WO2020087565A1 - 吲唑类激酶抑制剂及其用途 - Google Patents
吲唑类激酶抑制剂及其用途 Download PDFInfo
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present application relates to a kinase inhibitor, as well as methods and uses of such kinase inhibitors to inhibit kinase activity. More specifically, the present invention relates to inhibitors capable of inhibiting the activity of cKIT (particularly mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 kinase.
- Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract. The incidence of GIST is about 1 / 100,000 to 2 / 100,000, accounting for 1-3% of all gastrointestinal tumors. The disease is more common in middle-aged and elderly people. The median age of onset is 50 to 65 years old. It is rare before 40 years old, but it has also been reported in children. GIST is currently considered to be a tumor with potentially malignant behavior, and its biological behavior is difficult to predict.
- GIST can occur in any part of the digestive tract, the most common is the stomach (60% to 70%), followed by the small intestine (20% to 30%), and the incidence of esophagus, colon, and rectum is less than 10%, and it can also occur in the net Membranes and mesentery.
- cKIT mutant 80-85%
- PDGFR ⁇ mutant 5-10%
- cKIT wild-type GISTs 10 %
- the pathogenesis of gastrointestinal stromal tumors is related to the activation of cKIT protein (CD117) signaling pathway.
- the proto-oncogene cKIT is a homolog of the vKIT gene isolated from feline fibrosarcoma virus. It is located on human chromosome 4 (4q12-13) and is about 90 kb in length. It consists of 21 exons and 20 endogenous The sub-composition is highly conservative during evolution.
- the cKIT protein is a receptor tyrosine kinase (RTK) located on the cell membrane. Its relative molecular mass is 145000, and it is named CD117 according to its cell surface epitope.
- the cKIT protein belongs to the third type RTK family, consisting of 5 immunoglobulin-like domains (D1 ⁇ D5), 1 transmembrane domain, and 1 containing the proximal membrane domain (JMD) and tyrosine kinase (TK) The cytoplasmic region of the domain constitutes.
- the TK domain is further divided into adenosine triphosphate (ATP) domain (TK1) and phosphotransferase (phosphotransferase) domain (TK2).
- the ligand stem cell factor SCF (stem cell) combines with the extracellular domain to form a dimer, resulting in the autophosphorylation of tyrosine in the TK domain of the cytoplasmic region, which further causes the autophosphorylation of various downstream effects and completes various signals Of passing.
- the main signaling pathways include PI3K signaling pathway, JAK-STAT signaling pathway, Ras-Erk signaling pathway, Src family kinase signaling pathway and PLC signaling pathway, etc., which ultimately promotes cell proliferation, division and tissue growth and survival.
- the cKIT kinase inhibitors used in the clinical treatment of GIST so far mainly include Imatinib (cKIT / BCR-ABL / PDGFR) of Novartis and Sunitinib (cKIT / BCR-ABL / PDGFR) of Pfizer / VEGFR2 / FLT3).
- Imatinib is the first type II kinase inhibitor for the treatment of GIST
- Sunitinib is a type I cKIT kinase inhibitor approved by the FDA in 2006.
- type II kinase inhibitors with cKIT activity include Regorafenib, Nilotinib, Mastinib, Sorafenib, etc. These small molecule inhibitors are all multi-target inhibitors, and Nilotinib and Mastinib cannot overcome the T670I mutation. Although two small molecule inhibitors Regorafenib and Sorafenib with cKIT activity developed by Bayer have certain activity on the cKIT-T670I mutation, both are multi-target inhibitors.
- Axitinib is a multi-target small molecule inhibitor developed by Pfizer, and also has inhibitory activities of cKIT, BCR-ABL, VEGFR2 and other kinases.
- Ponatinib also has a strong inhibitory activity against cKIT kinase, and it can overcome the resistance of cKIT-T670I mutation, but it is ABL / PDGFR / RET / CSF1R / FGFR / VEGFR / FGFR / RET And other multi-target inhibitors of kinases.
- the present invention is mainly to find an inhibitor with a completely new structure and a strong inhibitory effect on the imatinib resistance mutation cKIT-T670I.
- the present invention provides a selective kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:
- Y is selected from -NH- or-(CH 2 ) n- , where n is an integer of 0-3;
- R 1 is selected is optionally substituted with 1-3 independent R 4 groups are phenyl, optionally substituted with 1-3 independent R 4 groups pyridyl, optionally substituted with 1-3 Pyrazolyl substituted with independent R 4 groups, and pyrimidinyl optionally substituted with 1-3 independent R 4 groups;
- R 2 is selected from hydrogen and C 1-6 alkyl
- R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino, optionally substituted with 1-2 independent R 5 groups, and optionally 1-3 independent R 4 groups substituted phenyl, optionally substituted with 1-3 independent R 4 groups naphthyl, optionally substituted with 1-3 independent R 4 groups pyridyl, optionally substituted with 1-3 Piperazinyl substituted with an independent R 4 group, and piperidinyl optionally substituted with 1-3 independent R 4 groups;
- R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1 -6 alkylamino, C 2-6 alkylamido, (4-methylpiperazin-1-yl) methyl, morpholinomethyl, morpholinyl, 4-methylpiperazin-1-yl, 4 -Piperidinyl, and 4-tetrahydropyranyl;
- R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
- Y is a direct bond or -CH 2- .
- R 1 is selected from phenyl, pyridyl, pyrazolyl, and pyrimidinyl optionally substituted with 1-3 independent R 4 groups, wherein R 4 is independently selected from halogen , Amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl; R 1 is more preferably optionally Methyl, amino or halogen substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyrazolyl, and 5-pyrimidinyl; R 1 is particularly preferably 2-pyridyl.
- R 2 is hydrogen or methyl
- R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino, optionally substituted by 1-2 independent R 5 groups, and optionally 1- 3 R 4 groups independently substituted with phenyl, naphthyl, pyridyl, piperazinyl, and piperidinyl, wherein R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl, R 5 is independently selected from amino, hydroxyl, and methylthio; R 3 is more preferably optionally C 1-6 alkyl substituted by amino, hydroxy, or methylthio, dimethylamino, N-piperazinyl optionally substituted by methyl, optionally halogen, trifluoromethyl, or methoxy Group substituted phenyl, naphthyl, 4-pyridyl, 3-piperidinyl, and 4-piperidinyl optionally substituted
- R 3 when Y is a direct bond, R 3 is selected from C 1-6 alkyl, and 4-pyridyl optionally substituted with amino, hydroxy, or methylthio; when Y is- When CH 2- , R 3 is selected from phenyl optionally substituted with methoxy, N-piperazinyl optionally substituted with methyl, and 4-piperidinyl optionally substituted with methyl.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising the kinase inhibitor of the invention, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
- the invention also relates to the use of kinase inhibitors or pharmaceutical compositions including them to reduce or inhibit cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 kinase activity methods and uses.
- the present invention also relates to the prevention or treatment of cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ in a subject using kinase inhibitors or pharmaceutical compositions including the same , PDGFR ⁇ , and / or VEGFR2 activity-related disorders methods and uses.
- cKIT especially mutant cKIT / T670I
- FLT3 including mutant FLT3-ITD
- PDGFR ⁇ in a subject using kinase inhibitors or pharmaceutical compositions including the same , PDGFR ⁇ , and / or VEGFR2 activity-related disorders methods and uses.
- Figure 1a shows the effect of compound 9 and sunitinib on the body weight of mice after administration in a tel-cKIT / T670I-BaF3 cell tumor transplantation mouse model
- Figure 1b shows compound 9 and sunitinib in tel- Tumor inhibition effect in cKIT / T670I-BaF3 cell tumor transplantation mouse model.
- Figure 2a shows the effect of compound 9 and sunitinib on the body weight of mice after administration in the GIST-T1-T670I cell tumor transplantation mouse model
- Figure 2b shows compound 9 and sunitinib in GIST-T1- Tumor suppressive effect in T670I cell tumor transplantation mouse model.
- the present invention uses conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the technical scope of the art.
- mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology
- nomenclature and laboratory operations and techniques that are chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
- the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
- alkyl refers to an aliphatic hydrocarbon group, which may be a branched or linear alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (ie, an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.
- alkyl mentioned herein includes all possible configurations and conformations of the alkyl group, for example, the "propyl” mentioned herein includes n-propyl and isopropyl, and the "butyl” includes n-butyl Group, isobutyl and tert-butyl, "pentyl” includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl and so on.
- alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
- alkoxyalkyl means that the alkyl group defined herein is substituted with an alkoxy group defined herein.
- cycloalkyl refers to a monocyclic or polycyclic group that contains only carbon and hydrogen. Cycloalkyl includes groups having 3-12 ring atoms. According to the structure, the cycloalkyl group may be a monovalent group or a divalent group (for example, cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a "lower cycloalkyl group" having 3 to 6 carbon atoms.
- cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
- alkyl (cycloalkyl) or "cycloalkylalkyl” means that the alkyl group defined herein is substituted with a cycloalkyl group defined herein.
- Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
- aromatic group refers to a planar ring having a delocalized ⁇ electron system and contains 4n + 2 ⁇ electrons, where n is an integer.
- the aromatic ring may be composed of five, six, seven, eight, nine, or more than nine atoms.
- the aromatic group may be optionally substituted.
- aryl includes carbocyclic aryl (eg phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg pyridine).
- the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
- aryl means that each atom in the aryl ring that constitutes the ring is a carbon atom.
- the aryl ring may be composed of five, six, seven, eight, nine, or more than nine atoms.
- the aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
- the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
- aryloxy refers to -O-aryl, where aryl is as defined herein.
- heteroaryl means that the aryl group includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the N-containing “heteroaryl” moiety means that at least one skeleton atom in the ring of the aromatic group is a nitrogen atom.
- the heteroaryl group may be a monovalent group or a divalent group (ie, a heteroarylene group).
- heteroaryl groups include, but are not limited to pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole Group, isothiazolyl group, pyrrolyl group, quinolinyl group, isoquinolinyl group, indolyl group, benzimidazolyl group, benzofuranyl group, indazolyl group, indazine group, phthalazinyl group, pyridazinyl group, isoindolin Indolyl, pteridyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofurazyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , Nap
- alkyl (aryl) or “aralkyl” means that the alkyl group defined herein is substituted with an aryl group defined herein.
- Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
- alkyl (heteroaryl) or “heteroarylalkyl” means that the alkyl group defined herein is substituted with a heteroaryl group defined herein.
- heteroalkyl means that one or more of the backbone chain atoms in the alkyl group defined herein are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof.
- the heteroatom (s) can be located at any position inside the heteroalkyl group or at a position where the heteroalkyl group is connected to the rest of the molecule.
- heterocycloalkyl refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms selected from nitrogen, oxygen, and sulfur.
- the heterocycloalkyl ring may be composed of three, four, five, six, seven, eight, nine, or more than nine atoms.
- the heterocycloalkyl ring may be optionally substituted.
- heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,4-dioxane, piperazine, 1,3-oxathiolane, 1,4- Oxythiacyclohexadiene, 1,4-oxathiolane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barium Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, t
- alkyl (heterocycloalkyl) or “heterocycloalkylalkyl” means that the alkyl group defined herein is substituted with a heterocycloalkyl group defined herein.
- alkoxy (heterocycloalkyl) or “heterocycloalkylalkoxy” means that the alkoxy group defined herein is substituted with a heterocycloalkyl group defined herein.
- halo or halogen refers to fluorine, chlorine, bromine and iodine.
- haloalkyl examples include structures of alkyl, alkoxy or heteroalkyl groups in which at least one hydrogen is replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are the same as or different from each other.
- hydroxyl refers to the -OH group.
- cyano refers to a -CN group.
- ester group refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclic group (attached through a ring carbon).
- amino refers to the -NH 2 group.
- aminoacyl refers to a -CO-NH 2 group.
- amido or “amido” refers to -NR-CO-R ', where R and R' are each independently hydrogen or alkyl.
- alkylamino refers to an amino substituent that is further substituted with one or two alkyl groups, specifically refers to the group -NRR ', where R and R' are each independently selected from hydrogen or lower alkyl, provided that- NRR 'is not -NH 2 .
- Alkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least one compound of an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
- “Dialkylamino” includes groups in which the nitrogen of -NH 2 connects at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
- arylamino and diarylamino refer to amino substituents that are further substituted with one or two aryl groups, specifically referring to the group -NRR ', where R and R' are each independently selected from hydrogen, Lower alkyl, or aryl, where N connects at least one or two aryl groups, respectively.
- cycloalkylamino refers to an amino substituent that is further substituted with one or two cycloalkyl groups as defined herein.
- heteroalkylamino refers to an amino substituent that is further substituted with one or two heteroalkyl groups as defined herein.
- aralkylamino herein refers to a group -NRR 'where R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
- heteroarylamino refers to an amino substituent that is further substituted with one or two heteroaryl groups as defined herein.
- heterocycloalkylamino means that the amino group defined herein is substituted with a heterocycloalkyl group defined herein.
- alkylaminoalkyl means that the alkyl group defined herein is substituted with an alkylamino group defined herein.
- aminoalkyl refers to an alkyl substituent that is further substituted with one or more amino groups.
- aminoalkoxy refers to an alkoxy substituent that is further substituted with one or more amino groups.
- hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent that is further substituted with one or more hydroxyl groups.
- cyanoalkyl refers to an alkyl substituent that is further substituted with one or more cyano groups.
- acyl refers to a monovalent radical remaining after removing the hydroxyl group of an organic or inorganic oxyacid, the general formula is R-M (O)-, where M is usually C.
- alkanoyl or “alkylcarbonyl” refers to a carbonyl group that is further substituted with an alkyl group.
- Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.
- arylcarbonyl means that the carbonyl group defined herein is substituted with an aryl group defined herein.
- alkoxycarbonyl refers to a carbonyl group that is further substituted with an alkoxy group.
- heterocycloalkylcarbonyl refers to a carbonyl group that is further substituted with a heterocycloalkyl group.
- alkylaminocarbonyl cycloalkylaminocarbonyl
- arylaminocarbonyl aralkylaminocarbonyl
- heteroarylaminocarbonyl respectively mean that the carbonyl groups defined herein are respectively defined herein Alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino substitution.
- alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted with an alkylcarbonyl group.
- alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted with an alkylcarbonyl group.
- heterocycloalkylcarbonylalkyl refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.
- mercapto refers to a -SH group.
- alkylthio means that the mercapto group defined herein is substituted with an alkyl group defined herein.
- alkylaminosulfone group means that the sulfone group defined herein is substituted with an alkylamino group defined herein.
- alkylsulfonylamino or "cycloalkylsulfonylamino” means that the amino group defined herein is substituted with an alkylsulfonyl group or cycloalkylsulfone group as defined herein.
- quaternary ammonium group refers to -N + RR'R ", wherein R, R 'and R" are each independently selected from alkyl groups having 1-8 carbon atoms.
- optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
- optionally substituted or “substituted” means that the mentioned group may be substituted with one or more additional groups, each of which is independently and independently selected from alkyl, cycloalkyl , Aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, cyano, halogen, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
- the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl and the like.
- tyrosine protein kinase is a type of kinase that catalyzes the transfer of ⁇ -phosphate from ATP to protein tyrosine residues and can catalyze a variety of substrate protein tyrosine residues Phosphorylation plays an important role in cell growth, proliferation and differentiation.
- the term “inhibition”, “inhibited”, or “inhibitor” of a kinase refers to the inhibition of phosphotransferase activity.
- the "metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized.
- active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
- the term “metabolized” refers to the sum of processes by which specific substances are changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural transformations into compounds.
- cytochrome P450 catalyzes various oxidation and reduction reactions
- glucosyl diphosphate transferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
- Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
- the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
- the compound is metabolized to a pharmaceutically active metabolite.
- the term "modulate" refers to directly or indirectly interacting with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
- target protein refers to a protein molecule or part of a protein that can be bound by a selective binding compound.
- the target protein is tyrosine kinase KIT (wild type or various mutations or combinations thereof), ABL (wild type or various mutations or combinations thereof), EGFR (wild type or various mutations or combinations thereof) Combination), FLT3 (wild type or various mutations or combinations thereof), VEGFR2 (wild type or various mutations or combinations thereof), RET (wild type or various mutations or combinations thereof), PDGFR ⁇ (wild type or various mutations) (Or combinations thereof), PDGFR ⁇ (wild type or various mutations or combinations thereof), BCR / ABL (wild type or various mutations or combinations thereof), FGFR1 (wild type or various mutations or combinations thereof), FGFR2 (wild type Or various mutations or combinations thereof), FGFR3 (wild type or various mutations or combinations thereof), FGFR4 (wild type or various mutations or combinations thereof).
- IC 50 as used herein refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximum effect in an analysis measuring such effects.
- EC 50 refers to the dose, concentration, or amount of an assay compound that causes a dose-dependent response of 50% of the maximum expression of a specific response induced, stimulated, or potentiated by a particular assay compound.
- GI 50 refers to the concentration of the drug required to inhibit the growth of 50% of the cells, that is, the concentration of the drug when the drug inhibits or controls the growth of 50% of the cells (such as cancer cells).
- novel kinase inhibitor of the present invention is derived from the novel kinase inhibitor of the present invention.
- the present invention provides a novel kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof,
- Y is selected from -NH- or-(CH 2 ) n- , where n is an integer of 0-3, and when n is 0, Y represents a direct bond;
- R 1 is selected from aryl and heteroaryl optionally substituted with 1-3 independent R 4 groups;
- R 2 is selected from hydrogen and C 1-6 alkyl
- R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino, optionally substituted with 1-2 independent R 5 groups, and optionally 1-3 independent R 4 groups Substituted aryl, heteroaryl and heterocyclic groups;
- R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1 -6 alkylamino, C 2-6 alkylamido, (4-methylpiperazin-1-yl) methyl, morpholinomethyl, morpholinyl, 4-methylpiperazin-1-yl, 4 -Piperidinyl, and 4-tetrahydropyranyl;
- R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
- Y is a direct bond or -CH 2- .
- R 1 is selected from phenyl, pyridyl, pyrazolyl, and pyrimidinyl optionally substituted with 1-3 independent R 4 groups, wherein R 4 is independently selected from halogen , Amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl; R 1 is more preferably optionally Methyl, amino or halogen substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyrazolyl, and 5-pyrimidinyl; R 1 is particularly preferably 2-pyridyl.
- R 2 is hydrogen or methyl
- R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino, optionally substituted by 1-2 independent R 5 groups, and optionally 1- 3 R 4 groups independently substituted with phenyl, naphthyl, pyridyl, piperazinyl, and piperidinyl, wherein R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl, R 5 is independently selected from amino, hydroxyl, and methylthio; R 3 is more preferably optionally C 1-6 alkyl substituted by amino, hydroxy, or methylthio, dimethylamino, N-piperazinyl optionally substituted by methyl, optionally halogen, trifluoromethyl, or methoxy Group substituted phenyl, naphthyl, 4-pyridyl, 3-piperidinyl, and 4-piperidinyl optionally substituted
- R 3 when Y is a direct bond, R 3 is selected from C 1-6 alkyl, and 4-pyridyl optionally substituted with amino, hydroxy, or methylthio; when Y is- When CH 2- , R 3 is selected from phenyl optionally substituted with methoxy, N-piperazinyl optionally substituted with methyl, and 4-piperidinyl optionally substituted with methyl.
- the inhibitors of the present invention include the compounds of Table 1 below or pharmaceutically acceptable salts, solvates, esters, acids, metabolites, or prodrugs thereof.
- novel kinase inhibitors are also described herein. Also described herein are pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites, and prodrugs of this compound.
- the compound described herein is metabolized in the body of an organism in need thereof to produce a metabolite, and the generated metabolite is then used to produce a desired effect, including a desired therapeutic effect.
- the compounds described herein can be made and / or used as pharmaceutically acceptable salts.
- the types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc .; or formed by reaction with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid Acid, 1,2-ethanedisulfonic acid, 2-
- the corresponding counter ion of the pharmaceutically acceptable salt can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them combination.
- the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or freeze-drying in the case of an aqueous solution.
- Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis.
- Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state).
- Various microscopy techniques include but are not limited to IR microscopy and Raman microscopy.
- the application also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of the compound, and a pharmaceutically acceptable Carriers or excipients, and optionally other therapeutic agents.
- the drug containing the compound of the present invention can be administered to a patient by at least one of injection, oral, inhalation, rectal, and transdermal administration.
- Other therapeutic agents can be selected from the following drugs: immunosuppressive agents (eg tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate or FTY720), glucocorticoid drugs (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydroxyprednisolone, beclomethasone , Fluhydrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (such as salicylate, arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, Xicams, corxixes, or thioanilides), allergic vaccines, antihistamines, antileukotrien
- the other therapeutic agents mentioned may also be rapamycin (Rapamycin), crizotinib (Crizotinib), tamoxifen, raloxifene, anastrozole, exemestane, letrozole , Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this CD, camptothecin, da
- the other therapeutic agent may be a cytokine such as G-CSF (granulocyte colony stimulating factor).
- other therapeutic agents may be, for example, but not limited to, CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), CAF (cyclophosphamide, adriamycin, and 5-fluorouracil), AC (subcutaneous Dririamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, (Aminopterin, 5-fluorouracil and prednisone).
- CMF cyclophosphamide, methotrexate, and 5-fluorouracil
- CAF cyclophosphamide, adriamycin, and 5-fluorouracil
- the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or disorder and its severity, the subject in need of treatment Or the uniqueness of the host (e.g. body weight), however, depending on the specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered may be known in the art
- the method is routinely decided.
- the dosage administered is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day.
- the desired dose may conveniently be presented as a single dose, or administered simultaneously (or within a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day.
- dose range is given, the specific effective amount can be appropriately adjusted according to the condition of the patient and combined with the diagnosis of the physician.
- the kinase inhibitors of the present invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs, or pharmaceutical compositions thereof for reducing or inhibiting the activity of cells or subjects cKIT (particularly mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 kinase activity, and / or prevent or treat cKIT (particularly mutant cKIT) in the subject / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 activity related disorders.
- cKIT particularly mutant cKIT / T670I
- FLT3 including mutant FLT3-ITD
- the compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition thereof can be used to treat, prevent, or ameliorate one or more diseases selected from the group consisting of : Solid tumors (including benign or especially malignant types), especially sarcomas, gastrointestinal stromal tumors (Gastrointestinal Stromal Tumors, GIST), colorectal cancer (colon cancer), acute myeloid leukemia (Acute Myeloblastic Leukemia, AML), chronic Chronic Myelogenous Leukemia (CML), neoplasia, thyroid cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, lupus erythematosus, graft-versus-host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, testicular intrae
- gastrointestinal stromal tumors colorectal cancer, acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer or similar diseases, or a combination thereof.
- the inhibitor of the present invention or a pharmaceutical composition thereof can be used for the treatment or prevention of gastrointestinal stromal tumors, especially cKIT-T670I mutant gastrointestinal stromal tumors.
- the compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition thereof can be used to treat, prevent, or ameliorate an autoimmune disease selected from the group consisting of: Arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes , Myasthenia gravis, Hashimoto's thyroiditis, Ord's hyroiditis, Graves' disease, rheumatoid arthritis syndrome ( syndrome), multiple sclerosis, infectious neuronitis (Guillain-Barrésyndrome), acute disseminated encephalomyelitis, Addison's disease, visual ocular twin-myoclonic syndrome, ankylosing Spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepati
- the reactions can be used in order to provide the compounds described herein; or they can be used to synthesize fragments that are subsequently added by methods described herein and / or methods known in the art.
- kinase inhibitor compounds described herein are provided herein and methods of use thereof.
- the compounds described herein can be synthesized using the following synthetic schemes. Compounds can be synthesized by using appropriate alternative starting materials using methods similar to those described below.
- the starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources.
- the compounds described herein and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art.
- the general method for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reaction can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts of the molecules provided herein.
- reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
- Non-limiting examples of synthetic schemes for preparing compounds of formula (I) are shown in the following synthetic routes.
- N- (4-methylthiazol-2-yl) acetamide Add 4-methylthiazol-2-amine (2g) to a 100mL round bottom flask, add anhydrous dichloromethane (50mL), triethylamine ( 3.9mL), slowly add acetyl chloride (1.5mL) dropwise. The reaction system was reacted under argon protection at room temperature for 4 hours. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was neutralized with saturated sodium bicarbonate to pH> 10, and then extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the reaction system was heated to 130 ° C for 14 hours under the protection of argon. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain pure product, MS (ESI) m / z (M + 1) +: 460.18.
- the reaction system was stirred at room temperature for 14 hours under the protection of argon. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product.
- the crude product was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added.
- the reaction system was stirred at room temperature for 14 hours under the protection of argon. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and neutralized with saturated sodium bicarbonate solution to pH> 10.
- the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- the organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product.
- the crude product was purified by pressurized silica gel column chromatography to obtain compound 1, MS (ESI) m / z (M + 1) +: 550.24.
- Example 2 The synthesis of Example 2 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 540.09.
- Example 3 The synthesis of Example 3 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 520.14.
- Example 4 The synthesis of Example 4 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 439.14.
- Example 5 The synthesis of Example 5 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 361.11.
- Example 6 The synthesis of Example 6 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 506.13.
- Example 7 The synthesis of Example 7 was completed using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 502.17.
- Example 8 The synthesis of Example 8 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 512.18.
- Example 9 The synthesis of Example 9 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 474.21.
- Example 10 The synthesis of Example 10 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 486.12.
- Example 11 The synthesis of Example 11 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 459.20.
- Example 12 The synthesis of Example 12 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 419.17.
- Example 13 The synthesis of Example 13 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 459.20.
- Example 14 The synthesis of Example 14 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 445.18.
- Example 15 The synthesis of Example 15 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 465.16.
- Example 16 The synthesis of Example 16 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 458.20.
- Example 17 The synthesis of Example 17 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 405.15.
- Example 18 The synthesis of Example 18 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 447.20.
- Example 19 The synthesis of Example 19 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 404.16.
- Example 20 The synthesis of Example 20 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 481.18.
- the reaction system was heated to 130 ° C for 14 hours under the protection of argon. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain pure product, MS (ESI) m / z (M + 1) +: 455.23.
- N- (5- (3-iodo-1H-indazole-6-yl) -4-methylthiazol-2-yl) -2- (4-methylpiperazin-1-yl) acetamide (21d) Add N- (5- (1H-indazol-6-yl) -4-methylthiazol-2-yl) -2- (4-methylpiperazin-1-yl) ethane to a 50mL round bottom flask After amide (0.6g), N, N-dimethylformamide (10mL), iodine (0.8g) and potassium hydroxide (0.4g) were added. The reaction system was stirred at room temperature for 8 hours under the protection of argon.
- the reaction system was heated to 80 ° C under the protection of argon for 14 hours. After the reaction was completed, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound 21, MS (ESI) m / z (M + 1) +: 451.21.
- Example 22 The synthesis of Example 22 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 448.18.
- Example 23 The synthesis of Example 23 was completed by using a procedure similar to that described in Example 21. MS (ESI) m / z (M + 1) +: 464.20.
- Example 24 The synthesis of Example 24 was completed by using a procedure similar to that described in Example 21. MS (ESI) m / z (M + 1) +: 448.19.
- Example 25 The synthesis of Example 25 was completed by using a procedure similar to that described in Example 21. MS (ESI) m / z (M + 1) +: 466.18.
- Example 26 The synthesis of Example 26 was completed by using a procedure similar to that described in Example 21. MS (ESI) m / z (M + 1) +: 465.19.
- Example 27 The synthesis of Example 27 was completed by using a procedure similar to that described in Example 1. MS (ESI) m / z (M + 1) +: 473.21.
- Example 28 The synthesis of Example 28 was completed by using a procedure similar to that described in Example 21. MS (ESI) m / z (M + 1) +: 494.13.
- Example 29 The synthesis of Example 29 was completed using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 521.14.
- Example 30 The synthesis of Example 30 was completed by using procedures similar to those described in Example 1. MS (ESI) m / z (M + 1) +: 376.13.
- the human gastrointestinal stromal tumor cell line GIST-T1 (expressing wild-type C-KIT gene) (purchased from Cosmo Bio Co., Ltd. (Japan)
- human gastrointestinal stromal tumor Cell line cells GIST-T1-T670I (expressing C-KIT-T670I mutant gene) (constructed by our laboratory using CRISPR technology)
- mouse proto-B cell BaF3 (purchased from ATCC).
- mouse Tel-cKit-BaF3 stable expression of C-KIT wild-type kinase
- mouse Tel-cKit / T670I-BaF3 stable expression of cKIT T670I mutant kinase
- mouse Tel-PDGFR ⁇ were also selected.
- the construction method was: PCR was used to amplify the human C-KIT, C-KIT T670I, PDGFR ⁇ , PDGFR ⁇ , VEGFR2, FLT3 kinase region sequences, and inserted into the N-terminal TEL fragment and / Or NPM fragment and / or TPR fragment of MSCV-Puro vector (purchased from Clontech), stably transferred into mouse BaF3 cells by retrovirus method, and the IL-3 growth factor was removed, and finally C-KIT, C-dependent -KIT / T670I, PDGFR ⁇ , PDGFR ⁇ , VEGFR2, FLT3 transfected protein cell lines.
- the GIST-T1-T670I (expressing the C-KIT-T670I mutant gene) cell line was constructed by our laboratory.
- the construction method was to target the sgRNA near the T670 site of the KIT gene by the CRISPR design tool of the Zhang Feng laboratory of the Massachusetts Institute of Technology Designed (website: crispr.mit.edu), and cloned into pSpCas9 (BB) -2A-Puro vector (Addgene, USA); the obtained vector and a segment of single-stranded oligomer with T670I mutation near T670 site Cells were co-transfected with nucleotides, after antibiotic selection, diluted and single-cell cultured in 96-well plates; Sanger sequencing method was used to verify the T670 site of cells.
- the compounds of the present invention and the control compound axiti of different concentrations (0.000508 ⁇ M, 0.00152 ⁇ M, 0.00457 ⁇ M, 0.0137 ⁇ M, 0.0411 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.11 ⁇ M, 3.33 ⁇ M, 10 ⁇ M in DMSO)
- Axitinib purchased from China, MedChem Express
- CCK-8 purchased from Bebo Biotech Co., Shanghai, China
- CCK-8 cell viability detection kit
- the dehydrogenase in is reduced to a yellow formazan product with high water solubility.
- the amount of formazan produced is proportional to the number of live cells.
- the experimental results shown in Table 2 show that the compounds of the present invention have a certain inhibitory effect on mutant cKIT-T670I, VEGFR2, PDGFR ⁇ , PDGFR ⁇ , FLT3, especially compared with cKIT wild type, it has more inhibitory effect on mutant cKIT-T670I Strong inhibitory effect.
- the preferred compounds of the present invention have comparable or stronger inhibitory activity against mutant cKIT-T670I, but relatively weaker inhibitory activity against wild-type cKIT.
- cKIT wild type plays a very important role in the early development of normal hematopoietic stem cells, so under unnecessary circumstances, inhibition of cKIT kinase will produce mechanistic toxicity, and there are reports in the literature that the simultaneous inhibition of FLT3 and cKIT will cause bone marrow suppression toxicity .
- Axitinib has a certain inhibitory effect on maternal BaF3 cells, and there is no selectivity between wild-type cKIT and mutant cKIT-T670I; and the compounds of the present invention are between mutant cKIT-T670I and wild-type cKIT and maternal BaF3
- the cells showed obvious selective inhibition, indicating that the preferred compounds of the present invention, while inhibiting mutant cKIT-T670I, will not cause the problem of myelosuppressive toxicity due to the inhibition of wild-type cKIT and FLT3.
- the compounds 7 and 9 of the present invention and the control compound Imatinib (purchased from China, MedChem Express) were resistant to the gastrointestinal stromal tumor cell line GIST-T1 and the Imaitinib constructed by our laboratory Testing on the mutated GIST-T1-T670I cell line revealed that the compounds of the present invention not only have a strong inhibitory effect on gastrointestinal stromal tumors sensitive to Imatinib, but also have a strong inhibition on GIST-T1-T670I resistant to Imatinib effect. This indicates that the compounds of the present invention can be used to treat T670I mutant gastrointestinal stromal tumors.
- mice were orally administered methylcellulose (HKI) vehicle (5 mice) daily; the dose was 10 mg / kg , 20 mg / kg, 40 mg / kg, 100 mg / kg compound 9 (5 mice each); dose of 40 mg / kg mouse weight Sunitinib (purchased from MedChemExpress, China) (5 mice) ).
- HKI methylcellulose
- mice For the mouse model of GIST-T1-T670I, starting from the 15th day, the corresponding mice were orally administered methylcellulose (HKI) vehicle (5 mice); the doses were 20 mg / kg, 30 mg / kg , 40 mg / kg of compound 9 (5 mice each); sunitinib (5 mice) at a dose of 40 mg / kg mouse weight.
- HKI methylcellulose
- Compound 9 has shown a certain effect of inhibiting tumors in mice in the TEL-cKIT / T670I-BaF3 and GIST-T1-T670I mouse tumor models at a dosage of 40 mg / kg, and with the increase in the number of days of medication, The inhibitory effect of compound 9 on mouse tumors is more significant, and the tumor inhibition rate is as high as 80% or more.
- the tumor inhibition is 11 days after administration The rate reached 100%.
- the tumor inhibition rate on the 28th day after administration in the GIST-T1-T670I mouse model was 84.3%.
- Compound 9 not only effectively inhibited the growth of tumors in mice, but basically had no effect on the body weight of mice, indicating that compound 9 can be applied to animal administration. This also proves that the CKIT / T670I inhibitor compound of the present invention can be used to treat gastrointestinal stromal tumors with T670I mutation.
- the present invention provides a novel kinase inhibitor compound that can be used to reduce or inhibit cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / Or VEGFR2 kinase activity, and / or prevent or treat cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 activity related disorders in the subject. Therefore, it can be made into a corresponding medicine, which is suitable for industrial applications.
- the present invention provides a novel kinase inhibitor compound that can be used to reduce or inhibit cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / Or VEGFR2 kinase activity, and / or prevent or treat cKIT (especially mutant cKIT / T670I), FLT3 (including mutant FLT3-ITD), PDGFR ⁇ , PDGFR ⁇ , and / or VEGFR2 activity related disorders in the subject. Therefore, it can be made into a corresponding medicine, which is suitable for industrial applications.
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Abstract
Description
GI 50(μM) | GIST-T1 | GIST-T1-T670I |
Imaitnib | 0.010 | >10 |
7 | 0.032 | 0.065 |
9 | 0.019 | 0.039 |
Claims (19)
- 一种激酶抑制剂,其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物,其中,X为-(CH=CH) m-,其中m为0或1;Y选自-NH-或-(CH 2) n-,其中n为0-3的整数;R 1选自任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的吡唑基、和任选地被1-3个独立的R 4基团取代的嘧啶基;R 2选自氢和C 1-6烷基;R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的萘基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的哌嗪基、和任选地被1-3个独立的R 4基团取代的哌啶基;R 4独立地选自卤素、氨基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟基烷基、C 1-6烷基氨基、C 2-6烷酰胺基、(4-甲基哌嗪-1-基)甲基、吗啉甲基、吗啉基、4-甲基哌嗪-1-基、4-哌啶基、和4-四氢吡喃基;R 5独立地选自氨基、羟基、和C 1-6烷硫基。
- 根据权利要求1所述的激酶抑制剂,其中X为-(CH=CH)-。
- 根据权利要求1所述的激酶抑制剂,其中Y为直接键或-CH 2-。
- 根据权利要求1所述的激酶抑制剂,其中R 1选自任选地被1-3 个独立的R 4基团取代的苯基、吡啶基、吡唑基、和嘧啶基,其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基;
- 根据权利要求4所述的激酶抑制剂,其中R 1选自任选地被甲基、氨基或卤素取代的苯基、2-吡啶基、3-吡啶基、4-吡唑基、和5-嘧啶基。
- 根据权利要求1所述的激酶抑制剂,其中R 2为氢或甲基。
- 根据权利要求1所述的激酶抑制剂,其中R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、萘基、吡啶基、哌嗪基、和哌啶基,其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基,R 5独立地选自氨基、羟基、和甲硫基。
- 根据权利要求7所述的激酶抑制剂,其中R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、二甲氨基、任选地被甲基取代的N-哌嗪基、任选地被卤素、三氟甲基、或甲氧基取代的苯基、萘基、4-吡啶基、3-哌啶基、和任选地被甲基取代的4-哌啶基。
- 根据权利要求1所述的激酶抑制剂,其中当Y为直接键时,R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、和4-吡啶基;当Y为-CH 2-时,R 3选自任选地被甲氧基取代的苯基、任选地被甲基取代的N-哌嗪基、和任选地被甲基取代的4-哌啶基。
- 一种药物组合物,其包括如权利要求1-10中任一项所述的激酶抑制剂,以及药学上可接受的载体或赋形剂,以及任选的其它治疗剂。
- 如权利要求1-10中任一项所述的激酶抑制剂在制备用于抑制cKIT、FLT3、PDGFRα、PDGFRβ、和/或VEGFR2激酶活性的药物中的用途。
- 如权利要求1-10中任一项所述的激酶抑制剂在制备用于抑制突变型cKIT/T670I激酶活性的药物中的用途。
- 如权利要求1-10中任一项所述的激酶抑制剂在制备用于治疗或预防cKIT、FLT3、PDGFRα、PDGFRβ、和/或VEGFR2活性相关疾病、障碍或病症的药物中的用途。
- 如权利要求1-10中任一项所述的激酶抑制剂在制备用于治疗或预防突变型cKIT/T670I活性相关疾病、障碍或病症的药物中的用途。
- 如权利要求15所述的用途,其中所述疾病、障碍或病症为cKIT-T670I突变型的胃肠道间质瘤。
- 如权利要求1-10中任一项所述的激酶抑制剂,用于抑制cKIT、FLT3、PDGFRα、PDGFRβ、和/或VEGFR2激酶活性,特别是用于抑制突变型cKIT/T670I激酶活性。
- 如权利要求1-10中任一项所述的激酶抑制剂,用于治疗或预防cKIT、FLT3、PDGFRα、PDGFRβ、和/或VEGFR2活性相关疾病、障碍或病症,特别是用于治疗或预防突变型cKIT/T670I活性相关疾病、障碍或病症。
- 如权利要求18所述的PDGFR激酶抑制剂,其中所述疾病、障碍或病症为cKIT-T670I突变型的胃肠道间质瘤。
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