WO2019178801A1 - Nouveau dérivé de phénoxy pipéridine et ses applications - Google Patents

Nouveau dérivé de phénoxy pipéridine et ses applications Download PDF

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WO2019178801A1
WO2019178801A1 PCT/CN2018/079991 CN2018079991W WO2019178801A1 WO 2019178801 A1 WO2019178801 A1 WO 2019178801A1 CN 2018079991 W CN2018079991 W CN 2018079991W WO 2019178801 A1 WO2019178801 A1 WO 2019178801A1
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cancer
disease
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optionally substituted
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刘青松
刘静
王强
王蓓蕾
齐紫平
刘飞扬
陈程
亓爽
邹凤鸣
王文超
王俊杰
任涛
王黎
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中国科学院合肥物质科学研究院
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Definitions

  • the present application relates to a compound that is a selective PDGFR kinase inhibitor, and a method and use for inhibiting PDGFR kinase activity using such a compound.
  • Platelet-derived growth factor is a family of potent mitogens directed against almost all mesenchyme-derived cells. There are four PDGF isoforms - A, B, C and D - which form five different dimeric proteins linked by disulfides - PDGF-AA, BB, -AB, -CC and DD. These growth factors exert their cellular effects through two structurally related tyrosine kinase receptors, PDGF receptor alpha (PDGFR ⁇ ) and PDGF receptor beta (PDGFR ⁇ ) (Sandy, JR (1998) Br. J. Orthod. 25: 269-74; Betsholtz, C. et al. (2001) BioEssays 23: 494-507).
  • PDGFR ⁇ is structurally similar to PDGFR ⁇ and is capable of forming heterodimers and homodimers.
  • PDGF-BB and PDGF-DD are the major activators of the ⁇ homodimer.
  • PDGF-AA only activates the alpha alpha receptor dimer, while PDGF-AB, PDGF-BB and PDGF-CC activate alpha alpha and alpha beta receptor dimers.
  • the dimeric ligand molecule binds simultaneously to both receptor proteins and induces receptor dimerization, autophosphorylation of specific residues within the cytoplasmic domain of the receptor, and cellular signaling.
  • Pulmonary vascular remodeling is the pathomorphological basis of chronic hypoxic pulmonary hypertension, mainly characterized by proliferation and migration of smooth muscle cells, while proliferation of smooth muscle cells depends on the effects of various growth factors, especially platelets.
  • Platelet derived growth factor (PDGF) a growth factor that regulates cell proliferation by binding to growth factor receptors and activating tyrosine protein kinase (TPK) to phosphorylate it.
  • PDGF Platelet derived growth factor
  • TPK tyrosine protein kinase
  • CEL chronic eosinophilic leukemia
  • HES hypereosinophilic syndrome
  • the diagnosis and treatment provide a powerful molecular marker, and reveals at the molecular level that HES is the essence of a malignant clonal disease of the hematopoietic system (Cools J., DeAngelo DJ, Gotlib J., A tyrosine kinase created by fusion of the PDGFRA and FIP1L1genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N. Engl. J. Med. 2003, 348(13): 1201-14).
  • transcriptional activator 5 STAT5
  • STAT5 transcriptional activator 5
  • Examples of currently reported selective inhibitors against both PDGFR ⁇ and PDGFR ⁇ include CP-673451 (CAS No. 343787-29-1; molecular weight: 417.5) and imatinib (CAS No. 152459-95-5; molecular weight: 493.60 ), but the selectivity is not good enough, in addition to inhibiting PDGFR ⁇ , ⁇ , they also inhibit cKIT, BCR-ABL and so on. Therefore, it is necessary to provide a selective PDGFR inhibitor to provide a research basis for precise targeted therapy.
  • the inventors of the present invention have experimentally discovered a selective PDGFR inhibitor which inhibits Rat A-10 and expresses FIP1L1- in rat pulmonary artery smooth muscle cells expressing the chemokine PDGF-BB and its receptor PDGFR ⁇ .
  • the PDGFR ⁇ fusion gene has a significant inhibitory effect on the proliferation of chronic eosinophilic leukemia cell line EOL-1, and can also significantly inhibit tumor growth in a mouse model of EOL-1 cell tumor transplantation.
  • the present invention provides a phenoxy piperidine derivative which is a selective PDGFR kinase inhibitor.
  • the invention provides a selective PDGFR kinase inhibitor comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, 3-7 membered heterocycloalkyl optionally substituted by R 6 , and ring heteroatom optionally R 6 a heteroaryl group substituted with a ring carbon atom optionally substituted by R 7 ;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen
  • R 3 is selected from the group consisting of hydrogen, and halogen
  • R 4 is selected from C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl (C 3 -C 6 cycloalkyl), adamantyl, C 3 -C 6 cycloalkenyl, C 1 -C 4 alkyl optionally substituted by R 5 (C1 -C6 alkylamino), R 7 is optionally substituted phenyl, hetero atom is optionally substituted with R 6 and the ring carbon atoms R 7 is optionally substituted heteroaryl, optionally substituted alkyl, and R 5 C1-C4 alkyl (phenyl);
  • R 5 is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
  • R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, and C 2 -C 6 alkanoyl;
  • R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylamino, phenyl, and 3-7 membered heterocyclic ring alkyl.
  • the above 3-7 membered heterocycloalkyl groups are each independently selected from the group consisting of tetrahydrofuranyl, piperidinyl, and morpholinyl.
  • the above heteroaryl groups are each independently selected from the group consisting of pyridyl, pyrrolyl, isoxazolyl, thienyl, oxazolyl, quinolyl, imidazolyl, pyrazolyl, and thiazolyl.
  • R 1 is selected from C1-C6 alkyl, C2-C6 alkenyl group, a hetero ring atom is optionally substituted with R 6 and the ring carbon atom is optionally substituted by R 7 heteroaryl;
  • R 6 is selected from from C1-C6 alkyl;
  • R 7 is selected from C1-C6 cyanoalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl group, and phenyl.
  • R 1 is selected from 3-pyridyl, 2-pyrrolyl, 5-isoxazolyl, 2, wherein the ring heteroatom is optionally substituted by R 6 and the ring carbon atom is optionally substituted by R 7 a thienyl group, a 3-thienyl group, a 3-oxazolyl group, a 3-quinolyl group, and a 4-imidazolyl group; R 6 is selected from a methyl group; and R 7 is selected from a cyclopropyl group and a phenyl group.
  • R 2 is selected from the group consisting of hydrogen, methyl, fluorine, and chlorine. In a further preferred embodiment, R 2 is selected from the group consisting of methyl.
  • R 3 is selected from the group consisting of hydrogen and fluorine, and more preferably hydrogen.
  • R 4 is selected from C3-C6 cycloalkyl, C1-C4 alkyl (C3-C6 cycloalkyl), adamantyl, optionally substituted with R 7 being phenyl groups, and a C1-C4 alkyl (phenyl) group optionally substituted by R 5 ;
  • R 5 is selected from C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
  • R 7 is selected from C 1 -C 6 cyanoalkyl, C 1 -C 6 Haloalkyl, C3-C6 cycloalkyl, C1-C6 alkylamino, and phenyl.
  • R 4 is selected from the group consisting of cyclopentylmethyl, phenyl optionally substituted by R 7 , and benzyl optionally substituted by R 5 ;
  • R 5 is selected from methoxy;
  • R 7 is selected from the group consisting of 2-cyanopropan-2-yl.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and the compound or pharmaceutical composition inhibiting tyrosine kinase (wild type or various And methods of using the mutation or combination thereof, and treating, preventing or ameliorating or affecting the activity of a tyrosine kinase (wild type or various mutations or combinations thereof) or involving a tyrosine kinase ( A method and use of a disease, disorder or condition in which a wild type or various mutations or a combination thereof is active, wherein the tyrosine kinase can be PDGFR.
  • the present invention also relates to a tyrosine kinase inhibitor which exhibits a more selective inhibition of PDGFR relative to one or more of the targets cKIT, BCR-ABL, FLT3, VEGFR2, and the tyrosine of the present invention
  • a tyrosine kinase inhibitor which exhibits a more selective inhibition of PDGFR relative to one or more of the targets cKIT, BCR-ABL, FLT3, VEGFR2, and the tyrosine of the present invention
  • the use and method of an acid kinase inhibitor for the selective inhibition of PDGFR is a tyrosine kinase inhibitor which exhibits a more selective inhibition of PDGFR relative to one or more of the targets cKIT, BCR-ABL, FLT3, VEGFR2, and the tyrosine of the present invention.
  • Figures 1a-1c show experimental results obtained by treating a mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1 using Compound 17 and a vehicle control, respectively, wherein:
  • Figure 1a shows the average body weight of mice in different treatment groups in a mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1 (shown as relative body weight in the figure: the weight of the mouse at the start of the experiment is The percentage of the baseline calculation) as a function of time;
  • Figure 1b shows the average size of tumors in different treatment groups in a mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1 (shown as relative tumor size in the figure: mouse load at the start of the experiment) The tumor size is calculated as a percentage of the baseline) as a function of time;
  • Figure 1c shows the mean tumor weight and calculated tumor inhibition rate on day 14 after administration of mice in different treatment groups in a mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1.
  • the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art.
  • naming and laboratory operations and techniques chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and procedures can be carried out 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 and may be a branched or straight chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1-8 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 as referred to herein includes all alkyl groups which may exist in all configurations and conformations, such as "propyl” as referred to herein includes n-propyl and isopropyl, and "butyl” includes n-butyl.
  • the base, isobutyl and tert-butyl groups, "pentyl” include n-pentyl, isopropyl, neopentyl, tert-amyl, and pent-3-yl and the like.
  • alkoxy refers to -O-alkyl, wherein alkyl is as defined herein.
  • Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen.
  • the cycloalkyl group includes a group having 3 to 12 ring atoms.
  • the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • alkyl (cycloalkyl) or "cycloalkylalkyl” refers to an alkyl group, as defined herein, substituted by a cycloalkyl group, as defined herein.
  • Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • aryl means that the planar ring has a delocalized ⁇ -electron system and contains 4n+2 ⁇ electrons, where n is an integer.
  • the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can 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 as used herein means that each of the atoms constituting the ring in the aryl 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 can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and fluorenyl.
  • the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
  • heteroaryl refers to a ring heteroatom comprising one or more selected from the group consisting of nitrogen, oxygen and sulfur in the aryl group.
  • the N-containing "heteroaryl” moiety means that at least one of the backbone atoms in the ring of the aryl group is a nitrogen atom.
  • the heteroaryl group can 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 , isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, pyridazinyl, pyridazinyl, pyridazinyl, isoindole Sulfhydryl, pteridinyl, fluorenyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naph
  • alkyl (aryl) or “aralkyl” refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein.
  • Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
  • alkyl (heteroaryl) or “heteroarylalkyl” refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
  • heteroalkyl as used herein means that one or more of the backbone chains of the alkyl groups defined herein are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at a position where the heteroalkyl group is attached to the remainder of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein means that one or more of the atoms constituting the ring in the non-aryl ring is a hetero atom selected from the group consisting of 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 can be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxetane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, bar Bitoteric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl examples include structures of alkyl, alkoxy or heteroalkyl groups in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by a halogen atom, the halogen atoms are the same or different from each other.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino refers to an -NH 2 group.
  • aminoacyl refers to -CO-NH 2.
  • amido or “amido” refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted with one or two alkyl groups, in particular a group -NRR', wherein 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.
  • Dialkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • acyl refers to a monovalent radical remaining after removal of a hydroxyl group by an organic or inorganic oxyacid having the formula R-M(O)-, wherein M is typically C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
  • optional means that one or more of the events described below may or may not occur, and include both events occurring and events not occurring.
  • the term “optionally substituted” or “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl An alkyl group, a heterocycloalkylalkyl group, an aminoacyl group, an amino protecting group, and the like.
  • the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
  • tyrosine protein kinase as used herein is a class of kinases that catalyze the transfer of gamma-phosphate from ATP to a protein tyrosine residue, which catalyzes a variety of substrate protein tyrosine residues. Phosphorylation plays an important role in cell growth, proliferation, and differentiation.
  • the term “inhibiting,” “inhibiting,” or “inhibiting,” a kinase refers to inhibition of phosphotransferase activity.
  • a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
  • the term “metabolized” refers to the sum of the processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • glucosinolate diphosphate 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.
  • modulate refers to interacting directly or indirectly with a target to alter the activity of the target, by way of example only, including enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • target protein refers to a protein molecule or a portion of a protein that can be bound by a selective binding compound.
  • the target protein is a tyrosine kinase PDGFR (including its wild type or various mutations or a combination thereof).
  • GI 50 refers to the concentration of a drug required to inhibit 50% of cell growth, that is, the concentration of a drug when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • IC 50 refers to an amount of a particular test compound to obtain 50% of the maximal effect in the inhibition effect of analytical measurements, concentration or dosage.
  • EC 50 refers to a measured dose, concentration or amount of a compound, at a dose of 50% of maximal expression of the compound to induce, stimulate or enhance a particular reaction assays rely on specific reaction caused.
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides a selective PDGFR kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, 3-7 membered heterocycloalkyl optionally substituted by R 6 , and ring heteroatom optionally R 6 a heteroaryl group substituted with a ring carbon atom optionally substituted by R 7 ;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen
  • R 3 is selected from the group consisting of hydrogen, and halogen
  • R 4 is selected from C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl (C 3 -C 6 cycloalkyl), adamantyl, C 3 -C 6 cycloalkenyl, C 1 -C 4 alkyl (C1 optionally substituted by R 5 ) -C6 alkylamino), R 7 is optionally substituted phenyl, hetero atom is optionally substituted with R 6 and the ring carbon atoms R 7 is optionally substituted heteroaryl, optionally substituted alkyl, and R 5 C1-C4 alkyl (phenyl);
  • R 5 is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
  • R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, and C 2 -C 6 alkanoyl;
  • R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylamino, phenyl, and 3-7 membered heterocyclic ring alkyl.
  • the above 3-7 membered heterocycloalkyl groups are each independently selected from the group consisting of tetrahydrofuranyl, piperidinyl, and morpholinyl.
  • the above heteroaryl groups are each independently selected from the group consisting of pyridyl, pyrrolyl, isoxazolyl, thienyl, oxazolyl, quinolyl, imidazolyl, pyrazolyl, and thiazolyl.
  • R 1 is selected from a C1-C6 alkyl group (e.g., methyl and ethyl), a C2-C6 alkenyl group (e.g., a vinyl group), a ring heteroatom optionally substituted by R 6 and a ring carbon atom a heteroaryl group substituted with R 7 (for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 5-isoxazolyl, 2-thienyl, 3-thienyl, 3- Oxazolyl, 3-quinolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 2-thiazolyl); R 6 is selected from C1-C6 alkyl (eg methyl); R 7 is selected From C1-C6 cyanoalkyl (eg 1-cyanoethyl and 2-cyanopropan-2-yl), C1-C6 haloalkyl (eg trifluoromethyl),
  • R 1 is selected from 3-pyridyl, 2-pyrrolyl, 5-isoxazolyl, 2, wherein the ring heteroatom is optionally substituted by R 6 and the ring carbon atom is optionally substituted by R 7 a thienyl group, a 3-thienyl group, a 3-oxazolyl group, a 3-quinolyl group, and a 4-imidazolyl group; R 6 is selected from a methyl group; and R 7 is selected from a cyclopropyl group and a phenyl group.
  • R 2 is selected from the group consisting of hydrogen, methyl, fluorine, and chlorine. In a further preferred embodiment, R 2 is selected from the group consisting of methyl.
  • R 3 is selected from hydrogen and fluoro, more preferably hydrogen.
  • R 4 is selected from C3-C6 cycloalkyl (eg, cyclobutyl, cyclopentyl, and cyclohexyl), C1-C4 alkyl (C3-C6 cycloalkyl) (eg, cyclopentane) methyl group), adamantyl, optionally substituted phenyl R 7, and R 5 groups are optionally substituted with C1-C4 alkyl (phenyl) (e.g., benzyl); R 5 is selected from C1 -C6 alkyl (e.g. methyl, ethyl and isopropyl), and C1-C6 alkoxy (e.g.
  • R 7 is selected from C1-C6 cyanoalkyl group (e.g., 1-cyanoethyl And 2-cyanopropan-2-yl), C1-C6 haloalkyl (eg trifluoromethyl), C3-C6 cycloalkyl (eg cyclopropyl), C1-C6 alkylamino (eg dimethyl) Amino), and phenyl.
  • C1-C6 cyanoalkyl group e.g., 1-cyanoethyl And 2-cyanopropan-2-yl
  • C1-C6 haloalkyl eg trifluoromethyl
  • C3-C6 cycloalkyl eg cyclopropyl
  • C1-C6 alkylamino eg dimethyl
  • R 4 is selected from the group consisting of cyclopentylmethyl, phenyl optionally substituted by R 7 , and benzyl optionally substituted by R 5 ;
  • R 5 is selected from methoxy;
  • R 7 is selected from the group consisting of 2-cyanopropan-2-yl.
  • Described herein are novel kinase inhibitors.
  • Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
  • the compounds described herein are metabolized in their body to produce a metabolite after administration to a desired organism, and the resulting metabolite is then used to produce the desired effect, including the desired therapeutic effect.
  • the compounds described herein can be made and/or used as pharmaceutically acceptable salts.
  • 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 a pharmaceutically acceptable mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid, metaphosphoric acid, etc.; or the free base form of the compound is formed by reacting with an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, or C.
  • a pharmaceutically acceptable mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid, metaphosphoric acid, etc.
  • an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, or C
  • organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Corresponding counterions of pharmaceutically acceptable salts can be analyzed and characterized using a variety of 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, evaporation of the solvent, or lyophilization using 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, microscopy, elemental analysis.
  • Various spectral 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 present 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 said compound, and pharmaceutically acceptable A carrier or excipient, and optionally other therapeutic agents.
  • the drug comprising a compound of the invention may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration.
  • Other therapeutic agents may be selected from the group consisting of immunosuppressive agents (eg, tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, guanidine, mycophenolate mofetil) Or FTY720), glucocorticoids (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fluorohydroxyprednisolone, chlorinated Rice pine, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylate,
  • rapamycin Herceptin (TM) (trastuzumab), Gleevec (TM) (imatinib mesylate), taxol (TM) (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), arabinose cytidine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole, teniposide, etoposide, Gemzar TM (gemcitabine), epothilone (epothilone), the only promise this, camptothecin, daunorubicin (Daunonibic)
  • the other therapeutic agent may also 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, doxorubicin and 5-fluorouracil), AC (Asia) Deriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Aminopterin, 5-fluorouracil and prednisone).
  • the amount of a given drug when treating a patient in accordance with the present invention depends on a number of factors, such as the particular dosage regimen, the type of disease or disorder and its severity, and the subject in need of treatment. Or the uniqueness of the host (eg, body weight), however, depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be known in the art. The method is routinely decided. Generally, the dosage administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg per day, for dosages used in adult treatment.
  • the desired dose may conveniently be presented as a single dose, or concurrently (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted depending on the condition of the patient and in connection with the diagnosis of the physician.
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or pharmaceutical composition thereof, is capable of selectively inhibiting PDGFR tyrosine kinase (wild type or various mutations or Combination) Activity, in particular PDGFR ⁇ and PDGFR ⁇ activity, more particularly PDGFR ⁇ activity.
  • sarcoma gastrointestinal stromal tumor (Gestintestinal Stromal Tumors, GIST), colorectal cancer, acute myelblastic leukemia (AML), chronic myeloid leukemia (CML), tumor Formation, thyroid carcinoma, systemic mastocytosis, eosinophilia syndrome, chronic eosinophilic leukemia, fibrosis, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Al Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, testicular intraepithelial neoplasia Melanoma, breast cancer, neuroblastoma, papillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin's lymphoma, type 2 multiple endocrine neoplasia, pheochromocytoma, thyroid cancer, parathyroid gland Prolifer
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition thereof may also be used to treat, prevent or ameliorate an autoimmune disease selected from the group consisting of: Arthritis, rheumatoid arthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis Disease, Hashimoto's thyroiditis, Ord's hyroiditis, Graves'disease, Rheumatoid Arthritis Syndrome ( Syndrome), multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, visual ocular palsy-myoclonus syndrome, rigidity Spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Good
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently added by the methods described herein and/or methods known in the art.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of use thereof.
  • the compounds described herein can be synthesized using the protocols synthesized below.
  • Compounds can be synthesized by methods analogous to those described below, using the appropriate starting materials.
  • reaction product can be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and map data.
  • N-(4-methyl-3-(piperidin-4-yloxy)phenyl)benzamide hydrochloride d 0.05 mmol of N-(4-methyl-3-(piperidin-4-yloxy)phenyl)benzamide hydrochloride d, 0.05 mmol of nicotinic acid, 0.1 mmol of N,N-diisopropyl Ethylamine (DIPEA) and 1 ml of N,N-dimethylformamide (DMF) were sequentially added to a 5 ml round bottom flask, and 0.06 mmol of 2-(7-azobenzotriazole) was added under stirring. N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). The reaction system was stirred at room temperature for 2 hours.
  • DIPEA N,N-diisopropyl Ethylamine
  • DMF N,N-dimethylformamide
  • Derivative compound 2-66 of Compound 1 (Table 1) can be prepared separately using the corresponding starting materials and using a synthesis method similar to Compound 1 (see the following scheme).
  • Example 3 Effect of novel kinase inhibitors on cancer cell growth
  • human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFR ⁇ ), rat pulmonary artery smooth muscle cell Rat A-10 (expressing PDGFR ⁇ ) and mouse proB cell BaF3 (purchased from ATCC, USA) were selected.
  • mouse Tel-cKit-BaF3 stable expression of wild-type cKit kinase
  • mouse Tel-PDGFR ⁇ -BaF3 stable expression of PDGFR ⁇ kinase
  • mouse Tel-PDGFR ⁇ -BaF3 stable expression of PDGFR ⁇ kinase
  • Mouse Tel-VEGFR2-BaF3 (stable expression of VEGFR2 kinase), mouse P210-BaF3 (stable expression of BCR-ABL kinase), mouse Tel-FLT3-BaF3 (stably expressed FLT3 kinase).
  • the above cell lines were constructed by our laboratory by PCR amplification of human cKIT, PDGFR ⁇ , PDGFR ⁇ , VEGFR2, BCR-ABL, and FLT3 kinase region sequences, respectively, and inserted into N-terminal TEL fragments and/or NPM.
  • the fragment and/or TPR fragment of MSCV-Puro vector (purchased from Clontech) was stably transferred into mouse BaF3 cells by retrovirus method, and IL-3 growth factor was removed, resulting in cKIT, PDGFR ⁇ , PDGFR ⁇ , VEGFR2.
  • CCK-8 cell viability assay kit purchased from Shanghai Qianyuan Chemical Technology Co., Ltd.
  • CCK-8 can be reduced to a highly water-soluble yellow formazan product by dehydrogenase in living cells, resulting in formazan
  • the number was proportional to the number of viable cells.
  • the cells after the incubation were examined, the number of viable cells was quantified by a microplate reader, and the GI 50 of each compound and the control compound was calculated (the results are shown in Table 3).
  • the compounds of the present invention have strong inhibitory effects on PDGFR ⁇ and PDGFR ⁇ , but have no significant inhibitory or inhibitory effects on cKIT, BCR-ABL, FLT3, VEGFR2, etc., indicating that compared with other targets, compounds of the present invention in significantly lower GI 50 (at least 2 fold, at least 5 fold, at least 10-fold, or at least 100-fold) selectively inhibits the target PDGFR.
  • compounds 4-9, 11, 12, 69, 70 and 78 significantly inhibited the proliferation of human chronic eosinophilic leukemia cell line EOL-1, indicating that these compounds have certain effects on human chronic eosinophilic leukemia. Therapeutic effect.
  • compounds 11, 12, 33, 34, 40-42, and 56 inhibited the proliferation of rat pulmonary artery smooth muscle cells Rat A-10 as well as imatinib or stronger than imatinib, indicating that these compounds are in the pulmonary artery.
  • High pressure has a certain therapeutic effect.
  • Example 4 Experimental results of compound 17 in a mouse model of human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFR ⁇ )
  • EOL-1 expressing PDGFR ⁇
  • ATCC human chronic eosinophilic leukemia cells
  • mice were divided into two groups for administration. One group of mice was intraperitoneally administered with methylcellulose solvent (4 mice); the other group was administered with a dose of 100 mg/kg mouse. Compound 17 (5 mice);
  • mice were sacrificed by carbon dioxide, and the subcutaneous tumors were removed and the tumors were weighed.
  • the experimental results in Figure 1b show that in the mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFR ⁇ ), the group administered with a dose of 100 mg/kg of compound 17 performed very well to inhibit tumor growth in mice. .
  • the 14th day after administration in the mouse model of human chronic eosinophilic leukemia cell EOL-1 (expressing PDGFR ⁇ ) ie, the abscissa "14" in Fig. 1b
  • the tumor inhibition rate [TGI (weight of control tumor - weight of tumor of experimental group) / weight of tumor of control group] was as high as 91.3% (see Fig.
  • the present invention provides a novel PDGFR kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, and the present invention also provides formula (I) Uses and methods of the compounds for preventing or treating disorders associated with PDGFR kinase activity, particularly the use and methods of preventing or treating disorders associated with PDGFR alpha and/or PDGFR beta kinase activity.
  • the above inhibitors can be made into corresponding drugs suitable for industrial applications.

Abstract

L'invention concerne un nouvel inhibiteur du récepteur PDGFR de kinase comprenant un composé de formule (I) ou son sel pharmaceutiquement acceptable, son solvate, son ester, son acide, son métabolite ou son promédicament. L'invention concerne en outre les applications dudit composé de formule (I) pour la prévention ou le traitement de maladies associées à l'activité du récepteur PDGFR de kinase et un procédé connexe, notamment les applications pour la prévention ou le traitement de maladies associées à l'activité du récepteur PDGFR béta de kinase et un procédé connexe.
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WANG Q.: "Discovery of 4-Methyl-N-(4-((4-methylpiperazinlyl) methyl)-3-(trifluoromethyl)phenyl)-3-((1- nicotinoylpiperidin-4-yl)oxy) benza- mide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding", JOURNAL OF MEDICINAL CHEMISTRY, vol. 1, no. 60, 31 December 2017 (2017-12-31), pages 273 - 289, XP055640883, ISSN: 0022-2623 *
WANG Q.: "Discovery of N- (3-((l-Isonicotinoylpiperidin-4-yl) oxy)-4- methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type lie KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs", JOURNAL OF MEDICINAL CHEMISTRY, vol. 8, 31 December 2016 (2016-12-31), pages 3964, XP055428612, ISSN: 0022-2623 *
WANG Q.: "Discovery of N-(3-(1-Isonicotinoylpiperidin-4-yl) oxy)-4- me- thylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs", JOURNAL OF MEDICINAL CHEMISTRY, vol. 8, no. 59, 31 December 2016 (2016-12-31), XP055428612, ISSN: 0022-2623 *

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