WO2019178801A1 - Novel phenoxy piperidine derivative and uses thereof - Google Patents

Novel phenoxy piperidine derivative and uses thereof 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
alkyl
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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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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.

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Abstract

The 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. The invention further provides uses of the compound of formula (I) for preventing or treating diseases related to PDGFR kinase activity, and a related method. The invention also specifically provides uses for preventing or treating diseases related to PDGFRα and/or PDGFRβ kinase activity, and a related method.

Description

一类新型的苯氧基哌啶衍生物及其用途A new class of phenoxy piperidine derivatives and uses thereof 技术领域Technical field
本申请涉及一种作为选择性的PDGFR激酶抑制剂的化合物、以及使用这样的化合物抑制PDGFR激酶活性的方法和用途。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.
背景技术Background technique
血小板衍生生长因子(PDGF)是针对几乎所有间充质源(mesenchyme-derived)细胞的有效促细胞分裂原的家族。有四种PDGF亚型(isoform)——A、B、C和D，它们形成五种不同的通过二硫化物连接的二体蛋白——PDGF-AA、BB、-AB、-CC和DD。这些生长因子通过两种结构相关的酪氨酸激酶受体——PDGF受体α(PDGFRα)和PDGF受体β(PDGFRβ)来发挥其细胞作用(Sandy,J.R.(1998)Br.J.Orthod.25:269-74；Betsholtz,C.等人(2001)BioEssays 23:494-507)。Platelet-derived growth factor (PDGF) 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 (PDGFRα) and PDGF receptor beta (PDGFRβ) (Sandy, JR (1998) Br. J. Orthod. 25: 269-74; Betsholtz, C. et al. (2001) BioEssays 23: 494-507).
PDGFRα与PDGFRβ结构相似，并能形成异源二聚体和同源二聚体。PDGF-BB和PDGF-DD是ββ同源二聚体的主要激活子。PDGF-AA仅活化αα受体二聚体，而PDGF-AB、PDGF-BB和PDGF-CC活化αα和αβ受体二聚体。二聚体配体分子与两种受体蛋白同时结合，并且诱导受体二聚化、受体胞质结构域内的特定残基的自身磷酸化和细胞信号传达。PDGFRα is structurally similar to PDGFRβ and is capable of forming heterodimers and homodimers. PDGF-BB and PDGF-DD are the major activators of the ββ 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.
肺血管构形重建(structural remodeling)是慢性缺氧性肺动脉高压的病理形态学基础，主要表现为中膜平滑肌细胞增殖及迁移，而平滑肌细胞的增殖依赖于多种生长因子的作用，尤其是血小板衍生生长因子(platelet derived growth factor，PDGF)，生长因子的作用是通过与生长因子受体结合，激活受体内酪氨酸蛋白激酶(tyrosine protein kinase，TPK)使其磷酸化而调节细胞的增殖。Schermuly等人在2005年JCI上报道了伊马替尼作为PDGFR抑制剂能够显著改善肺动脉高压的症状(Schermuly,R.T.,et al.2005.Reversal of experimental pulmonary hypertension by PDGF inhibition.J.Clin.Invest.115:2811–2821.doi:10.1172/JCI24838.)，作者还检测了正在进行肺移植的肺动脉高压患者的肺组织，发现在肺动脉高压患者中PDGF表达量显著增加。作者认为PDGFR抑制剂可能是临床中治疗肺动脉高压的新治疗方法。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. . Schermuly et al. reported in JCI in 2005 that imatinib as a PDGFR inhibitor can significantly ameliorate the symptoms of pulmonary hypertension (Schermuly, RT, et al. 2005. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115:2811–2821.doi:10.1172/JCI24838.), the authors also examined the lung tissue of patients with pulmonary hypertension who were undergoing lung transplantation and found a significant increase in PDGF expression in patients with pulmonary hypertension. The authors believe that PDGFR inhibitors may be a new treatment for the treatment of pulmonary hypertension in the clinic.
此外，慢性嗜酸性粒细胞白血病(Chronic eosinophilic leukemia，CEL)是高嗜酸性粒细胞综合征(hypereosinophilic syndrome，HES)的一种，慢性嗜酸性粒细胞白血病是一种少见的、原因不明的嗜酸性粒细胞持续增高并伴有多脏器损害的血液系统疾病，2001年Schaller等首次报道甲磺酸伊马替尼(商品名：格列卫，一种abl、kit及PDGFR酪氨酸激酶小分子抑制剂)治疗1例HES患者，疗效显著，故提出HES可能存在ABL、KIT、PDGFR或其他不明靶基因的固有激活(Schaller,J.L.,&Burkland,G.A.(2001).Case report:rapid and complete control of idiopathic  hypereosinophilia with imatinib mesylate.MedGenMed.,3(5),9)。2003年，Cools等分别在HES患者及体外培养的EOL-1细胞(慢性嗜酸性粒细胞白血病细胞系)中检测到FIP1L1-PDGFRα融合基因，不仅确定了格列卫治疗HES的分子靶，为HES的诊断及治疗提供了有力的分子标志，而且从分子水平揭示HES是一种造血系统恶性克隆性疾病的本质(Cools J.,DeAngelo D.J.,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)。Cools等的研究证明，转录活化因子5(STAT5)是FIP1L1-PDGFRα融合基因作用的下游靶标，STAT5的激活有助于嗜酸粒细胞增殖。In addition, chronic eosinophilic leukemia (CEL) is a type of hypereosinophilic syndrome (HES), a rare, unexplained eosinophilic condition. In the 2001, Schaller et al first reported imatinib mesylate (trade name: Gleevec, a small molecule of abl, kit and PDGFR tyrosine kinase), a granulocyte that continues to increase and is associated with multiple organ damage. Inhibitors) in the treatment of a patient with HES, the effect is significant, it is suggested that HES may have the intrinsic activation of ABL, KIT, PDGFR or other unknown target genes (Schaller, JL, & Burkland, GA (2001). Case report: rapid and complete control of Idiopathic hypereosinophilia with imatinib mesylate. MedGenMed., 3(5), 9). In 2003, Cools et al detected FIP1L1-PDGFRα fusion gene in HES patients and EOL-1 cells (chronic eosinophilic leukemia cell line) cultured in vitro, which not only confirmed the molecular target of GLEW in the treatment of HES, but also HES. 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). Studies by Cools et al. demonstrated that transcriptional activator 5 (STAT5) is a downstream target of the FIP1L1-PDGFRα fusion gene, and activation of STAT5 contributes to eosinophil proliferation.
目前报道的针对PDGFRα和PDGFRβ二者的选择性抑制剂的例子包括CP-673451(CAS号343787-29-1；分子量：417.5)和伊马替尼(CAS号152459-95-5；分子量：493.60)，但选择性均不够好，它们除了对PDGFRα、β有抑制作用外还对cKIT、BCR-ABL等有抑制作用。因此，有必要提供一种选择性的PDGFR抑制剂，以便为精准靶向治疗提供研究基础。Examples of currently reported selective inhibitors against both PDGFRα and PDGFRβ 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 PDGFRα, β, 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.
因此，本发明的发明人经过实验，发现了一种选择性PDGFR抑制剂，该抑制剂对表达趋化因子PDGF-BB及其受体PDGFRβ的大鼠肺动脉平滑肌细胞Rat A-10以及表达FIP1L1-PDGFRα融合基因的慢性嗜酸性粒细胞白血病细胞EOL-1增殖有明显的抑制作用，并且在小鼠用EOL-1细胞肿瘤移植模型中也能够明显抑制肿瘤的生长。Therefore, 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 PDGFRβ. The PDGFRα 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.
发明内容Summary of the invention
本发明提供了一种苯氧基哌啶衍生物，其是一种选择性PDGFR激酶抑制剂。The present invention provides a phenoxy piperidine derivative which is a selective PDGFR kinase inhibitor.
更具体地，本发明提供一种选择性的PDGFR激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：More specifically, 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:
Figure PCTCN2018079991-appb-000001
Figure PCTCN2018079991-appb-000001
其中，among them,
R 1选自C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、环杂原子任选被R 6取代的3-7元杂环烷基、和环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基； 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选自氢、C1-C6烷基、和卤素； R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
R 3选自氢、和卤素； R 3 is selected from the group consisting of hydrogen, and halogen;
R 4选自任选被R 5取代的C3-C6环烷基、C1-C4烷基(C3-C6环烷基)、金刚烷基、 C3-C6环烯基、C1-C4烷基(C1-C6烷基氨基)、任选被R 7取代的苯基、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基、和烷基任选被R 5取代的C1-C4烷基(苯基)； 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独立地选自卤素、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基； R 5 is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
R 6独立地选自C1-C6烷基、和C2-C6烷酰基； R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, and C 2 -C 6 alkanoyl;
R 7独立地选自C1-C6烷基、C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、苯基、和3-7元杂环烷基。 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.
优选地，上述3-7元杂环烷基各自独立地选自四氢呋喃基、哌啶基、和吗啉基。另外优选地，上述杂芳基各自独立地选自吡啶基、吡咯基、异噁唑基、噻吩基、吲唑基、喹啉基、咪唑基、吡唑基、和噻唑基。Preferably, the above 3-7 membered heterocycloalkyl groups are each independently selected from the group consisting of tetrahydrofuranyl, piperidinyl, and morpholinyl. Further preferably, the above heteroaryl groups are each independently selected from the group consisting of pyridyl, pyrrolyl, isoxazolyl, thienyl, oxazolyl, quinolyl, imidazolyl, pyrazolyl, and thiazolyl.
在优选的实施方式中，R 1选自C1-C6烷基、C2-C6烯基、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基；R 6选自C1-C6烷基；R 7选自C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、和苯基。在进一步优选的实施方式中，R 1选自环杂原子任选被R 6取代且环碳原子任选被R 7取代的3-吡啶基、2-吡咯基、5-异噁唑基、2-噻吩基、3-噻吩基、3-吲唑基、3-喹啉基、和4-咪唑基；R 6选自甲基；R 7选自环丙基和苯基。 In a preferred embodiment, 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. In a further preferred embodiment, 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.
在另外优选的实施方式中，R 2选自氢、甲基、氟和氯。在进一步优选的实施方式中，R 2选自甲基。 In another preferred embodiment, 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.
在又一优选的实施方式中，R 3选自氢和氟，且更优选为氢。 In yet another preferred embodiment, R 3 is selected from the group consisting of hydrogen and fluorine, and more preferably hydrogen.
在其它优选的实施方式中，R 4选自C3-C6环烷基、C1-C4烷基(C3-C6环烷基)、金刚烷基、任选被R 7取代的苯基、和烷基任选被R 5取代的C1-C4烷基(苯基)；R 5选自C1-C6烷基、和C1-C6烷氧基；R 7选自C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、和苯基。在进一步优选的实施方式中，R 4选自环戊基甲基、任选被R 7取代的苯基、和烷基任选被R 5取代的苯甲基；R 5选自甲氧基；R 7选自2-氰基丙-2-基。 In other preferred embodiments, 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. In a further preferred embodiment, 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.
本发明还涉及包括以上化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药的药物组合物，以及该化合物或药物组合物抑制酪氨酸激酶(野生型或各种突变或其组合)活性的方法和用途，及其治疗、预防或改善由酪氨酸激酶(野生型或各种突变或其组合)活性调节的或者受其影响的或者其中涉及酪氨酸激酶(野生型或各种突变或其组合)活性的疾病、障碍或病症的方法和用途，其中酪氨酸激酶可以为PDGFR。The present invention also relates to 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.
本发明还涉及相对于靶标cKIT、BCR-ABL、FLT3、VEGFR2中的一种或多种，对PDGFR表现出选择性的更强的抑制作用的酪氨酸激酶抑制剂，以及本发明的酪氨酸激酶抑制剂用于选择性抑制PDGFR的用途和方法。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 The use and method of an acid kinase inhibitor for the selective inhibition of PDGFR.
附图说明DRAWINGS
图1a-1c示出使用化合物17和溶媒对照分别对人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型进行处理得到的实验结果，其中：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:
图1a示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中，不同处理组中的小鼠平均体重(在图中显示为相对体重：以实验开始时的小鼠重量为基准计算的百分数)随时间的变化；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;
图1b示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中，不同处理组中的肿瘤的平均大小(在图中显示为肿瘤相对大小：以实验开始时小鼠荷载的肿瘤大小为基准计算的百分数)随时间的变化；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;
图1c示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中，不同处理组中的小鼠在用药后第14天的平均肿瘤重量和计算出的抑瘤率。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.
具体实施方式detailed description
术语the term
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs, unless otherwise defined.
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。Unless otherwise indicated, 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. Unless otherwise provided, 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. In general, 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.
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。The term "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. It should be understood that "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.
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。The term "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.
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。The term "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. Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group). In the present invention, 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. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
术语“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。The term "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.
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。The term "aryl" means that the planar ring has a delocalized π-electron system and contains 4n+2 π 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. The term "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.
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。The term "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. Depending on the structure, the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。The term "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. Depending on the structure, the heteroaryl group can be a monovalent group or a divalent group (ie, a heteroarylene group). Examples of 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 , naphthyridinyl and furopyridinyl and the like.
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。The term "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.
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。The term "alkyl (heteroaryl)" or "heteroarylalkyl" refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。The term "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.
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷、吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂 环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。The term "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. Examples of 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, Tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1,3-dioxolane, 1 , 3-dithiolelen, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group may be a monovalent group or a divalent group (i.e., a heterocycloalkyl group).
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。The terms "haloalkyl", "haloalkoxy" and "haloheteroalkyl" 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.
术语“羟基”是指-OH基团。The term "hydroxy" refers to an -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to a -CN group.
术语“氨基”是指-NH 2基团。 The term "amino" refers to an -NH 2 group.
术语“氨酰基”是指-CO-NH 2。 The term "aminoacyl" refers to -CO-NH 2.
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。The term "amido" or "amido" refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH 2。“烷基氨基”包括其中-NH 2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH 2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。 The term "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.
术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。The term "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.
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。The term "carbonyl" is an organic functional group (C=O) formed by the bonding of two atoms of carbon and oxygen through a double bond.
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。The term "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.
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。The term "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. Among them, the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
本文使用的术语“酪氨酸激酶(tyrosine protein kinase，TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。The term "tyrosine protein kinase (TPK)" 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.
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。As used herein, the term "inhibiting," "inhibiting," or "inhibiting," a kinase, refers to inhibition of phosphotransferase activity.
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。A "metabolite" of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, 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. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while glucosinolate diphosphate catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill (1996). 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. In some embodiments, the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite. The term "modulate" as used herein, 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.
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋白质分子或部分蛋白质。在某些实施方式中，靶蛋白是酪氨酸激酶PDGFR(包括其野生型或各种突变或其组合)。The term "target protein" as used herein refers to a protein molecule or a portion of a protein that can be bound by a selective binding compound. In certain embodiments, the target protein is a tyrosine kinase PDGFR (including its wild type or various mutations or a combination thereof).
本文使用的GI 50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。 As used herein, 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.
本文使用的IC 50是指在测量效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。 As used herein, 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.
本文使用的EC 50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。 As used herein, 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.
本发明新型的激酶抑制剂Novel kinase inhibitor of the present invention
本发明提供一种选择性的PDGFR激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：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:
Figure PCTCN2018079991-appb-000002
Figure PCTCN2018079991-appb-000002
其中，among them,
R 1选自C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、环杂原子任选被R 6取代的3-7元杂环烷基、和环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基； 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选自氢、C1-C6烷基、和卤素； R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
R 3选自氢、和卤素； R 3 is selected from the group consisting of hydrogen, and halogen;
R 4选自任选被R 5取代的C3-C6环烷基、C1-C4烷基(C3-C6环烷基)、金刚烷基、C3-C6环烯基、C1-C4烷基(C1-C6烷基氨基)、任选被R 7取代的苯基、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基、和烷基任选被R 5取代的C1-C4烷基(苯基)； 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独立地选自卤素、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基； R 5 is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
R 6独立地选自C1-C6烷基、和C2-C6烷酰基； R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, and C 2 -C 6 alkanoyl;
R 7独立地选自C1-C6烷基、C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、苯基、和3-7元杂环烷基。 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.
优选地，上述3-7元杂环烷基各自独立地选自四氢呋喃基、哌啶基、和吗啉基。另外优选地，上述杂芳基各自独立地选自吡啶基、吡咯基、异噁唑基、噻吩基、吲唑基、喹啉基、咪唑基、吡唑基、和噻唑基。Preferably, the above 3-7 membered heterocycloalkyl groups are each independently selected from the group consisting of tetrahydrofuranyl, piperidinyl, and morpholinyl. Further preferably, the above heteroaryl groups are each independently selected from the group consisting of pyridyl, pyrrolyl, isoxazolyl, thienyl, oxazolyl, quinolyl, imidazolyl, pyrazolyl, and thiazolyl.
在优选的实施方式中，R 1选自C1-C6烷基(例如甲基和乙基)、C2-C6烯基(例如乙烯基)、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基(例如2-吡啶基、3-吡啶基、4-吡啶基、2-吡咯基、5-异噁唑基、2-噻吩基、3-噻吩基、3-吲唑基、3-喹啉基、4-咪唑基、5-咪唑基、3-吡唑基、2-噻唑基)；R 6选自C1-C6烷基(例如甲基)；R 7选自C1-C6氰基烷基(例如1-氰基乙基和2-氰基丙-2-基)、C1-C6卤代烷基(例如三氟甲基)、C3-C6环烷基(例如环丙基)、C1-C6烷基氨基(例如二甲基氨基)、和苯基。在进一步优选的实施方式中，R 1选自环杂原子任选被R 6取代且环碳原子任选被R 7取代的3-吡啶基、2-吡咯基、5-异噁唑基、2-噻吩基、3-噻吩基、3-吲唑基、3-喹啉基、和4-咪唑基；R 6选自甲基；R 7选自环丙基和苯基。 In a preferred embodiment, 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), C3-C6 cycloalkyl (eg ring Propyl), a C1-C6 alkylamino group (e.g., dimethylamino), and a phenyl group. In a further preferred embodiment, 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.
在另外优选的实施方式中，R 2选自氢、甲基、氟和氯。在进一步优选的实施方式中，R 2选自甲基。 In another preferred embodiment, 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.
在又一优选的实施方式中，R 3选自 氢和氟，且更优选为氢。 In a further preferred embodiment, R 3 is selected from hydrogen and fluoro, more preferably hydrogen.
在其它优选的实施方式中，R 4选自C3-C6环烷基(例如环丁基、环戊基、和环己基)、C1-C4烷基(C3-C6环烷基)(例如环戊基甲基)、金刚烷基、任选被R 7取代的苯基、和烷基任选被R 5取代的C1-C4烷基(苯基)(例如苯甲基)；R 5选自C1-C6烷基(例如甲基、乙基和异丙基)、和C1-C6烷氧基(例如甲氧基)；R 7选自C1-C6氰基烷基(例如1-氰基乙基、和2-氰基丙-2-基)、C1-C6卤代烷基(例如三氟甲基)、C3-C6环烷基(例如环丙基)、C1-C6烷基氨基(例如二甲基氨基)、和苯基。在进一步优选的实施方式中，R 4选自环戊基甲基、任选被R 7取代的苯基、和烷基任选被R 5取代的苯甲基；R 5选自甲氧基；R 7选自2-氰基丙-2-基。 In other preferred embodiments, 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. methoxy); 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. In a further preferred embodiment, 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.
对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。Any combination of the above groups is also contemplated herein for each variable. It will be appreciated that the substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide compounds that are chemically stable and that can be synthesized using techniques known in the art and the techniques set forth herein.
本文描述的是新型的激酶抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。Described herein are novel kinase inhibitors. Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
在另外的或近一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。In additional or further embodiments, 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.
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐，其通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或将化合物的游离碱形式与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺，等等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。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. Diacid, malic acid, citric 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, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene- 1-carboxylic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid , trimethylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) base addition salts, which are in the parent compound Acidic protons are gold Forming ion substitution, for example, an alkali metal ion (e.g. lithium, sodium, potassium), alkaline earth metal ions (e.g. magnesium or calcium), or an aluminum ion; or with organic base ligands. Acceptable 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.
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。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.
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。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.
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。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.
本发明的药物组合物Pharmaceutical composition of the invention
本申请还提供药物组合物，其包含至少一种式(I)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前药，以及药学可接受的 载体或赋形剂，以及任选的其它治疗剂。The present application also provides 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.
在治疗过程中，可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物：免疫抑制剂(例如他克莫司、环孢菌素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如泼尼松、醋酸可的松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、氟羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、变态反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外，所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀 TM(曲妥珠单抗)、格列卫 TM(甲磺酸伊马替尼)、紫杉醇 TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔 TM(多西他赛)、诺雷德 TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择 TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者，其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者，其它治疗剂也可以是，例如但不限于，CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和泼尼松)。 During treatment, it may be used alone or in combination with one or more other therapeutic agents, as appropriate. 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, aryl alkanoic acid, 2-arylpropionic acid, N-aryl anthranilic acid) , oxicam, oxicam or thioanilide, allergy vaccine, antihistamine, anti-leukotriene, beta-agonist, theophylline, anticholinergic or other selective kinase inhibitors (eg mTOR inhibition) Agent, c-Met inhibitor) or her2 antibody-drug. In addition, other therapeutic agents mentioned may also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole. , 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 (Daunonibicin), dactinomycin, meters Toxic, ampicillin, doxorubicin (adriamycin), epirubicin or idarubicin. Alternatively, the other therapeutic agent may also be a cytokine such as G-CSF (granulocyte colony stimulating factor). Alternatively, 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).
在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。In an embodiment of the invention, 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.
本发明的药物的用途Use of the medicament of the present invention
式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或药物组合物能够选择性地抑制PDGFR酪氨酸激酶(野生型或各种突变或其组合) 活性，特别是PDGFRα和PDGFRβ活性，更特别是PDGFRα活性。式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或其药物组合物可用于治疗、预防或改善一种或多种由PDGFR(特别是PDGFRα和PDGFRβ)活性调节的或者受其影响的或者其中涉及PDGFR(特别是PDGFRα和PDGFRβ)活性的疾病、障碍或病症，例如选自下组的疾病：肺动脉高压、实体瘤(包括良性或者恶性类型)、肉瘤、胃肠道间质瘤(Gastrointestinal Stromal Tumors，GIST)、结直肠癌(colon cancer)、急性粒细胞白血病(Acute Myeloblastic Leukemia，AML)、慢性髓性白血病(Chronic Myelogenous Leukemia,CML)、瘤形成、甲状腺癌(thyroid carcinoma)、系统性肥大细胞病、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳腺癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、以及其他增生性或增殖性疾病或类似疾病、或其组合。特别优选治疗肺动脉高压、慢性嗜酸性粒细胞白血病、或类似疾病、或其组合。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 PDGFRα and PDGFRβ activity, more particularly PDGFRα activity. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition thereof, for use in the treatment, prevention or amelioration of one or more of PDGFR (particularly PDGFRα) And a disease, disorder or condition which is modulated by or affected by PDGFRβ activity or which involves PDGFR (particularly PDGFRα and PDGFRβ) activity, for example, a disease selected from the group consisting of pulmonary hypertension, solid tumors (including benign or malignant types). , 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 Proliferative/adenomas, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma , kidney cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, cervical and head tumors, and other proliferative or proliferative diseases or the like Or a combination thereof. Particular preference is given to the treatment of pulmonary hypertension, chronic eosinophilic leukemia, or a similar disease, or a combination thereof.
式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或其药物组合物还可用于治疗、预防或改善选自下组的自身免疫性疾病：关节炎、风湿性关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病(Still's disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto's thyroiditis)、奥德甲状腺炎(Ord's hyroiditis)、格雷夫斯病(Graves'disease)、类风湿性关节炎综合征(
Figure PCTCN2018079991-appb-000003
syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barré syndrome)、急性播散性脑脊髓炎、阿狄森病(Addison's disease)、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture's syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter's syndrome)、高安动脉炎(Takayasu's arteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener's granulomatosis)、银屑病、全身脱毛、贝赫切特病(Behcet's disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛或其组合。 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 (
Figure PCTCN2018079991-appb-000003
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, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, Scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis (Wegener's Granulomatosis), psoriasis, generalized hair removal, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular rigidity, scleroderma, Vulvar pain or a combination thereof.
化合物的制备Preparation of compounds
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描 述的方法组合，可以合成式(I)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。Compounds of formula (I) can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. Additionally, the solvents, temperatures, and other reaction conditions presented herein can vary depending on the skill of the art. As a further guide, the following synthesis methods can also be utilized.
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。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.
在某些实施方式中，本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。In certain embodiments, provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of use thereof. In certain embodiments, 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.
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。Starting materials for the synthesis of the compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and starting materials known to those skilled in the art. The general methods of preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified to introduce various moieties in the molecules provided herein by reagents and conditions deemed appropriate by those skilled in the art.
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。If desired, the 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.
实施例1：N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)苯甲酰胺1的合成Example 1: Synthesis of N-(4-methyl-3-(1-nicotinoylpiperidin-4-yloxy)phenyl)benzamide 1
Figure PCTCN2018079991-appb-000004
Figure PCTCN2018079991-appb-000004
4-(2-甲基-5-硝基苯氧基)哌啶-1-羧酸叔丁酯a的合成Synthesis of 4-(2-methyl-5-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester a
将5mmol 2-甲基-5-硝基苯酚、6mmol 1-叔丁氧羰基-4-甲烷磺酰氧基哌啶以及10mmol无水碳酸钾分别依次加入15毫升无水的N,N-二甲基甲酰胺(DMF)中。反应体系于80摄氏度反应过夜，冷却至室温，反应体系用乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥。旋转蒸发仪除去溶剂，粗产品用硅胶色谱柱分离得产品4-(2-甲基-5-硝基苯氧基)哌啶-1-羧酸叔丁酯a(产率：89％)。Exact Mass(计算值):336.17；MS(ESI)m/z(M+Na)+:359.20。5 mmol of 2-methyl-5-nitrophenol, 6 mmol of 1-tert-butoxycarbonyl-4-methanesulfonyloxypiperidine and 10 mmol of anhydrous potassium carbonate were sequentially added to 15 ml of anhydrous N,N-dimethyl Carboxamide (DMF). The reaction was allowed to react at 80 ° C overnight, cooled to room temperature, and then extracted with ethyl acetate. The solvent was removed by a rotary evaporator, and the crude product was separated to silica gel column to give 4-(2-methyl-5-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (yield: 89%). Exact Mass (calc.): 336.17; MS (ESI) m/z (M+Na)+: 359.20.
4-(2-甲基-5-氨基苯氧基)哌啶-1-羧酸叔丁酯b的合成Synthesis of 4-(2-methyl-5-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester b
将4mmol 4-(2-甲基-5-硝基苯氧基)哌啶-1-羧酸叔丁酯a溶解于20毫升乙酸乙酯中，然后加入0.05当量的Pd/C(10％)。体系于一个大气压氢气环境下反应6小时。反应体系用硅藻土过滤，收集滤液并除去溶剂得产品4-(2-甲基-5-氨基苯氧基)哌啶-1-羧酸叔丁酯b(产率：96％)。Exact Mass(计算值):306.19；MS(ESI)m/z(M+Na)+:329.23。4 mmol of tert-butyl 4-(2-methyl-5-nitrophenoxy)piperidine-1-carboxylate was dissolved in 20 ml of ethyl acetate, then 0.05 equivalent of Pd/C (10%) was added. . The system was reacted for 6 hours in a hydrogen atmosphere at atmospheric pressure. The reaction system was filtered through celite, and the filtrate was collected and solvent was evaporated to give the product 4-(2-methyl-5-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester b (yield: 96%). Exact Mass (calc.): 306.19; MS (ESI) m/z (M+Na)+: 329.23.
4-(5-苯甲酰胺基-2-甲基苯氧基)哌啶-1-羧酸叔丁酯c的合成Synthesis of 4-(5-benzamide-2-methylphenoxy)piperidine-1-carboxylic acid tert-butyl ester c
将5mmol的4-(2-甲基-5-氨基苯氧基)哌啶-1-羧酸叔丁酯b、5mmol苯甲酸、10mmol N,N-二异丙基乙胺(DIPEA)以及15毫升N,N-二甲基甲酰胺(DMF)依次加入50毫升的圆底烧瓶，搅拌状态下加入6mmol的2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。反应体系于室温搅拌反应2小时。乙酸乙酯萃取反应体系，无水硫酸钠干燥；旋转蒸发仪除去溶剂，粗产品用硅胶色谱柱分离得产品4-(5-苯甲酰胺基-2-甲基苯氧基)哌啶-1-羧酸叔丁酯c(产率：78％)。Exact Mass(计算值):410.22；MS(ESI)m/z(M+H)+:411.22。5 mmol of tert-butyl 4-(2-methyl-5-aminophenoxy)piperidine-1-carboxylate b, 5 mmol of benzoic acid, 10 mmol of N,N-diisopropylethylamine (DIPEA) and 15 ML N,N-dimethylformamide (DMF) was added to a 50 ml round bottom flask in turn, and 6 mmol of 2-(7-azobenzotriazole)-N,N,N',N was added with stirring. '-Tetramethylurea hexafluorophosphate (HATU). The reaction system was stirred at room temperature for 2 hours. The reaction system was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed on a rotary evaporator, and the crude product was separated on silica gel column to give 4-(5-benzamide-2-methylphenoxy)piperidine-1 - tert-butyl carboxylate c (yield: 78%). Exact Mass (calc.): 410.22; MS (ESI) m/z (M+H)+: 41.22.
N-(4-甲基-3-(哌啶-4-基氧基)苯基)苯甲酰胺盐酸盐d的合成Synthesis of N-(4-methyl-3-(piperidin-4-yloxy)phenyl)benzamide hydrochloride d
将3mmol 4-(5-苯甲酰胺基-2-甲基苯氧基)哌啶-1-羧酸叔丁酯c于25mL圆底烧瓶中加入20mL的4N盐酸乙酸乙酯溶液并在室温搅拌5h，抽滤得固体并用乙酸乙酯洗涤，然后干燥得产品N-(4-甲基-3-(哌啶-4-基氧基)苯基)苯甲酰胺盐酸盐d(产率：79％)。Exact Mass(计算值):310.16；MS(ESI)m/z(M+H)+:311.63。Add 3 mmol of 4-(5-benzamide-2-methylphenoxy)piperidine-1-carboxylic acid tert-butyl ester c to a 25 mL round bottom flask, add 20 mL of 4N hydrochloric acid ethyl acetate solution and stir at room temperature. After 5 h, a solid was obtained by suction filtration and washed with ethyl acetate and then dried to give the product N-(4-methyl-3-(piperidin-4-yloxy)phenyl)benzamide hydrochloride d (yield: 79%). Exact Mass (calculated value): 310.16; MS (ESI) m/z (M+H)+: 311.63.
N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)苯甲酰胺1的合成Synthesis of N-(4-methyl-3-(1-nicotinoylpiperidin-4-yloxy)phenyl)benzamide 1
将0.05mmol的N-(4-甲基-3-(哌啶-4-基氧基)苯基)苯甲酰胺盐酸盐d、0.05mmol烟酸、0.1mmol N,N-二异丙基乙胺(DIPEA)以及1毫升N,N-二甲基甲酰胺(DMF)依次加入5毫升的圆底烧瓶，搅拌状态下加入0.06mmol的2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。反应体系于室温搅拌反应2小时。乙酸乙酯萃取反应体系，无水硫酸钠干燥；旋转蒸发仪除去溶剂，粗产品用硅胶色谱柱分离得产品N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)苯甲酰胺1(产率：76％)。Exact Mass(计算值):415.19；MS(ESI)m/z(M+H)+:416.19。1H NMR(400MHz,d6-DMSO)δ10.16(s,1H),8.67(s,2H),7.94-7.89(m,3H),7.59-7.49(m,5H),7.31(s,1H),7.13(d,J＝7.3Hz,1H),4.61(s,1H),3.87(s,1H),3.70-3.55(m,2H),3.34(s,1H),2.18(s,3H),2.02(s,2H),1.79(s,2H)。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. The reaction system was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed on a rotary evaporator, and the crude product was separated on silica gel column to obtain product N-(4-methyl-3-(1-nicotinoylpiperidine-4-yloxy) Phenyl)benzamide 1 (yield: 76%). Exact Mass (calculated): 415.19; MS (ESI) m/z (M+H)+: 416.19. 1H NMR (400 MHz, d6-DMSO) δ 10.16 (s, 1H), 8.67 (s, 2H), 7.94-7.89 (m, 3H), 7.59-7.49 (m, 5H), 7.31 (s, 1H), 7.13 (d, J = 7.3 Hz, 1H), 4.61 (s, 1H), 3.87 (s, 1H) , 3.70-3.55 (m, 2H), 3.34 (s, 1H), 2.18 (s, 3H), 2.02 (s, 2H), 1.79 (s, 2H).
化合物2-化合物66的合成：Synthesis of Compound 2 - Compound 66:
以相应的起始原料，并采用类似于化合物1合成方法(见以下反应路线)，可以分别制备出化合物1的衍生化合物2-66(表1)。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).
Figure PCTCN2018079991-appb-000005
Figure PCTCN2018079991-appb-000005
表1.化合物1-66的结构、化合物名称以及表征数据。Table 1. Structure, compound name and characterization data for compounds 1-66.
Figure PCTCN2018079991-appb-000006
Figure PCTCN2018079991-appb-000006
Figure PCTCN2018079991-appb-000007
Figure PCTCN2018079991-appb-000007
Figure PCTCN2018079991-appb-000008
Figure PCTCN2018079991-appb-000008
Figure PCTCN2018079991-appb-000009
Figure PCTCN2018079991-appb-000009
Figure PCTCN2018079991-appb-000010
Figure PCTCN2018079991-appb-000010
Figure PCTCN2018079991-appb-000011
Figure PCTCN2018079991-appb-000011
Figure PCTCN2018079991-appb-000012
Figure PCTCN2018079991-appb-000012
Figure PCTCN2018079991-appb-000013
Figure PCTCN2018079991-appb-000013
Figure PCTCN2018079991-appb-000014
Figure PCTCN2018079991-appb-000014
Figure PCTCN2018079991-appb-000015
Figure PCTCN2018079991-appb-000015
实施例2：N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)-4-吗啉代苯甲酰胺67的合成Example 2: Synthesis of N-(4-methyl-3-(1-nicotinopiperidin-4-yloxy)phenyl)-4-morpholinobenzamide 67
Figure PCTCN2018079991-appb-000016
Figure PCTCN2018079991-appb-000016
4-(2-甲基-5-硝基苯氧基)哌啶盐酸盐e的合成Synthesis of 4-(2-methyl-5-nitrophenoxy)piperidine hydrochloride e
将3mmol 4-(2-甲基-5-硝基苯氧基)哌啶-1-羧酸叔丁酯a于25mL圆底烧瓶中加入20mL的4N盐酸乙酸乙酯溶液并在室温搅拌5h，抽滤得固体并用乙酸乙酯洗涤，然后干燥得产品4-(2-甲基-5-硝基苯氧基)哌啶盐酸盐e(产率：76％)。Exact Mass(计算值):236.12；MS(ESI)m/z(M+H) +:237.12。 3 mmol of 4-(2-methyl-5-nitrophenoxy)piperidine-l-carboxylic acid tert-butyl ester a was added to a 25 mL round-bottomed flask to 20 mL of 4N hydrochloric acid ethyl acetate and stirred at room temperature for 5 h. The solid was suction filtered, washed with ethyl acetate, and then dried to ethyl 4-(2-methyl-5-nitrophenoxy)piperidine hydrochloride (yield: 76%). Exact Mass (calc.): 236.12; MS (ESI) m/z (M+H) + : 237.12.
(4-(2-甲基-5-硝基苯氧基)哌啶-1-基)吡啶-3-基)甲酮f的合成Synthesis of (4-(2-methyl-5-nitrophenoxy)piperidin-1-yl)pyridin-3-yl)methanone f
将2mmol的4-(2-甲基-5-硝基苯氧基)哌啶盐酸盐e、2mmol烟酸、3mmol N,N-二异丙基乙胺(DIPEA)以及6毫升N,N-二甲基甲酰胺(DMF)依次加入25毫升的圆底烧瓶，搅拌状态下加入2.4mmol的2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。反应体系于室温搅拌反应2小时。乙酸乙酯萃取反应体系，无水硫酸钠干燥；旋转蒸发仪除去溶剂，粗产品用硅胶色谱柱分离得产品(4-(2-甲基-5-硝基苯氧基)哌啶-1-基)吡啶-3-基)甲酮f(产率：82％)。Exact Mass(计算值):341.14；MS(ESI)m/z(M+H) +:342.14。 2 mmol of 4-(2-methyl-5-nitrophenoxy)piperidine hydrochloride e, 2 mmol of nicotinic acid, 3 mmol of N,N-diisopropylethylamine (DIPEA) and 6 ml of N,N -Dimethylformamide (DMF) was added to a 25 ml round bottom flask in turn, and 2.4 mmol of 2-(7-azobenzotriazole)-N,N,N',N'-four was added with stirring. Methylurea hexafluorophosphate (HATU). The reaction system was stirred at room temperature for 2 hours. The reaction system was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed on a rotary evaporator, and the crude product was separated by silica gel chromatography (4-(2-methyl-5-nitrophenoxy)piperidine-1- Base pyridin-3-yl)methanone f (yield: 82%). Exact Mass (calc.): 341.14; MS (ESI) m/z (M+H) + : 342.14.
(4-(5-氨基-2-甲基苯氧基)哌啶-1-基)(吡啶-3-基)甲酮g的合成Synthesis of (4-(5-Amino-2-methylphenoxy)piperidin-1-yl)(pyridin-3-yl)methanone g
将1mmol(4-(2-甲基-5-硝基苯氧基)哌啶-1-基)吡啶-3-基)甲酮f溶解于5毫升乙酸乙酯中，然后加入0.05当量的Pd/C(10％)。体系于一个大气压氢气环境下反应6小时。反应体系用硅藻土过滤，收集滤液并除去溶剂得产品(4-(5-氨基-2-甲基苯氧基)哌啶-1-基)(吡啶-3-基)甲酮g(产率：95％)。Exact Mass(计算值):311.16；MS(ESI)m/z(M+H) +:312.16。 1 mmol of (4-(2-methyl-5-nitrophenoxy)piperidin-1-yl)pyridin-3-yl)methanone f was dissolved in 5 ml of ethyl acetate, then 0.05 equivalent of Pd was added. /C (10%). The system was reacted for 6 hours in a hydrogen atmosphere at atmospheric pressure. The reaction system was filtered through celite, and the filtrate was collected to remove the solvent to give the product (4-(5-amino-2-methylphenoxy)piperidin-1-yl)(pyridin-3-yl)methanone g. Rate: 95%). Exact Mass (calc.): 311.16; MS (ESI) m/z (M+H) + : 312.16.
N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)-4-吗啉代苯甲酰胺67的合成。Synthesis of N-(4-methyl-3-(1-nicotinopiperidin-4-yloxy)phenyl)-4-morpholinobenzamide 67.
将0.05mmol的(4-(5-氨基-2-甲基苯氧基)哌啶-1-基)(吡啶-3-基)甲酮g、0.05mmol 4-吗啉苯甲酸、0.1mmol N,N-二异丙基乙胺(DIPEA)以及1毫升N,N-二甲基甲酰胺(DMF)依次加入5毫升的圆底烧瓶，搅拌状态下加入0.06mmol 的2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。反应体系于室温搅拌反应2小时。乙酸乙酯萃取反应体系，无水硫酸钠干燥；旋转蒸发仪除去溶剂，粗产品用硅胶色谱柱分离得产品N-(4-甲基-3-(1-烟酰基哌啶-4-基氧基)苯基)-4-吗啉代苯甲酰胺67(产率：63％)。Exact Mass(计算值):500.24；MS(ESI)m/z(M+1) +:501.24。 0.05 mmol of (4-(5-amino-2-methylphenoxy)piperidin-1-yl)(pyridin-3-yl)methanone g, 0.05 mmol of 4-morpholinebenzoic acid, 0.1 mmol N , N-diisopropylethylamine (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-azo) was added with stirring. Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). The reaction system was stirred at room temperature for 2 hours. The reaction system was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed on a rotary evaporator, and the crude product was separated on silica gel column to obtain product N-(4-methyl-3-(1-nicotinoylpiperidine-4-yloxy) Phenyl)-4-morpholinobenzamide 67 (yield: 63%). Exact Mass (calculated): 500.24; MS (ESI) m/z (M+1) + : 501.24.
化合物68-79的合成：Synthesis of Compound 68-79:
以相应的羧酸化合物与化合物g(4-(5-氨基-2-甲基苯氧基)哌啶-1-基)(吡啶-3-基)甲酮作为起始原料，并采用类似于实施例2中化合物67的合成方法，可以分别制备出化合物68-79。Taking the corresponding carboxylic acid compound and the compound g(4-(5-amino-2-methylphenoxy)piperidin-1-yl)(pyridin-3-yl)methanone as starting materials, and adopting similar For the synthesis of compound 67 in Example 2, compounds 68-79 can be prepared separately.
表2.化合物67-79结构、化合物名称以及表征数据。Table 2. Structure 67-79 structure, compound name, and characterization data.
Figure PCTCN2018079991-appb-000017
Figure PCTCN2018079991-appb-000017
Figure PCTCN2018079991-appb-000018
Figure PCTCN2018079991-appb-000018
Figure PCTCN2018079991-appb-000019
Figure PCTCN2018079991-appb-000019
实施例3：新型激酶抑制剂对癌细胞生长的影响Example 3: Effect of novel kinase inhibitors on cancer cell growth
通过测试本发明的化合物作为抑制剂对癌细胞增殖的影响，我们对本发明的化合物在癌细胞增殖抑制试验中的活性和选择性进行了评估，并以伊马替尼(购自上海皓元化学科技有限公司，中国上海)作为参照。By testing the effects of the compounds of the invention as inhibitors on cancer cell proliferation, we evaluated the activity and selectivity of the compounds of the invention in cancer cell proliferation inhibition assays, and imatinib (purchased from Shanghai Qianyuan Chemical) Technology Co., Ltd., Shanghai, China) as a reference.
本实施例选用了在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、大鼠肺动脉平滑肌细胞Rat A-10(表达PDGFRβ)及小鼠原B细胞BaF3(购自ATCC，美国)。此外，本实施例还选用了小鼠Tel-cKit-BaF3(稳定表达野生型cKit激酶)、小鼠Tel-PDGFRα-BaF3(稳定表达PDGFRα激酶)、小鼠Tel-PDGFRβ-BaF3(稳定表达PDGFRβ激酶)、小鼠Tel-VEGFR2-BaF3(稳定表达VEGFR2激酶)、小鼠P210-BaF3(稳定表达BCR-ABL激酶)、小鼠Tel-FLT3-BaF3(稳定表达FLT3激酶)。上述细胞株均由本实验室构建，构建方法为：经PCR分别扩增人类cKIT、PDGFRα、PDGFRβ、VEGFR2、BCR-ABL、FLT3激酶区序列，并分别插入到带有N端TEL片段和/或NPM片段和/或TPR片段的MSCV-Puro载体(购自Clontech)，通过逆转录病毒方法，稳定转入小鼠BaF3细胞，并且撤除IL-3生长因子，最终得到依赖cKIT、PDGFRα、PDGFRβ、VEGFR2、BCR-ABL、FLT3转入蛋白的细胞系。In this example, human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFRα), rat pulmonary artery smooth muscle cell Rat A-10 (expressing PDGFRβ) and mouse proB cell BaF3 (purchased from ATCC, USA) were selected. In addition, in this example, mouse Tel-cKit-BaF3 (stable expression of wild-type cKit kinase), mouse Tel-PDGFRα-BaF3 (stable expression of PDGFRα kinase), and mouse Tel-PDGFRβ-BaF3 (stable expression of PDGFRβ kinase) were also selected. ) 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, PDGFRα, PDGFRβ, 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, PDGFRα, PDGFRβ, VEGFR2. BCR-ABL, FLT3 transfected into cell lines.
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM)的本发明化合物及对照化合物伊马替尼分别加入到上述细胞中(对于Rat A-10细胞需要先用PDGFR-BB(购自美国R&D，货号520-BB)和1％的培养基刺激4小时然后按照上述浓度给药)，并孵育72小时，通过CCK-8细胞活力检测试剂盒(购自上海皓元化学科技有限公司)(CCK-8可被活细胞中的脱氢酶还原为具有高度水溶性的黄色甲瓒产物，生成的甲瓒物数量与活细胞的数量成正比)对孵育后的细胞进行检测，通过酶标仪对活细胞的数目进行定量，并计算各个化合物和对照化合物的GI 50(结果示于表3)。 In the examples, different concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM) of the compound of the present invention and the control compound imatinib were separately added. To the above cells (for Rat A-10 cells, first use PDGFR-BB (purchased from R&D, USA, Cat. No. 520-BB) and 1% medium for 4 hours and then according to the above concentration), and incubate for 72 hours. 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).
结果显示，本发明的化合物对PDGFRα和PDGFRβ均有很强的抑制作用，而 对cKIT、BCR-ABL、FLT3、VEGFR2等没有明显的抑制作用或抑制作用明显较弱，这表明相对于其他靶标，本发明的化合物以显著更低的GI 50(低至少2倍、至少5倍、至少10倍或者至少100倍)选择性地抑制靶标PDGFR。其中化合物4-9、11、12、69、70和78对人慢性嗜酸性粒细胞白血病细胞EOL-1的增殖有明显的抑制作用，这说明这些化合物对人慢性嗜酸性粒细胞白血病有一定的治疗作用。此外，化合物11、12、33、34、40-42和56对大鼠肺动脉平滑肌细胞Rat A-10增殖的抑制作用与伊马替尼相当或者要强于伊马替尼，这表明这些化合物对肺动脉高压有一定的治疗作用。 The results showed that the compounds of the present invention have strong inhibitory effects on PDGFRα and PDGFRβ, 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. Among them, 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. In addition, 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.
表3.不同的抑制剂对癌细胞生长的影响(结果示为GI 50值，单位为μM) Table 3. Effects of different inhibitors on cancer cell growth (result shown as GI 50 value, in units of [mu] M)
Figure PCTCN2018079991-appb-000020
Figure PCTCN2018079991-appb-000020
Figure PCTCN2018079991-appb-000021
Figure PCTCN2018079991-appb-000021
Figure PCTCN2018079991-appb-000022
Figure PCTCN2018079991-appb-000022
表3(续).不同的抑制剂对癌细胞生长的影响(结果示为GI 50值，单位为μM) Table 3 (continued). Effect of different inhibitors on cancer cell growth (results shown as GI 50 values in μM)
Figure PCTCN2018079991-appb-000023
Figure PCTCN2018079991-appb-000023
Figure PCTCN2018079991-appb-000024
Figure PCTCN2018079991-appb-000024
Figure PCTCN2018079991-appb-000025
Figure PCTCN2018079991-appb-000025
实施例4：化合物17在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)小鼠模型中的实验结果Example 4: Experimental results of compound 17 in a mouse model of human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFRα)
1.从上海斯莱克实验动物有限责任公司购买饲养4-6周龄的Bal b/c雌性小鼠，饲养于SPF级实验室中，饮水及垫料均经高压消毒无菌处理，有关小鼠的所有操作均在无菌条件下进行；1. Purchase 4 to 6 weeks old Bal b/c female mice from Shanghai Slack Laboratory Animals Co., Ltd., and store them in SPF-level laboratory. The drinking water and litter are aseptically treated by autoclaving. All operations are carried out under aseptic conditions;
2.第0天分别在所有小鼠左侧背部皮下注入约1×10 7个人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)(购自ATCC)； 2. On day 0, approximately 1×10 7 human chronic eosinophilic leukemia cells EOL-1 (expressing PDGFRα) (purchased from ATCC) were injected subcutaneously into the left side of all mice.
3.将小鼠分为两组分别进行给药，对其中一组小鼠腹腔给药甲基纤维素溶媒(4只小鼠)；对另一组小鼠施用剂量为100mg/kg鼠重的化合物17(5只小鼠)；3. The 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);
4.第15天开始，每天用游标卡尺测量皮下肿瘤的长/宽，并每天记录小鼠体 重，确定化合物17对小鼠体重的影响；4. On the 15th day, the length/width of the subcutaneous tumor was measured with a vernier caliper every day, and the body weight of the mouse was recorded every day to determine the effect of Compound 17 on the body weight of the mice;
5.第29天，二氧化碳处死小鼠，取出皮下肿瘤，将肿瘤称重比较；5. On day 29, the mice were sacrificed by carbon dioxide, and the subcutaneous tumors were removed and the tumors were weighed.
6.统计15-29天内皮下肿瘤生长趋势，肿瘤体积计算方法：长×宽×宽/2mm 3。 6. Count the trend of subcutaneous tumor growth within 15-29 days, and calculate the tumor volume: length × width × width / 2 mm 3 .
图1b的实验结果显示，在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)的小鼠肿瘤模型中，给药剂量为100mg/kg化合物17的小组表现非常好的抑制小鼠肿瘤效果。对于该化合物17给药剂量为100mg/kg的小组，在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)小鼠模型中用药后第14天(即图1b中横坐标“14”处)的抑瘤率【TGI＝(对照组肿瘤的重量-实验组肿瘤的重量)/对照组肿瘤的重量】高达91.3％(见图1c)，这说明本发明的化合物17在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)动物模型中能够明显抑制肿瘤的生长。另外，图1a的结果还表明，化合物17不仅有效地抑制小鼠肿瘤的生长，并且对小鼠的体重基本没有影响，表明化合物17可适用于动物给药。The experimental results in Figure 1b show that in the mouse tumor model of human chronic eosinophilic leukemia cell line EOL-1 (expressing PDGFRα), the group administered with a dose of 100 mg/kg of compound 17 performed very well to inhibit tumor growth in mice. . For the group in which the compound 17 was administered at a dose of 100 mg/kg, the 14th day after administration in the mouse model of human chronic eosinophilic leukemia cell EOL-1 (expressing PDGFRα) (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. 1c), which indicates that compound 17 of the present invention is in human chronic eosinophilic granules. In the animal model of cell leukemia cell EOL-1 (expressing PDGFRα), tumor growth can be significantly inhibited. In addition, the results of Figure 1a also show that Compound 17 not only effectively inhibited the growth of mouse tumors, but also had little effect on the body weight of mice, indicating that Compound 17 is suitable for animal administration.
工业应用性Industrial applicability
本发明提供一种新型的PDGFR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、或前药，本发明还提供式(I)的化合物用于预防或治疗与PDGFR激酶活性相关的病症的用途和方法，特别是预防或治疗与PDGFRα和/或PDGFRβ激酶活性相关的病症的用途和方法。因而，可将上述抑制剂制成相应的药物，适于工业应用。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. Thus, the above inhibitors can be made into corresponding drugs suitable for industrial applications.
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。Although the present invention has been described in detail herein, the present invention is not limited thereto, and those skilled in the art can make modifications in accordance with the principles of the present invention. Therefore, various modifications in accordance with the principles of the present invention should be understood as falling within The scope of protection of the present invention.

Claims (20)

  1. 一种PDGFR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、代谢物或前药：A PDGFR kinase inhibitor comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
    Figure PCTCN2018079991-appb-100001
    Figure PCTCN2018079991-appb-100001
    其中，among them,
    R 1选自C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、环杂原子任选被R 6取代的3-7元杂环烷基、和环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基； 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选自氢、C1-C6烷基、和卤素； R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
    R 3选自氢、和卤素； R 3 is selected from the group consisting of hydrogen, and halogen;
    R 4选自任选被R 5取代的C3-C6环烷基、C1-C4烷基(C3-C6环烷基)、金刚烷基、C3-C6环烯基、C1-C4烷基(C1-C6烷基氨基)、任选被R 7取代的苯基、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基、和烷基任选被R 5取代的C1-C4烷基(苯基)； 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独立地选自卤素、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基； R 5 is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
    R 6独立地选自C1-C6烷基、和C2-C6烷酰基； R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, and C 2 -C 6 alkanoyl;
    R 7独立地选自C1-C6烷基、C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、苯基、和3-7元杂环烷基。 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.
  2. 如权利要求1所述的PDGFR激酶抑制剂，其中所述3-7元杂环烷基各自独立地选自四氢呋喃基、哌啶基、和吗啉基；所述杂芳基各自独立地选自吡啶基、吡咯基、异噁唑基、噻吩基、吲唑基、喹啉基、咪唑基、吡唑基、和噻唑基。The PDGFR kinase inhibitor according to claim 1, wherein the 3-7 membered heterocycloalkyl group is each independently selected from the group consisting of tetrahydrofuranyl, piperidinyl, and morpholinyl; the heteroaryl groups are each independently selected from Pyridyl, pyrrolyl, isoxazolyl, thienyl, oxazolyl, quinolyl, imidazolyl, pyrazolyl, and thiazolyl.
  3. 如权利要求1或2所述的PDGFR激酶抑制剂，其中R 1选自C1-C6烷基、C2-C6烯基、环杂原子任选被R 6取代且环碳原子任选被R 7取代的杂芳基；R 6选自C1-C6烷基；R 7选自C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、和苯基。 The PDGFR kinase inhibitor according to claim 1 or 2, wherein R 1 is selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a ring hetero atom is optionally substituted by R 6 and the ring carbon atom is optionally substituted by R 7 Heteroaryl; R 6 is selected from C 1 -C 6 alkyl; R 7 is selected from C 1 -C 6 cyanoalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylamino, and phenyl .
  4. 如权利要求3所述的PDGFR激酶抑制剂，其中R 1选自环杂原子任选被R 6取代且环碳原子任选被R 7取代的3-吡啶基、2-吡咯基、5-异噁唑基、2-噻吩基、3-噻吩基、3-吲唑基、3-喹啉基、和4-咪唑基；R 6选自甲基；R 7选自环丙基和苯基。 The PDGFR kinase inhibitor according to claim 3, wherein R 1 is selected from the group consisting of a 3-pyridyl group, a 2-pyrrolyl group, a 5-heterocyclic ring optionally substituted by R 6 and a ring carbon atom optionally substituted by R 7 Oxazolyl, 2-thienyl, 3-thienyl, 3-oxazolyl, 3-quinolyl, and 4-imidazolyl; R 6 is selected from methyl; R 7 is selected from cyclopropyl and phenyl.
  5. 如权利要求1或2所述的PDGFR激酶抑制剂，其中R 2选自氢、甲基、氟 和氯。 The PDGFR kinase inhibitor according to claim 1 or 2, wherein R 2 is selected from the group consisting of hydrogen, methyl, fluorine and chlorine.
  6. 如权利要求1或2所述的PDGFR激酶抑制剂，其中R 3选自 氢和氟。 PDGFR kinase inhibitor or claim 12 wherein R 3 is selected from hydrogen and fluorine as claimed in claim.
  7. 如权利要求1或2所述的PDGFR激酶抑制剂，其中R 4选自C3-C6环烷基、C1-C4烷基(C3-C6环烷基)、金刚烷基、任选被R 7取代的苯基、和烷基任选被R 5取代的C1-C4烷基(苯基)；R 5选自C1-C6烷基、和C1-C6烷氧基；R 7选自C1-C6氰基烷基、C1-C6卤代烷基、C3-C6环烷基、C1-C6烷基氨基、和苯基。 The PDGFR kinase inhibitor according to claim 1 or 2, wherein R 4 is selected from the group consisting of C3-C6 cycloalkyl, C1-C4 alkyl (C3-C6 cycloalkyl), adamantyl, optionally substituted by R 7 a phenyl group, and a C1-C4 alkyl group (phenyl group) optionally substituted by R 5 ; R 5 is selected from a C1-C6 alkyl group, and a C1-C6 alkoxy group; and R 7 is selected from a C1-C6 cyanide group; Alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkylamino, and phenyl.
  8. 如权利要求7所述的PDGFR激酶抑制剂，其中R 4选自环戊基甲基、任选被R 7取代的苯基、和烷基任选被R 5取代的苯甲基；R 5选自甲氧基；R 7选自2-氰基丙-2-基。 PDGFR kinase inhibitor according to claim 7, wherein R 4 is selected from cyclopentylmethyl, optionally substituted with R 7 being phenyl optionally substituted alkyl and R 5 is benzyl; R 5 is selected from From methoxy; R 7 is selected from 2-cyanopropan-2-yl.
  9. 如权利要求1或2所述的PDGFR激酶抑制剂，其中式(I)的化合物选自以下化合物：The PDGFR kinase inhibitor according to claim 1 or 2, wherein the compound of the formula (I) is selected from the group consisting of the following compounds:
    Figure PCTCN2018079991-appb-100002
    Figure PCTCN2018079991-appb-100002
    Figure PCTCN2018079991-appb-100003
    Figure PCTCN2018079991-appb-100003
    Figure PCTCN2018079991-appb-100004
    Figure PCTCN2018079991-appb-100004
  10. 一种药物组合物，其包括如权利要求1-9中任一项所述的PDGFR激酶抑制剂、和药学可接受的载体或赋形剂，以及任选的其它治疗剂。A pharmaceutical composition comprising the PDGFR kinase inhibitor of any of claims 1-9, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
  11. 如权利要求1-9中任一项所述的PDGFR激酶抑制剂在制备用于抑制PDGFRα和/或PDGFRβ活性的药物中的用途。The use of a PDGFR kinase inhibitor according to any one of claims 1 to 9 for the preparation of a medicament for inhibiting PDGFRα and/or PDGFRβ activity.
  12. 如权利要求1-9中任一项所述的PDGFR激酶抑制剂在制备用于治疗、预防或改善由PDGFRα和/或PDGFRβ活性调节的或者受其影响的或者其中涉及PDGFRα和/或PDGFRβ活性的疾病、障碍或病症的药物中的用途。The PDGFR kinase inhibitor of any of claims 1-9, which is useful for the treatment, prevention or amelioration of, or is affected by, modulation of PDGFRα and/or PDGFRβ activity or which is involved in PDGFRα and/or PDGFRβ activity. Use in medicines for diseases, disorders or conditions.
  13. 如权利要求12所述的用途，其中所述疾病、障碍或病症选自以下增殖性疾病：肺动脉高压、实体瘤、肉瘤、胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳腺癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成、或其组合。The use according to claim 12, wherein the disease, disorder or condition is selected from the group consisting of proliferative diseases: pulmonary hypertension, solid tumor, sarcoma, gastrointestinal stromal tumor, colorectal cancer, acute granulocyte leukemia, chronic medulla Leukemia, thyroid cancer, systemic mastocytosis, eosinophilia syndrome, chronic eosinophilic leukemia, fibrosis, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease 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 hyperplasia/adenomas, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma , brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal cancer, bladder , Gastric cancer, colorectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, head and neck tumors, neoplasia, or a combination thereof.
  14. 如权利要求12所述的用途，其中所述疾病、障碍或病症选自以下自身免疫性疾病：关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛、或其组合。The use according to claim 12, wherein the disease, disorder or condition is selected from the group consisting of autoimmune diseases: arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, Psoriatic Arthritis, Still's Disease, Adolescent Arthritis, Diabetes, Myasthenia Gravis, Hashimoto's Thyroiditis, Ord Thyroiditis, Graves' Disease, Rheumatoid Arthritis Syndrome, Multiple Sclerosis , infectious neuron inflammation, acute disseminated encephalomyelitis, Addison's disease, visual ocular palsy - myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmunity Hepatitis, celiac disease, Goodpasch syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Lytle syndrome, high arteritis, temporal arteritis, Warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic hair loss, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis , By muscle rigidity, scleroderma, vulvodynia, or a combination thereof.
  15. 如权利要求12所述的用途，其中所述疾病、障碍或病症为肺动脉高压、慢性嗜酸性粒细胞白血病、或其组合。The use according to claim 12, wherein the disease, disorder or condition is pulmonary hypertension, chronic eosinophilic leukemia, or a combination thereof.
  16. 如权利要求1-9中任一项所述的PDGFR激酶抑制剂，用于抑制PDGFRα和/或PDGFRβ活性。A PDGFR kinase inhibitor according to any one of claims 1-9 for use in inhibiting PDGFRα and/or PDGFRβ activity.
  17. 如权利要求1-9中任一项所述的PDGFR激酶抑制剂，用于治疗、预防或改善由PDGFRα和/或PDGFRβ活性调节的或者受其影响的或者其中涉及PDGFRα 和/或PDGFRβ活性的疾病、障碍或病症的药物。A PDGFR kinase inhibitor according to any one of claims 1 to 9 for use in the treatment, prevention or amelioration of a disease modulated by or affecting PDGFRα and/or PDGFRβ activity or which is involved in PDGFRα and/or PDGFRβ activity , a drug for a disorder or condition.
  18. 如权利要求17所述的PDGFR激酶抑制剂，其中所述疾病、障碍或病症选自以下增殖性疾病：肺动脉高压、实体瘤、肉瘤、胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳腺癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成、或其组合。The PDGFR kinase inhibitor according to claim 17, wherein the disease, disorder or condition is selected from the group consisting of proliferative diseases: pulmonary hypertension, solid tumor, sarcoma, gastrointestinal stromal tumor, colorectal cancer, acute myeloid leukemia. , chronic myelogenous leukemia, thyroid cancer, 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, malignancy Lymphoma, non-Hodgkin's lymphoma, type 2 multiple endocrine neoplasia, pheochromocytoma, thyroid cancer, parathyroid hyperplasia / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, gelatinization Astrocytoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal gland Cancer, bladder cancer, gastric cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, cervical and head tumors, neoplasia, or a combination thereof.
  19. 如权利要求17所述的PDGFR激酶抑制剂，其中所述疾病、障碍或病症选自以下自身免疫性疾病：关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛、或其组合。The PDGFR kinase inhibitor according to claim 17, wherein the disease, disorder or condition is selected from the group consisting of autoimmune diseases: arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory Enteropathy, psoriatic arthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Odd thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple Sclerosing disease, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, visual ocular hemorrhoids - myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia , autoimmune hepatitis, celiac disease, Goodpasch syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Lytle syndrome, high arteritis, sputum Arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized hair loss, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial Cystitis, neuromyotonia, scleroderma, vulvodynia, or a combination thereof.
  20. 如权利要求17所述的PDGFR激酶抑制剂，其中所述疾病、障碍或病症为肺动脉高压、慢性嗜酸性粒细胞白血病、或其组合。The PDGFR kinase inhibitor of claim 17, wherein the disease, disorder or condition is pulmonary hypertension, chronic eosinophilic leukemia, or a combination thereof.
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