WO2020083332A1 - 作为ret抑制剂的嘧啶衍生物 - Google Patents

作为ret抑制剂的嘧啶衍生物 Download PDF

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WO2020083332A1
WO2020083332A1 PCT/CN2019/112967 CN2019112967W WO2020083332A1 WO 2020083332 A1 WO2020083332 A1 WO 2020083332A1 CN 2019112967 W CN2019112967 W CN 2019112967W WO 2020083332 A1 WO2020083332 A1 WO 2020083332A1
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pharmaceutically acceptable
acceptable salt
acid
compound according
reaction
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PCT/CN2019/112967
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English (en)
French (fr)
Inventor
付志飞
罗妙荣
孙继奎
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2020083332A1 publication Critical patent/WO2020083332A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention relates to a compound with a pyrimidine structure and its application in the preparation of a medicament for treating diseases related to RET kinase inhibitors. Specifically, it relates to the compound represented by formula (I) and its pharmaceutically acceptable salts.
  • RET protein is a receptor tyrosine kinase RTK and a transmembrane glycoprotein. It is expressed by the proto-oncogene RET (REarranged during Transfection) on chromosome 10. It develops during the embryonic stage of the kidney and enteric nervous system. Plays an important role in addition to homeostasis in a variety of tissues, such as neurons, neuroendocrine, hematopoietic tissue, and male germ cells. Unlike other RTKs, RET does not directly bind to ligand molecules: such as artemin, glial cell line-derived neurotrophic factor (GDNF), neuroturin, and persephin, which belong to the GNDF family of ligands (GFLs ).
  • ligand molecules such as artemin, glial cell line-derived neurotrophic factor (GDNF), neuroturin, and persephin, which belong to the GNDF family of ligands (GFLs ).
  • GFLs usually bind to the GDNF family receptor alpha (GFR ⁇ ), and the formed GFLs-GFR ⁇ complex mediates the self-dimerization of the RET protein, causing trans autophosphorylation of tyrosine on the intracellular domain .
  • GFR ⁇ GDNF family receptor alpha
  • RET protein GDNF family receptor alpha
  • recruit relevant linker proteins, activate cell proliferation and other signaling cascades, and related signaling pathways include MAPK, PI3K, JAK-STAT, PKA, PKC, etc.
  • RET carcinogenic activation There are two main mechanisms of RET carcinogenic activation: one is that the rearrangement of chromosomes produces new fusion proteins, usually the fusion of the kinase domain of RET and the protein containing the self-dimerization domain; the second is that the RET mutations are directly or indirectly Activates the kinase activity of RET. These changes in somatic or germ cell levels are involved in the pathogenesis of various cancers. 5% -10% of patients with papillary thyroid cancer have RET chromosome rearrangement; and 60% of medullary medullary thyroid carcinomas have RET point mutations; of all NSCLC patients, about 1-2% have Among RET fusion proteins, KIF5B-RET is the most common.
  • RET inhibitors have potential clinical value in tumor or intestinal disorders.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I and C 1-4 alkyl, the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from H, F, Cl, Br, I and C 1-4 alkyl, the C 1-4 alkyl is optionally substituted with 1, 2 or 3 R;
  • R 3 is selected from F, Cl, Br, I, and C 1-4 alkyl, the C 1-4 alkyl is optionally substituted with 1, 2, or 3 R;
  • R 4 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • D 1 , D 2 and D 3 are each independently selected from -C 1-3 alkyl-;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • R 1 is selected from CH 3 , CH 2 CH 3 , The CH 3 , CH 2 CH 3 , It can be optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , Other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , and other variables are as defined in the invention.
  • R 2 is selected from CH 3 , CH 2 CH 3 , The CH 3 , CH 2 CH 3 , It can be optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.
  • R 2 is selected from CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , Other variables are as defined in the present invention.
  • R 2 is selected from CH 3 , and other variables are as defined in the invention.
  • R 3 is selected from CH 3 , CH 2 CH 3 , The CH 3 , CH 2 CH 3 , It can be optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.
  • R 3 is selected from CH 3 , CH 2 CH 3 , Other variables are as defined in the present invention.
  • R 3 is selected from CH 3 , and other variables are as defined in the invention.
  • R 4 is selected from H, F, Cl, Br, and I, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
  • the present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of a RET kinase inhibitor.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; similar acids; also includes amino acids (such as arginine, etc.) Salts, and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers in a mirror image relationship with each other.
  • cis-trans isomer or “geometric isomer” is caused by the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and there is a non-mirror relationship between the molecules.
  • wedge-shaped solid line key And wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys And straight dotted keys Represents the relative configuration of the three-dimensional center
  • wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dotted keys
  • tautomer or “tautomeric form” means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton migration such as ketone-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include some recombination of bond-forming electrons for mutual conversion.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “isomer enriched”, “rich in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or pairs
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater or equal 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess of isomer or enantiomer (ee value) is 80% .
  • optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography, which uses a chiral stationary phase, and is optionally combined with chemical derivatization methods (for example, the formation of amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have lower toxicity and increase drug stability. , Strengthen the efficacy, extend the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R in each case has independent options.
  • combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , it means that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc .; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-4 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc .; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl) and so on.
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc .; similarly, n yuan to n + m member means that the number of atoms in the ring is n to n + m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered ring, 11-membered ring, and 12-membered
  • halogen or halogen itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc .; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyld
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl groups (such as acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-flu
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • aq stands for water
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • m-CPBA stands for 3-chloroperoxybenzoic acid
  • eq stands for equivalent, equivalent
  • M stands for mol / L
  • CDI stands for carbonyldiimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF stands for N, N-dimethylformamide
  • DMSO stands for dimethylsulfoxide Sulfone
  • EtOH for ethanol
  • MeOH for methanol
  • CBz benzyl
  • the compound of the present invention exhibits good inhibitory activity against wild-type and V804M mutant RET, and will have excellent therapeutic effects in patients with abnormal RET tumors.
  • compound 001-1 (3g, 17.63mmol, 1eq) was dissolved in dichloromethane (30mL), oxalyl chloride (4.48g, 35.26mmol, 3.09mL, 2eq) and N, N-dimethyl Formamide (64.43mg, 881.51 ⁇ mol, 67.82 ⁇ L, 0.05eq) was added to the reaction system in sequence, the ice bath was removed, the reaction system was raised to 28 ° C, and the reaction was stirred for 30 minutes. The reaction solution was directly concentrated under reduced pressure to obtain the corresponding acid chloride.
  • the intermediate 001-3 (800 mg, 5.29 mmol, 1 eq) was dissolved in methanol (16 mL), followed by sodium methoxide (5M, 105.85 ⁇ L, 0.1 eq), and the reaction was stirred for 1 hour. Then ammonium bromide (569.93 mg, 5.82 mmol, 234.54 ⁇ L, 1.1 eq) was added to the reaction system and the reaction was stirred for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain intermediate 001-4, which can be directly used in the next reaction.
  • the intermediate 001-4 (880 mg, 5.23 mmol, 1 eq) was dissolved in methanol (8.8 mL), sodium methoxide methanol solution (5M, 2.09 mL, 2 eq) was added, and after stirring for 10 minutes, the acetoacetic acid The methyl ester (546.77 mg, 4.71 mmol, 506.27 ⁇ L, 0.9 eq) was added to the reaction system, the temperature was raised to 60 ° C., and the reaction was stirred for 2 hours.
  • triphenylphosphine (1.12g, 4.27mmol, 5eq) was dissolved in 1,2-dichloroethane (30mL), and then carbon tetrachloride (656.66mg, 4.27mmol, 410.41 ⁇ L, 5eq) was added to the reaction system, and the reaction was stirred for 0.5 hour.
  • carbon tetrachloride (656.66mg, 4.27mmol, 410.41 ⁇ L, 5eq) was added to the reaction system, and the reaction was stirred for 0.5 hour.
  • dissolving intermediate 001-5 200 mg, 853.79 ⁇ mol, 1 eq
  • 1,2-dichloroethane 20 mL
  • reaction solution was poured into a system of ethyl acetate (50 mL) and water (30 mL), the organic phase was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • 50 mL of methyl tert-butyl ether was added to the above crude product for beating, the triphenylphosphine oxide produced during the reaction was precipitated, filtered, and the filter cake was washed with 20 mL of methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain intermediate 001 -6, can be directly used in the next reaction.
  • Step 8 Synthesis of compound 001
  • intermediate 001-9 (57.31 mg, 191.46 ⁇ mol, 1 eq) was dissolved in N, N-dimethylformamide (2.5 mL), N, N-diisopropylethylamine (74.24 mg , 574.39 ⁇ mol, 100.05 ⁇ L, 3eq) and 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (145.60mg, 382.93 ⁇ mol, 2eq) After being added to the reaction system and stirring for 0.5 hours, compound 001-10 (78.97 mg, 382.93 ⁇ mol, 2 eq) was added to the reaction system and stirred for 8 hours.
  • the reaction solution was diluted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (20 mL * 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by preparative chromatography analyzer (column: Luna C18 100 ⁇ 30mm 5 ⁇ m; mobile phase: [water (0.05% hydrochloric acid) -acetonitrile]; acetonitrile%: 15% -40%, 10min).
  • the salt of target compound 001 was isolated Acid salt.
  • the hydrochloride salt of compound 001 can be obtained by adding to NaHCO 3 solution, extracting with ethyl acetate, and concentrating the organic phase.
  • compound 002-1 (10 g, 47.12 mmol, 1 eq) was dissolved in dichloromethane (100 mL), and then oxalyl chloride (11.96 g, 94.23 mmol, 8.25 mL, 2 eq) and N, N-di Methylformamide (172.19 mg, 2.36 mmol, 181.26 ⁇ L, 0.05 eq) was added to the reaction system in sequence, and the reaction was stirred for 0.5 hour. The reaction solution is directly concentrated under reduced pressure to obtain active acid chloride, which can be directly used in the next reaction.
  • the intermediate 002-2 (5g, 23.67mmol, 1eq) was dissolved in dichlorosulfoxide (32.80g, 275.70mmol, 20.00mL, 11.65eq), heated to 75 ° C, and stirred under reflux for 2 hours.
  • the reaction solution was directly concentrated under reduced pressure to remove excess dichlorosulfoxide to obtain intermediate 002-3.
  • the intermediate 002-3 (2g, 10.35mmol, 1eq) was dissolved in a methanol solution of hydrochloric acid (4M, 38.81mL, 15eq), and the reaction was stirred for 12 hours.
  • the reaction solution was directly concentrated under reduced pressure to obtain an active intermediate.
  • the above active intermediate (33, 10.34 mmol, 1 eq) was dissolved in methanol (40 mL), and then ammonium bromide (1.11 g, 11.38 mmol, 458.55 ⁇ L, 1.1 eq) was added to the reaction system, The reaction was stirred for 2 hours.
  • the reaction solution was directly concentrated under reduced pressure to obtain intermediate 002-4, which was directly used in the next reaction.
  • the intermediate 002-4 (2.17g, 10.32mmol, 1eq) was dissolved in methanol (40mL), sodium methoxide (5M, 4.13mL, 2eq) was added, and after stirring for 10 minutes, the methyl acetoacetate (1.08g, 9.29mmol, 998.63 ⁇ L, 0.9eq) was added to the reaction system, the temperature was raised to 70 ° C, and the reaction was stirred for 2 hours.
  • reaction solution Slowly cool the reaction solution to 28 ° C, pour the reaction solution into dilute hydrochloric acid, concentrate under reduced pressure to remove methanol, adjust the system pH to 5-6, extract the aqueous phase with ethyl acetate (80 mL * 5), and combine the organic phases, Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by column chromatography to obtain intermediate 002-5.
  • triphenylphosphine 949.19 mg, 3.62 mmol, 5 eq
  • 1,2-dichloroethane 30 mL
  • carbon tetrachloride 556.65 mg, 3.62 mmol, 347.91 ⁇ L, 5eq
  • the reaction was stirred for 0.5 hour.
  • dissolving intermediate 002-5 200 mg, 723.77 ⁇ mol, 1 eq
  • 1,2-dichloroethane 20 mL
  • reaction solution was diluted with ethyl acetate (50 mL), washed with water (20 mL * 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate 002-8. Used for the next reaction.
  • the intermediate 002-9 (24 mg, 70.30 ⁇ mol, 1 eq) was dissolved in N, N-dimethylformamide (3 mL), N, N-diisopropylethylamine (27.26 mg, 210.89 ⁇ mol, 36.73 ⁇ L, 3eq) and 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (53.46mg, 140.59 ⁇ mol, 2eq) were added to In the reaction solution, the reaction was stirred for 0.5 hours, compound 001-10 (28.99 mg, 140.59 ⁇ mol, 2 eq) was added to the reaction solution, and the reaction was stirred for 6 hours.
  • the hydrochloride salt of the target compound 002 was isolated.
  • the hydrochloride salt of compound 002 can be obtained by adding to sodium bicarbonate solution, extracting with ethyl acetate, and concentrating the organic phase.
  • the 33 P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC 50 value to evaluate the test compound's ability to inhibit human wild-type, V804M mutant RET.
  • Buffer conditions 20 mM hydroxyethylpiperazine ethanesulfonic acid (Hepes) (pH 7.5), 10 mM MgCl 2 , 1 mM ethylene glycol diaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene dodecyl ether ( Brij35), 0.02 mg / ml BSA, 0.1 mM Na 3 VO 4 , 2 mM dithiothreitol (DTT), 1% DMSO.
  • test compound treatment The test compound was dissolved in 100% DMSO and serially diluted by Integra Viaflo Assist with DMSO to a specific concentration.
  • Test procedure Dissolve the substrate in the newly prepared buffer solution, add the tested kinase to it and mix gently. Using the acoustic technique (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above-mentioned mixed reaction solution, and incubated at room temperature for 20 minutes. The compound concentration in the reaction solution was 3 ⁇ M, 1 ⁇ M, 0.333 ⁇ M, 0.111 ⁇ M, 0.0370 ⁇ M, 0.0123 ⁇ M, 4.12nM, 1.37nM, 0.457nM, 0.152nM. After incubating for 15 minutes, 33 P-ATP (activity 0.01 ⁇ Ci / ⁇ l, Km concentration) was added to start the reaction.
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (containing only DMSO).
  • the IC 50 value was obtained by curve fitting using Prism4 software (GraphPad).
  • the compounds of the present invention exhibit good inhibitory activity against wild-type and V804M mutant RET.

Abstract

公开了一系列带有嘧啶结构的化合物，及其在制备RET激酶抑制剂的应用。具体公开了式(Ι)所示化合物或其药学上可接受的盐。

Description

作为RET抑制剂的嘧啶衍生物
本申请主张如下优先权：
CN201811248349.1，申请日2018.10.24。
技术领域
本发明涉及一类带有嘧啶结构的化合物及其在制备治疗与RET激酶抑制剂相关疾病的药物中的应用。具体涉及式(I)所示化合物及其药学上可接受的盐。
背景技术
RET蛋白是一个受体酪氨酸激酶RTK，同时也是一个跨膜的糖蛋白，由位于10号染色体上的原癌基因RET(REarranged during Transfection)表达，在胚胎阶段的肾脏和肠神经系统的发育中起着重要作用，另外在多种组织内稳态也很关键，如神经元、神经内分泌、造血组织和男性生殖细胞等。和其他的RTK不同，RET并不是直接结合到配体分子：如神经导向素(artemin)、胶质细胞源性神经营养因子(GDNF)、neurturin和persephin，这些都是属于GNDF家族配体(GFLs)。这些配体GFLs通常结合到GDNF家族受体α(GFRα)，形成的GFLs-GFRα复合物介导了RET蛋白的自二聚化，引起胞内结构域上酪氨酸的反式自磷酸化反应，招募相关接头蛋白，激活细胞增殖等信号传导的级联反应，相关的信号通路包括MAPK、PI3K、JAK-STAT、PKA、PKC等等。
RET的致癌激活机制主要有两个：一是染色体的重排产生了新的融合蛋白，通常是RET的激酶结构域和包含自二聚化结构域的蛋白融合；二就是RET突变直接或间接的激活了RET的激酶活性。这些体细胞或生殖细胞水平的改变涉及多种癌症的发病机制。5％-10％的乳头状甲状腺癌患者存在RET染色体重排；而在髓样性甲状腺髓样癌中发现有60％存在RET点突变；在所有NSCLC患者中，大概有1-2％的具有RET融合蛋白，其中KIF5B-RET最为多见。
总之，在多种肿瘤和胃肠道紊乱如过敏性肠道综合症中均发现异常的RET表达或激活。因此RET抑制剂在肿瘤或肠道紊乱疾病中具有潜在的临床价值。
发明内容
本发明提供式(I)示化合物或其药学上可接受的盐，
Figure PCTCN2019112967-appb-000001
其中，
R 1选自H、F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
R 2选自H、F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
R 3选自F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
R 4选自H、F、Cl、Br、I、OH和NH 2；
R选自F、Cl、Br、I、OH、NH 2和CH 3；
D 1、D 2和D 3分别独立地选自-C 1-3烷基-；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000002
所述CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000003
Figure PCTCN2019112967-appb-000004
任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CF 3、CH 2CH 3、CH 2CF 3、
Figure PCTCN2019112967-appb-000005
其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000006
所述CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000007
Figure PCTCN2019112967-appb-000008
任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自CH 3、CF 3、CH 2CH 3、CH 2CF 3、
Figure PCTCN2019112967-appb-000009
其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000010
所述CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000011
Figure PCTCN2019112967-appb-000012
任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自CH 3、CH 2CH 3、
Figure PCTCN2019112967-appb-000013
其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br和I，其它变量如本发明所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2019112967-appb-000014
其中，R 1、R 2、R 3和R 4如本发明所定义。
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明还有一些方案是由上述变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐：
Figure PCTCN2019112967-appb-000015
本发明还提供了下式所示化合物或其药学上可接受的盐：
Figure PCTCN2019112967-appb-000016
本发明还提供了一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物在在制备RET激酶抑制剂的应用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的1酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛 酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019112967-appb-000017
和楔形虚线键
Figure PCTCN2019112967-appb-000018
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019112967-appb-000019
和直形虚线键
Figure PCTCN2019112967-appb-000020
表示立体中心的相对构型，用波浪线
Figure PCTCN2019112967-appb-000021
表示楔形实线键
Figure PCTCN2019112967-appb-000022
或楔形虚线键
Figure PCTCN2019112967-appb-000023
或用波浪线
Figure PCTCN2019112967-appb-000024
表示直形实线键
Figure PCTCN2019112967-appb-000025
和直形虚线键
Figure PCTCN2019112967-appb-000026
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；M代表mol/L；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO 代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；EA代表乙酸乙酯；；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2019112967-appb-000027
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物对野生型、V804M突变型RET都展现出较好的抑制活性，将会在RET异常肿瘤患者中具有优异的治疗效果。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：化合物001
Figure PCTCN2019112967-appb-000028
Figure PCTCN2019112967-appb-000029
步骤1：中间体001-2的合成
在0℃条件下，将化合物001-1(3g,17.63mmol,1eq)溶于二氯甲烷(30mL)，草酰氯(4.48g,35.26mmol,3.09mL,2eq)和N,N-二甲基甲酰胺(64.43mg,881.51μmol,67.82μL,0.05eq)依次加入反应体系中，撤去冰浴，反应体系升至28℃，搅拌反应30分钟。反应液直接减压浓缩，得到相应的酰氯。将上述酰氯(3.33g,17.66mmol,1eq)溶于二氯甲烷(33.3mL)，将反应体系降至0℃，向反应体系中通入氨气(3.01g,176.56mmol,10eq)，搅拌反应45分钟，反应体系中有大量固体产生。过滤除去反应过程中产生的不溶物，滤饼用二氯甲烷(100mL)洗涤，滤液经减压浓缩后得到中间体001-2。
LCMS:MS(ESI)m/z:170.1[M+1] +
步骤2：中间体001-3的合成
将中间体001-2(1.8g,10.64mmol,1eq)溶于二氯亚砜(8.20g,68.92mmol,5mL,6.48eq)，加热至90℃，回流搅拌反应2小时。将反应液减压浓缩，得到中间体001-3，可直接用于下一步反应。
LCMS:MS(ESI)m/z:152.1[M+1] +.
1H NMR(400MHz,CDCl 3)δ＝3.69(s,3H),2.51(s,6H).
步骤3：中间体001-4的合成
在28℃条件下，将中间体001-3(800mg,5.29mmol,1eq)溶于甲醇(16mL)，随后将甲醇钠(5M,105.85μL,0.1eq)，搅拌反应1小时后。然后将溴化铵(569.93mg,5.82mmol,234.54μL,1.1eq)加入到反应体系中搅拌反应1小时。将反应液直接减压浓缩，得到中间体001-4，可直接用于下一步反应。
LCMS:MS(ESI)m/z:169.1[M+1] +.
1H NMR(400MHz,CD 3OD)δ＝3.68(s,3H),2.51(s,6H)
步骤4：中间体001-5的合成
在0℃下，将中间体001-4(880mg,5.23mmol,1eq)溶于甲醇(8.8mL)中，加入甲醇钠甲醇溶液(5M,2.09mL,2eq)，搅拌10分钟后，将乙酰乙酸甲酯(546.77mg,4.71mmol,506.27μL,0.9eq)加入到反应体系中，升温至60℃，搅拌反应2小时。将反应液提出，缓慢冷却到28℃，将反应液倒入稀盐酸(0.05N,20mL)中，减压浓缩除去甲醇，用0.5N盐酸将体系pH值调到5-6，用乙酸乙酯(20mL*5)萃取水相，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩后，经柱层析纯化得到中间体001-5。
LCMS:MS(ESI)m/z:235.0[M+1] +
1H NMR(400MHz,CD 3OD)δ＝6.16(s,1H),3.71(s,3H),2.43(s,6H),2.27(d,J＝1.0Hz,3H).
步骤5：中间体001-6的合成
在28℃条件下，将三苯基膦(1.12g,4.27mmol,5eq)溶于1,2-二氯乙烷(30mL)，随后将四氯化碳(656.66mg,4.27mmol,410.41μL,5eq)加入到反应体系中，搅拌反应0.5小时。将中间体001-5(200mg,853.79μmol,1eq)溶于1,2-二氯乙烷(20mL)后，加入到反应体系中，升温到80℃，搅拌反应8小时。将反应液倒入乙酸乙酯(50mL)和水(30mL)的体系中，分离有机相，用饱和食盐水(30mL)洗涤，经无水硫酸钠干燥后，减压浓缩，得到粗品。向上述粗品中加入甲基叔丁基醚50mL打浆，反应过程中产生的三苯基氧磷析出，过滤，用甲基叔丁基醚20mL洗涤滤饼，将滤液减压浓缩，得到中间体001-6，可直接用于下一步反应。
LCMS:MS(ESI)m/z:253.1[M+1] +.
步骤6：中间体001-8的合成
在28℃条件下，将对甲苯磺酸(154.59mg,897.71μmol,1.5eq)溶于1,4-二氧六环(12mL)中，然后将中间体001-6(440mg,598.47μmol,1eq)和化合物001-7(75.56mg,778.02μmol,1.3eq)加入到反应液中，加热到100℃，搅拌回流反应6小时。将反应液用乙酸乙酯(100mL)稀释后，用饱和食盐水(30mL*3)洗涤，有机相干燥后，经减压浓缩，经柱层析纯化得到中间体001-8。
LCMS:MS(ESI)m/z:314.1[M+1] +
1H NMR(400MHz,CD 3OD)δ＝6.77(br s,1H),6.22(br s,1H),4.60(s,1H),3.71(s,3H),2.40(s,6H),2.34(s,3H),2.28(s,3H).
步骤7：中间体001-9的合成
在28℃条件下，将中间体001-8(60mg,191.48μmol,1eq)溶于四氢呋喃(3.6mL)，甲醇(1.2mL)和水(1.2mL)中，把氢氧化锂一水合物(32.14mg,765.91μmol,4eq)加入反应体系中，搅拌反应2小时。用0.05M的盐酸将反应液PH值调至6～7，直接将反应液经减压浓缩后，得到中间体001-9。无需纯化，直接用于下一步反应。
LCMS:MS(ESI)m/z:300.1[M+1] +
步骤8：化合物001的合成
在28℃条件下，将中间体001-9(57.31mg,191.46μmol,1eq)溶于N,N-二甲基甲酰胺(2.5mL)，N,N-二异丙基乙胺(74.24mg,574.39μmol,100.05μL,3eq)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(145.60mg,382.93μmol,2eq)依次加入到反应体系中，搅拌反应0.5小时后，将化合物001-10(78.97mg,382.93μmol,2eq)加入反应体系中搅拌反应8小时。将反应液用乙酸乙酯(100mL)稀释后，用饱和食盐水(20mL*3)洗涤有机相，有机相经无水硫酸钠干燥后，减压浓缩，得到粗品。粗品经制备色谱分析仪分离纯化(柱子:Luna C18 100×30mm 5μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:15％-40％,10min)分离得到目标化合物001的盐酸盐。化合物001的盐酸盐可以通过加入到NaHCO 3溶液中，乙酸乙酯萃取，浓缩有机相的方法得到化合物001。
LCMS:MS(ESI)m/z:488.3[M+1] +
1H NMR(400MHz,CD 3OD)δ＝8.51(d,J＝4.4Hz,1H),8.41(s,1H),7.99-7.89(m,2H),7.71(d,J＝4.1Hz,1H),7.57(br s,1H),6.81(br s,1H),5.15(q,J＝7.1Hz,1H),2.56(br s,4H),2.54-2.54(m,1H),2.59-2.54(m,1H),2.53(s,3H),2.35(br s,3H),1.57(d,J＝7.2Hz,3H).
实施例2：化合物002
Figure PCTCN2019112967-appb-000030
Figure PCTCN2019112967-appb-000031
步骤1：中间体002-2的合成
在28℃条件下，将化合物002-1(10g,47.12mmol,1eq)溶于二氯甲烷(100mL)，随后将草酰氯(11.96g,94.23mmol,8.25mL,2eq)和N,N-二甲基甲酰胺(172.19mg,2.36mmol,181.26μL,0.05eq)依次加入到反应体系中，搅拌反应0.5小时。直接将反应液减压浓缩，得到活性酰氯，可直接用于下一步反应。在0℃条件下，将上述活性酰氯溶于二氯甲烷(200mL)，向反应体系中通入氨气(8.02g,471.20mmol,10eq)，搅拌反应1小时。过滤，滤液经减压浓缩后，得到中间体002-2。
LCMS:MS(ESI)m/z:212.1[M+1] +.
1H NMR(400MHz,DMSO-d 6)δ＝6.94(br s,1H),6.72(br s,1H),3.65-3.49(m,3H),1.73-1.60(m,12H).
步骤2：中间体002-3的合成
在28℃条件下，将中间体002-2(5g,23.67mmol,1eq)溶于二氯亚砜(32.80g,275.70mmol,20.00mL,11.65eq)，加热到75℃，回流搅拌2小时。将反应液直接经减压浓缩除去多余的二氯亚砜，得到中间体002-3。
1H NMR(400MHz,CDCl 3)δ＝3.66(s,3H),2.01-1.92(m,6H),1.88-1.79(m,6H).
步骤3：中间体002-4的合成
在28℃条件下，将中间体002-3(2g,10.35mmol,1eq)溶于盐酸甲醇溶液(4M,38.81mL,15eq)，搅拌反应12小时。将反应液直接经减压浓缩，得到活性中间体。在28℃条件下，将上述活性中间体(33,10.34mmol,1eq)溶于甲醇(40mL)，然后将溴化铵(1.11g,11.38mmol,458.55μL,1.1eq)加入到反应体系中，搅拌反应2小时。直接将反应液减压浓缩，得到中间体002-4，直接用于下一步反应。
LCMS:MS(ESI)m/z:211.2[M+1] +
步骤4：中间体002-5的合成
在0℃下，将中间体002-4(2.17g,10.32mmol,1eq)溶于甲醇(40mL)中，加入甲醇钠(5M,4.13mL,2eq)，搅拌10分钟后，将乙酰乙酸甲酯(1.08g,9.29mmol,998.63μL,0.9eq)加入到反应体系中，升温至70℃，搅拌反应2小时。将反应液缓慢冷却到28℃，将反应液倒入稀盐酸中，减压浓缩除去甲醇，调体系pH值到5-6，用乙酸乙酯(80mL*5)萃取水相，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离纯化得到中间体002-5。
LCMS:MS(ESI)m/z:277.1[M+1] +
步骤5：中间体002-6的合成
在28℃条件下，将三苯基膦(949.19mg,3.62mmol,5eq)溶于1,2-二氯乙烷(30mL)，随后将四氯化碳(556.65mg,3.62mmol,347.91μL,5eq)加入到反应体系中，搅拌反应0.5小时。将中间体002-5(200mg,723.77μmol,1eq)溶于1,2-二氯乙烷(20mL)后，加入到反应体系中，升温到80℃，搅拌反应8小时。将反应液减压浓缩后，用乙酸乙酯(150mL)溶解，用饱和食盐水(50mL*3)洗涤，有机相经无水硫酸钠干燥后，减压浓缩，得到粗品。将上述粗品用甲基叔丁基醚打浆，过滤除去不溶的三苯基氧磷，滤液减压浓缩后，得到中间体002-6，直接用于下一步反应。
LCMS:MS(ESI)m/z:295.1[M+1] +
步骤6：中间体002-8的合成
在28℃条件下，将对甲苯磺酸(184.01mg,1.07mmol,1.5eq)溶于1,4-二氧六环(15mL)中，然后将化合物001-7(89.94mg,926.13μmol,1.3eq)和中间体002-6(210mg,712.41μmol,1eq)加入到反应液中，加热到100℃，搅拌回流反应6小时。将反应液用乙酸乙酯(50mL)稀释后，用水(20mL*3)洗涤，有机相经无水硫酸钠干燥后，过滤，减压浓缩后经柱层析得到中间体002-8，可直接用于下一步反应。
LCMS:MS(ESI)m/z:356.2[M+1] +.
步骤7：中间体002-9的合成
在28℃条件下，将002-8(25mg,70.34μmol,1eq)溶于四氢呋喃(3mL)，甲醇(1mL)和水(1mL)中，把氢氧化锂一水合物(11.81mg,281.35μmol,4eq)加入到反应液中搅拌反应2小时。用0.05M稀盐酸将反应的PH值调至6-7后，将反应液直接减压浓缩，得到中间体002-9可直接用于下一步反应。LCMS:MS(ESI)m/z:342.2[M+1] +.
步骤8：化合物002的合成
在28℃条件下，将中间体002-9(24mg,70.30μmol,1eq)溶于N,N-二甲基甲酰胺(3mL)，N,N-二异丙基乙胺(27.26mg,210.89μmol,36.73μL,3eq)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(53.46mg,140.59μmol,2eq)依次加入到反应液中，搅拌反应0.5小时，将化合物001-10(28.99mg,140.59μmol,2eq)加入到反应液中，搅拌反应6小时。将反应液用乙酸乙酯(30mL)稀释后，用饱和食盐水(10mL*3)洗涤反应液，经无水硫酸钠干燥后，过滤，减压浓缩后粗品经制备色谱分析仪分离纯化(柱子:Luna C18 100×30mm 5μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:25％-40％,10min)分离得到目标化合物002的盐酸盐。化合物002的盐酸盐可以通过加入到碳酸氢钠溶液中，乙酸乙酯萃取，浓缩有机相的方法得到化合物002。
LCMS:MS(ESI)m/z:530.3[M+1] +.
1H NMR(400MHz,CD 3OD)δ＝8.51(br d,J＝4.1Hz,1H),8.38(s,1H),7.92(s,2H),7.71(br d,J＝4.0Hz,1H),7.50(s,1H),6.81(s,1H),5.10(q,J＝7.0Hz,1H),2.54(s,3H),2.35(br s,3H),2.09(br d,J＝7.3Hz,6H),2.01-1.86(m,6H),1.54(d,J＝7.0Hz,3H).
生物测试数据：
实验例1：野生型、V804M突变型激酶体外抑制活性评价
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对人野生型、V804M突变型RET的抑制能力。
缓冲液条件：20mM羟乙基哌嗪乙硫磺酸(Hepes)(pH 7.5),10mM MgCl 2,1mM乙二醇双氨乙基醚四乙酸(EGTA),0.02％聚氧乙烯十二烷醚(Brij35),0.02mg/ml BSA,0.1mM Na 3VO 4,2mM二硫苏糖醇(DTT),1％DMSO。
化合物处理：将测试化合物溶于100％DMSO中并由Integra Viaflo Assist用DMSO连续稀释至特定浓度。
试验步骤：将底物溶解在新配制的缓冲液中，向其中加入受测激酶并轻轻混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中，并在室温下孵育20分钟。反应液中化合物浓度为3μM,1μM,0.333μM,0.111μM,0.0370μM,0.0123μM,4.12nM,1.37nM,0.457nM,0.152nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μl，Km浓度)开始反应。反应在室温下进行120分钟后，通过过滤器结合方法检测放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC 50值，实验结果如表1所示。
表1：本发明化合物体外筛选试验结果
化合物 IC 50(nM)
  野生型 V804M
001的盐酸盐 3.14 7.66
002的盐酸盐 3.80 8.90
结论：本发明化合物对野生型、V804M突变型RET都展现出较好的抑制活性。

Claims (17)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2019112967-appb-100001
    其中，
    R 1选自H、F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
    R 2选自H、F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
    R 3选自F、Cl、Br、I和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
    R 4选自H、F、Cl、Br、I、OH和NH 2；
    R选自F、Cl、Br、I、OH、NH 2和CH 3；
    D 1、D 2和D 3分别独立地选自-C 1-3烷基-；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100002
    所述CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100003
    任选被1、2或3个R取代。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 1选自CH 3、CF 3、CH 2CH 3、CH 2CF 3、
    Figure PCTCN2019112967-appb-100004
    Figure PCTCN2019112967-appb-100005
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R 1选自CH 3。
  5. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 2选自CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100006
    Figure PCTCN2019112967-appb-100007
    所述CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100008
    任选被1、2或3个R取代。
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R 2选自CH 3、CF 3、CH 2CH 3、CH 2CF 3、
    Figure PCTCN2019112967-appb-100009
    Figure PCTCN2019112967-appb-100010
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R 2选自CH 3。
  8. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 3选自CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100011
    Figure PCTCN2019112967-appb-100012
    所述CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100013
    任选被1、2或3个R取代。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，R 3选自CH 3、CH 2CH 3、
    Figure PCTCN2019112967-appb-100014
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，R 3选自CH 3。
  11. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 4选自H、F、Cl、Br和I。
  12. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2019112967-appb-100015
    其中，R 1、R 2、R 3和R 4如权利要求1～11任意一项所定义。
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  13. 下式所示化合物或其药学上可接受的盐，其选自
    Figure PCTCN2019112967-appb-100016
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，其选自
    Figure PCTCN2019112967-appb-100017
  15. 一种药物组合物，包括治疗有效量的根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  16. 根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐在制备RET激酶抑制剂的应用。
  17. 根据权利要求15所述的组合物在制备RET激酶抑制剂的应用。
PCT/CN2019/112967 2018-10-24 2019-10-24 作为ret抑制剂的嘧啶衍生物 WO2020083332A1 (zh)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2016127074A1 (en) * 2015-02-06 2016-08-11 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors
US20170267661A1 (en) * 2016-03-17 2017-09-21 Blueprint Medicines Corporation Inhibitors of ret
US20180022732A1 (en) * 2016-07-22 2018-01-25 Blueprint Medicines Corporation Compounds useful for treating disorders related to ret
WO2018136663A1 (en) * 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016127074A1 (en) * 2015-02-06 2016-08-11 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors
US20170267661A1 (en) * 2016-03-17 2017-09-21 Blueprint Medicines Corporation Inhibitors of ret
US20180022732A1 (en) * 2016-07-22 2018-01-25 Blueprint Medicines Corporation Compounds useful for treating disorders related to ret
WO2018136663A1 (en) * 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors

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