhesive tape forming the base layer, a container containing the compound or plus adjuvant, optionally plus a means for controlling the rate of administration to the skin of the host, such that administration is accomplished at a controlled and pre-set rate over a prolonged period of time, and means for affixing the device to the skin. Matrix transdermal formulations may also be used. Suitable dosage forms for topical use, e.g. for application to the skin and eye, are preferably aqueous solutions, ointments, creams or gels well known in the art. These formulations may contain co-solvents, stabilizers, synergists, buffers and preservatives.
The compounds of the present invention may be administered in combination with one or more other therapeutic agents at a therapeutically effective dose (drug combination). For example, synergistic effects in combination with other immunomodulatory or anti-inflammatory substances, such as: cyclosporine (cyclosporine); rapamycin (rapamycin); ascomycin (Ascomycin) or an immunosuppressive analogue such as cyclosporin a (CsA), cyclosporin G, FK-506, rapamycin or a similar immunosuppressive compound; a corticosteroid; cyclophosphamide (cyclophosphamide); azathioprine (azathioprine); methotrexate (methotrexate); brequinar (Brequinar); leflunomide (Leflunomide); mizoribine (Mizoribine); mycophenolic acid (mycophenolic acid); mycophenolate mofetil (Mycophenolate mofetil); 1, 5-deoxyspergualin (15 deoxysperguali); immunosuppressant antibodies, especially monoclonal antibodies to leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands; alternatively, other immunomodulatory compounds, such as CTLA41 g. When the compounds of the present invention are used in combination with other therapies, the dosage of the co-administered compounds will, of course, depend on the type of combination employed, the particular drug being used in combination, and the physical condition of the subject.
The invention also provides a pharmaceutical composition, such as a kit package, comprising: (1) a first agent, i.e. any form of a compound of the invention as disclosed herein, or a pharmaceutically acceptable salt thereof; and (2) at least one combination. The kit may include instructions for its use.
The term "co-administration" or similar methods of use herein means the selection of therapeutic agents around a single patient and is intended to encompass treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
The term "pharmaceutical composition" as used herein refers to a product that is mixed or otherwise associated with more than one active ingredient and includes a combination of active ingredients in fixed and non-fixed proportions. The term "fixed composition" means that the compound of formula I, II or III and the active ingredients of the combination are administered to a patient simultaneously as a single entity or agent. The term "non-fixed composition" means that the compound of formula I, II or III and the active ingredients of the combination are each administered to the patient as separate substances or agents, which may be administered simultaneously, nearly simultaneously or sequentially with no specific time limitation, and the effective drug levels of both compounds may be achieved in the patient. The latter is also suitable for cocktail therapy, such as taking 3 or more effective components.