CN102216300B - Compounds and compositions as protein kinase inhibitors - Google Patents

Compounds and compositions as protein kinase inhibitors Download PDF

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CN102216300B
CN102216300B CN201080003084.4A CN201080003084A CN102216300B CN 102216300 B CN102216300 B CN 102216300B CN 201080003084 A CN201080003084 A CN 201080003084A CN 102216300 B CN102216300 B CN 102216300B
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phenyl
urea
pyridin
trifluoromethyl
chloro
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CN102216300A (en
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康心汕
理查德·M·费恩
博里斯·克里伯安斯基
龙伟
马存波
李海军
王燕萍
胡云雁
王印祥
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Zhejiang Beta Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Flt3, PDGFR, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c- RAF, AbI, Bcr-Abl, Aurora- A, AxI, BMX, CHK2, CSR0, Fes, FGFRi, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB Kinases.

Description

Compounds and compositions as protein kinase inhibitors
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.
Technical Field
The present invention provides a novel class of compounds, pharmaceutical compositions comprising them and methods of using them to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders associated with abnormalities in Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, AbI, Bcr-Abl, Aurora-A, AxI, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKKA, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, ROCK-II, Ros, Rsk1, SAPK2a, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB kinases.
Background
Protein kinases encompass a large class of proteins that play a central role in a wide variety of intracellular events and in ensuring control of intracellular functions. A list of partially incomplete protein kinases includes: tyrosine receptor kinases such as platelet-derived growth factor kinase (PDGF-R), nerve growth factor, trkB tyrosine protein kinase genes, receptors for brain-derived neurotropic factor and neurotrophin-3, Met, and fibroblast growth factor receptor, FGFR 3; non-receptor tyrosine kinases like Abl and the fusion kinase BCR-Abl, Lck, Csk, Fes, Bmx and c-src; and serine-threonine kinases such as b-RAF, c-RAF, sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and stress-activated protein kinase 2a, stress-activated protein kinase 2P and stress-activated protein kinase 3. Abnormal kinase activity is observed in many diseases including benign and malignant tumors, as well as in inappropriate activation of the immune and nervous systems.
The novel compounds of the present invention inhibit one or more protein kinase activities and are therefore expected to be useful in the treatment of protein kinase related diseases.
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.
Detailed description of the preferred embodiments
The invention also includes processes for preparing the compounds of the invention. In the reaction, reactive groups in the end product, such as hydroxyl, amino, imino, thiol (thio) or carboxyl groups, must be protected to avoid unwanted reactions. Following standard process procedures, conventional protecting groups are used. For example, reference may be made to the book "Protective Groups in Organic Synthesis" published by John Wiley and Sons, 1991 (T.W.Greene and P.G.M.Wuts, eds Protective Groups in Organic Chemistry).
Specific examples of the synthesis of compounds of formula I, II or III are described in detail in the examples below.
Additional preparation of Compounds of the invention
The compounds of the present invention can be prepared into pharmaceutically acceptable acid addition salts by reacting the free base with pharmaceutically acceptable inorganic or organic acids. Similarly, the compounds of the present invention may be prepared as pharmaceutically acceptable base addition salts by reacting the free acid with a pharmaceutically acceptable organic or inorganic base.
Likewise, salts of these compounds of the present invention can be prepared from salts of the starting materials or intermediates.
The free acid or the free base of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt, respectively. For example, an acid addition salt of a compound of the present invention can be converted to the corresponding free base by reaction with a suitable base such as aqueous ammonia, sodium hydroxide, and the like. Base addition salts of the compounds of the present invention can be converted to the corresponding free acids by reaction with a suitable acid (e.g., hydrochloric acid, etc.).
The non-oxides of the compounds of the present invention may be prepared by reacting the N-oxidation of the compounds of the present invention with a reducing agent (e.g., sulfur dioxide, phosphorus trichloride, lithium borohydride, sodium tetrahydroborate, phosphorus trichloride, tribromide, or the like) in a suitable inert solvent (e.g., acetonitrile, ethanol, water-soluble dioxane, or the like) at a temperature of about 0 to 80 ℃.
Prodrug derivatives of the compounds of the invention can be prepared by methods known in the art (see, e.g., Saul nier et al Bioorganic and Medicinal Chemistry letters.1994, 4: 1985). For example, suitable prodrugs can be prepared by reacting a derivative of a compound of the present invention with a suitable carbamoylating agent (e.g., 1-acyloxyalkylcarbamoyl chloride, p-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of the present invention may be prepared by conventional techniques known in the art. Details of the techniques for applying Protecting groups and deprotection are described in the book "Protecting groups in Organic Synthesis", published by John Wiley and Sons, Inc. 1999 (T.W. Greene, protection group in Organic Chemistry, third edition).
The compounds of the invention can be conveniently prepared or formed, for example, as solvates (e.g., hydrates) by the methods provided herein. Hydrates of the compounds of the invention can conveniently be prepared by recrystallisation from water/organic solvent mixtures using organic solvents such as dioxins, tetrahydrofuran or ethanol.
The compounds of the present invention can be prepared as single optical isomers by treating racemic mixtures of these compounds with an optically active resolving agent to form a pair of diastereomers thereof, resolving the diastereomers and recovering the optically pure enantiomers. When the enantiomeric resolution of the compounds of the invention can employ covalent diastereomeric derivatives thereof, readily separable complexes (e.g., crystalline diastereomeric salts) are preferred. Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, activities, etc.) and can be readily resolved using these distinct properties. Diastereomers can be separated by chromatography, or preferably by separation/resolution techniques based on differences in solubility. The optically pure enantiomers can then be recovered along with the resolving agent by any practical method that does not result in racemization. A more detailed description of the various techniques suitable for resolving stereoisomers of these compounds from racemic mixtures thereof can be found in the book Enantiomers, racemes And solutions (Jean Jacques, Andre Collet And Samuel H.Wilen) published by John Wiley And Sons, 1981.
Briefly, compounds of formula I, II or III can be prepared by the following processes, which include:
(1) reaction schemes widely adopted by medicinal chemists or disclosed in the examples described below; or
(2) Optionally converting a compound of the invention into a pharmaceutically acceptable salt thereof;
(3) optionally converting a salt form of a compound of the invention to its non-salt form;
(4) optionally converting the non-oxidized form of the compound of the invention to its pharmaceutically acceptable N-oxide;
(5) optionally converting the N-oxide of the compound of the invention to its non-oxidized form;
(6) optionally resolving an isomeric mixture of the compounds of the invention into its individual isomers;
(7) optionally converting a non-derivative of a compound of the invention into a pharmaceutically acceptable prodrug derivative thereof; or
(8) Prodrug derivatives of the compounds of the invention may be selectively converted to their underivatized form.
If the preparation of the starting materials is not specifically described, these compounds can be prepared analogously using methods known or in the art or as described in the examples below.
Those skilled in the art will also appreciate that the above-described preparation procedures are merely representative of the methods of preparing the compounds of the present invention, and that other well-known methods may similarly be used.
Detailed Description
The present invention is further, but not limited to, demonstrated by the following examples illustrating the preparation of the compounds of formula I, II or III according to the present invention.
Example 1
Synthesis of 1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
118.1 g (0.1mol) of the compound was dissolved in 100ml of concentrated sulfuric acid, and 14.3g (0.05mol) of 1, 3-dibromo-5, 5-dimethylhydantoin (DBDMH) was added in portions, and the reaction was stirred at room temperature for 16 hours. The reaction solution was poured into 400g of crushed ice and stirred for 20 minutes. The precipitated solid was filtered and dried to yield 22.1g of product 2 in 85% yield.
At a temperature below-5 ℃, 7.2g (0.06mol) of thionyl chloride (Thiolyl chloride) is added into 50ml of methanol dropwise, 13.0g (0.05mol) of 3-bromo-4-methyl-5-nitrobenzoic acid (3-bromo-4-methyl-5-nitrobenzoic acid) is added, and the mixture is stirred at room temperature for 30 minutes and then refluxed for 2 hours. The methanol was distilled off under reduced pressure, and the residue was passed through a silica gel column to give 11.2g of product 3 in 82% yield.
35.1 g (0.02mol) of the product was dissolved in 100ml of THF, 10ml of acetic acid and 5.6g of iron powder were added, and the mixture was stirred and heated under reflux for 10 hours. After cooling to room temperature, the mixture was filtered through celite. The filtrate was evaporated to dryness under reduced pressure. The residue was extracted with water and ethyl acetate, and anhydrous sodium sulfate (Na)2SO4) Drying and filtering to remove the drying agent. The filtrate was dried by spinning, and 100ml of acetic acid and 1.52g (0.022mol) of sodium nitrite were added to the residue, and the mixture was stirred and heated under reflux for 10 hours. Concentrating under reduced pressure to remove acetic acid, adding water, extracting with ethyl acetate, concentrating the organic phase of the ethyl acetate layer under reduced pressure to remove solvent, and purifying by rapid column chromatography to obtain 3.1g of product 4 with yield of 61%.
43.1 g (0.012mol) of the product was dissolved in 50ml of ethanol (EtOH), and a 10ml aqueous solution of 0.43g (0.018mol) of lithium hydroxide (LiOH) was added to the solution to react at room temperature for 20 hours. The ethanol was evaporated by concentration under reduced pressure, and the obtained residue was diluted with water and then adjusted to pH 4 with 1N hydrochloric acid (HCl). The solid precipitate which separated out was filtered off and dried to give 2.32g of product 5 in 80% yield.
51.21 g (0.005mol), 0.82g (0.005mol) of Carbonyldiimidazole (CDI), 0.83g (0.005mol) of 2-piperidinylethylamine hydrochloride (2- (piperidin-1-yl) ethaneamine) and 0.65g (0.005mol) of Diisopropylethylamine (DIPEA) were dissolved in 20ml of DMF, and the reaction was stirred at room temperature for 2 hours. After DMF was evaporated by concentration under reduced pressure, 1.05g of product 6 was obtained by purification by fast column chromatography.
60.351 g of the product, 0.21g of 4-aminophenylboronic acid (4-aminophenylboronic acid), 0.32g of anhydrous Sodium carbonate (Sodium carbonate) and palladium tetrakistriphenylphosphine (Pd (PPh) under a nitrogen atmosphere3)4)115.6mg in DME/H2O (4: 1)8ml, and the reaction was stirred at 95 ℃ for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted 3 times with 25ml of ethyl acetate, and the organic phases obtained by 3 times were combined, washed with saturated brine, and then with anhydrous sodium sulfate (Na)2SO4) Drying and filtering to remove the drying agent. The filtrate was evaporated, concentrated and dried, and purified by flash column chromatography to give 0.2g of compound 7 in 51% yield.
Dissolving 70.363 g of compound in THF, adding 0.297g of phenyl 3- (trifluoromethyl) phenyl carbamate, stirring at 25 ℃ for reaction for 1 hour, evaporating and concentrating the reaction liquid of the rotary drying system after the reaction is finished, adding dichloromethane into the obtained residue, filtering, collecting the obtained filter cake, namely compound 8, wherein the yield is 0.45g and 80%, and LC-MS (liquid chromatography-mass spectrometry) M + H]+m/z is 567.5.
Example 2
Synthesis of 1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a similar synthetic route to example 1, the title compound was prepared, which was LC-MS [ M + H ]]+m/z is 568.6.
Example 3
Synthesis of 1- (4- (6- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 553.4.
Example 4
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 558.3.
Example 5
Synthesis of 1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 544.6.
Example 6
Synthesis of 1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 603.4.
Example 7
Synthesis of 1- (4- (6- (N- (2- (piperazin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 604.5.
Example 8
Synthesis of 1- (4- (6- (N- (2- (tetrahydropyrrole-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 589-4.
Example 9
Synthesis of 1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
The above synthetic route was used to give the title compound 8, LC-MS [ M + H [ ]]+m/z is 594.4.
Example 10
Synthesis of 1- (4- (6- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a similar synthetic route to example 9, the title compound was prepared, which was LC-MS [ M + H ]]+m/z is 580.3.
Example 11
Synthesis of 1- (4- (6- (2- (piperidin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 540.4.
Example 12
Synthesis of 1- (4- (6- (2- (piperazin-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 541.3.
Example 13
Synthesis of 1- (4- (6- (2- (tetrahydropyrrole-1-yl) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 526.6.
Example 14
Synthesis of 1- (4- (6- (2- (2-methoxyethoxy) ethoxy) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 531.4.
Example 15
Synthesis of 1- (4- (6- (2- (piperidin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 539.5.
Example 16
Synthesis of 1- (4- (6- (2- (piperazin-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 540.5.
Example 17
Synthesis of 1- (4- (6- (2- (tetrahydropyrrole-1-yl) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 525.4.
Example 18
Synthesis of 1- (4- (6- (2- (2-methoxyethoxy) ethylamino) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 530.5.
Example 19
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 585.9.
Example 20
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 587.0.
Example 21
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 572.1.
Example 22
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 576.9.
Example 23
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 562.7.
Example 24
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 622.0.
Example 25
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 623.1.
Example 26
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 608.0.
Example 27
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 598.9.
Example 28
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperidin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 571.1.
Example 29
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (piperazin-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 571.9.
Example 30
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (tetrahydropyrrolyl-1-yl) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 557.1.
Example 31
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (4- (2-methoxyethoxy) butyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 561.9.
Example 32
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (3- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [2, 3-c ] pyridin-1-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+The m/z is 533.8.
Example 33
Synthesis of 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
To obtainThe title compound 7, its LC-MS [ M + H]+m/z is 585.8.
Example 34
Synthesis of 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
Using a similar synthetic route to example 33, the title compound was prepared as LC-MS [ M + H ]]+m/z is 586.9.
Example 35
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 571.8.
Example 36
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 576.9.
Example 37
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminocarbonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 562.8.
Example 38
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 622.0.
Example 39
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 623.1.
Example 40
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 607.9.
EXAMPLE 41
Synthesis of 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
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 612.9.
Example 42
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (N- ((2-methoxyethoxy) methyl) aminosulfonyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 599.0.
Example 43
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperidin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 572.8.
Example 44
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (piperazin-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 574.0.
Example 45
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (3- (tetrahydropyrrole-1-yl) propoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 558.9.
Example 46
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethoxy) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+m/z is 549.8.
Example 47
Synthesis of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1- (2- (2-methoxyethoxy) ethyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl) phenyl) urea
Using a synthetic route analogous to the previous example, the title compound was prepared as LC-MS [ M + H ]]+The m/z is 533.8.
The compounds listed in table 1 below can also be synthesized by reference to the general methods described above.
TABLE 1
TABLE 1
TABLE 1
TABLE 1
TABLE 1
TABLE 1
Test of
Upstate KinaseprofilerTMRadioactive enzyme Filter assay
The compounds of the invention were tested for inhibitory activity against each kinase of the kinase list. These compounds were repeated twice at a final concentration of 0.5. mu.M following the following general procedure. Note that the kinase lists differ in kinase buffers and substrates used for the different kinases. Kinase buffer (2.5. mu.L, containing 10 XMnCl)2If desired), activated kinase (0.001-0.01 units; 2.5 μ L), specifically or Poly (Glu4-Tyr) peptides (5-500 μ M or 0.01mg/mL) kinase buffer and kinase buffer (50 uM; 5 μ L) were mixed in an eppendorf tube placed in an ice bath. Add A Mg/ATP compound (10. mu.L; 67.5mM MgCl)2Or 33.75mM MgCl2450 μ M or 225 μ M ATP and 1Ci/μ L-32P](3000Ci/mmol)) and the reaction was incubated at a temperature of 30 ℃ for 10 minutes. Pipette 20. mu.L of reaction solution onto 2 cm. times.2 cm of P81 (phosphorescent cellulose for positively charged peptide substrates) or Whatman No.1 (for poly (Glu4-Tye) peptide substrates) checkerboard. The paper squares were washed 4 times for 5 minutes each with 0.75% phosphoric acid and 1 time for 5 minutes with acetone. Transfer the paper into a test flask, add 5mL of test solution (hybridization cocktail), label on the polypeptide substrate32P (cpm), counted with a Beckmann scintillation counter. The inhibition rate for each reaction was calculated.
The unsalified forms of the compounds of formulae I, II and III, or pharmaceutically acceptable salts thereof, both exhibit valuable pharmaceutical properties, such as the results of in vitro assays described herein. For example, compounds of structural formulae I, II and III, at a concentration of 0.2. mu.M, exhibit greater than 25%, and more preferably greater than 50%, inhibition of Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl-T315I, FGFR1 and FGFR3 kinases.
It is understood that the specific embodiments and implementations described herein are for illustrative purposes and to provide those skilled in the art with the full scope of the invention including the spirit and scope of the appended claims. All documents, patents and patent applications cited herein are provided for common disclosure purposes.
Table 2 shows the inhibition values of certain example compounds of the invention in enzyme assays.
TABLE 2

Claims (5)

1. The following compounds and pharmaceutically acceptable salts thereof:
1- (4- (6- (N- (2- (piperidin-1-yl) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea; or
1- (4- (6- (N- (2- (2-methoxyethoxy) ethyl) aminosulfonyl) -1H-indazol-4-yl) phenyl) -3- (3- (trifluoromethoxy) phenyl) urea.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, and at least one other compound.
4. Use of a pharmaceutical composition according to claim 2 or 3 for the preparation of a medicament for the treatment of a pathological and/or disease state associated with a kinase activity selected from Flt1, Flt3, KDR, PDGFRa, Ret and/or Tie 2.
5. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a pathological and/or disease state associated with a kinase activity selected from Flt1, Flt3, KDR, pdgfra, RET and/or Tie 2.
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