WO2020094084A1 - Dérivé tricyclique utilisé comme inhibiteur de ret - Google Patents

Dérivé tricyclique utilisé comme inhibiteur de ret Download PDF

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WO2020094084A1
WO2020094084A1 PCT/CN2019/116167 CN2019116167W WO2020094084A1 WO 2020094084 A1 WO2020094084 A1 WO 2020094084A1 CN 2019116167 W CN2019116167 W CN 2019116167W WO 2020094084 A1 WO2020094084 A1 WO 2020094084A1
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alkyl
pharmaceutically acceptable
isomer
acceptable salt
compound according
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PCT/CN2019/116167
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English (en)
Chinese (zh)
Inventor
付志飞
罗妙荣
张杨
陈楚璇
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 WO2020094084A1 publication Critical patent/WO2020094084A1/fr

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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
    • A61K31/495—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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to a series of compounds with triple ring structure and their application in the preparation of RET kinase inhibitors. Specifically, it relates to a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.
  • 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, and it develops in the embryonic kidney and enteric nervous system Plays an important role in addition to homeostasis in a variety of tissues, such as neurons, neuroendocrine, hematopoietic tissues, 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), nerve growth factor (neurturin, persephin), these are all GNDF Family ligands (GFLs).
  • GDNF glial cell line-derived neurotrophic factor
  • nerve growth factor neurotrophic factor
  • GFLs GNDF Family ligands
  • GFLs usually bind to the GDNF family receptor ⁇ (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 ⁇
  • RET protein GDNF family receptor ⁇
  • 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 The kinase activity of RET is activated. 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 rearrangements; and 60% of medullary medullary thyroid cancers 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 (II), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, 5-6 membered heteroaryl, and 5-10 membered heterocycloalkenyl, the C 1 -6 alkyl, C 1- 6 alkoxy group, a 5 to 6 membered heteroaryl and 5 to 10-membered heterocycloalkenyl group is optionally substituted with 1, 2 or 3 substituents R a;
  • R 1 is selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, pyrazolyl and 3,6-dihydropyranyl, the C 1-6 alkyl group, C 1-6 alkoxy, 3,6-dihydro-pyrazolyl, and pyranyl optionally substituted with 1, 2 or 3 substituents R a;
  • R 2 is selected from H, F, Cl, Br, I, CN, and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1, 2 or 3 R c substitutions;
  • n is selected from 0, 1, 2, 3 and 4;
  • Ring A is selected from phenyl and 5-8 membered heteroaryl
  • Ring A is selected from phenyl and pyridyl
  • R a is selected from H, F, Cl, Br, I, NH 2 , CN and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R;
  • R b is selected from H, F, Cl, Br, I, NH 2 and CN;
  • R c is selected from H, F, Cl, Br and I;
  • R d is selected from H, F, Cl, Br, I, OH, NH 2 and CN;
  • R is selected from H, F, Cl, Br, I, OH, NH 2 and CN;
  • 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 provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected H, F, Cl, Br, I , and C 1-6 alkoxy, a C 1-6 alkoxy group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, CN, and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I, and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2, or 3 R c ;
  • R a is selected from H, F, Cl, Br and I;
  • R b is selected from H, F, Cl, Br, I, NH 2 and CN;
  • R c is selected from H, F, Cl, Br and I;
  • R d is selected from H, F, Cl, Br, I, OH, NH 2 and CN;
  • 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 above R 1 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, pyrazolyl, imidazolyl and 3,6-di Hydrogen-2H-pyranyl, the C 1-3 alkyl, C 1-3 alkoxy, pyrazolyl, imidazolyl and 3,6-dihydro-2H-pyranyl are optionally 1, 2 Or 3 Ra substitutions, other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, The C 1-3 alkyl group, C 1-3 alkoxy group, Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is selected from H
  • Other variables are as defined in the present invention.
  • R 1 is selected from H and a C 1-3 alkoxy group, a C 1-3 alkoxy said alkoxy optionally substituted with 1, 2 or 3 R a, of the present invention other variables are as As defined.
  • R 1 is selected from H
  • Other variables are as defined in the present invention.
  • R 1 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, CN and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b instead, other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, CN, CH 2 NH 2 , CH 2 CN and Other variables are as defined in the present invention.
  • R 2 is selected from CN, and other variables are as defined in the invention.
  • R 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-
  • the 3 alkoxy groups are optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 , CF 3 and -OCH 3 , and other variables are as defined in the invention.
  • R 3 is selected from H, F, Cl, Br, I, and CH 3 , the CH 3 is optionally substituted with 1, 2, or 3 R c , and other variables are as defined in the present invention .
  • R 3 is selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, and I, and other variables are as defined in the invention.
  • the A ring is selected from phenyl and pyridyl, and other variables are as defined in the present invention.
  • the above L 1 is selected from Said It can be optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • the above L 1 is selected from Other variables are as defined in the present invention.
  • the above L 1 is selected from Other variables are as defined in the present invention.
  • L 1 is selected from And -CH 2- , described And -CH 2 -are optionally substituted with 1, 2, or 3 Rd , and other variables are as defined in the present invention.
  • the above L 1 is selected from And -CH 2- , 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 and R 3 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , L 1 and R 3 are as defined in the present invention.
  • 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
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the invention also provides the application of the above compound, its isomer or pharmaceutically acceptable salt thereof in the preparation of RET kinase inhibitor.
  • the invention also provides the application of the above composition in the preparation of RET kinase inhibitors.
  • 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 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 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; also includes salts of amino acids (such as arginine, etc.) , 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 or
  • 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 the 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 mixtures thereof 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.
  • diastereomers refers to stereoisomers in which molecules have two or more chiral centers and are in a non-mirror relationship.
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or as both formula (B-1) and formula (B-2) There is a mixture of isomers.
  • the following formula (C) indicates that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) In the form of a mixture.
  • 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 known as prototropic tautomers
  • proton tautomers include interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomer (valence tautomer) includes 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 than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers 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%, then 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, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer 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 done by using 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 radioisotopes, 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.
  • deuterated drugs have reduced toxic and side effects and increased drug stability. , Strengthen efficacy, prolong 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 in the scope of the present invention.
  • “Optional” or “optionally” means that the subsequently described events or conditions may, but need not necessarily occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution 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 that they are chemically achievable.
  • 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.
  • substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group.
  • connection direction is arbitrary, for example,
  • the linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and / or variants thereof are only allowed if such combinations will produce stable compounds.
  • any one or more sites of the group may be connected to other groups by chemical bonds.
  • the chemical bond connecting the site with other groups can be a straight solid bond Straight dotted key Or wavy lines Said.
  • the straight solid line bond in-°C H 3 indicates that the oxygen atom in the group is connected to other groups;
  • the straight dashed bond in means that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that it is connected to other groups through the carbon atoms at the 1 and 2 positions of the phenyl group.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc .; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples 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), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.
  • 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 2-8 alkenyl is used to denote a linear or branched hydrocarbon group consisting of at least one carbon-carbon double bond consisting of 2 to 8 carbon atoms, a carbon-carbon double bond It can be located anywhere on the group.
  • the C 2-8 alkenyl group includes C 2-6 , C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl groups; it may be monovalent, divalent or multivalent.
  • Examples of C 2-8 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through one oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • halogen or halogen itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • 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 , and also includes any range from n to n + m, for example, C 1-12 includes C 1- 3 , 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
  • 5-8 membered heteroaryl ring and “5-8 membered heteroaryl group” of the present invention may be used interchangeably.
  • the term “5-8 membered heteroaryl group” means from 5 to 8 ring atoms
  • the cyclic group composed of a conjugated ⁇ electron system has 1, 2, 3, or 4 ring atoms as heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. It can be a monocyclic ring or a fused bicyclic ring system, where each ring is aromatic. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • the 5-8 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom.
  • the 5-8 membered heteroaryl group includes 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups.
  • Examples of the 5-8 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazoly
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl group” of the present invention can be used interchangeably, and the term “5-6 membered heteroaryl group” means from 5 to 6 ring atoms
  • the monocyclic group with a conjugated ⁇ electron system consists of 1, 2, 3, or 4 ring atoms that are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-iso
  • the term "5-10 membered heterocyclenyl” by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 10 ring atoms containing at least one carbon-carbon double bond , Whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S (O) p , p is 1 or 2).
  • the 5-10 membered heterocyclic alkenyl group includes 5-8 membered, 5-6 membered, 4-5 membered, 4 membered, 5 membered, and 6 membered heterocyclic alkenyls. Examples of 5-10 membered heterocyclic alkenyl groups include, but are not limited to
  • 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 well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with Bruker D8 venture diffractometer to diffract the intensity data, the light source is CuK ⁇ radiation, scanning mode: After scanning and collecting the relevant data, the crystal structure can be further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with Bruker D8 venture diffractometer to diffract the intensity data
  • the light source is CuK ⁇ radiation
  • scanning mode After scanning and collecting the relevant data, the crystal structure can be further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.
  • 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 and equivalent
  • CDI stands for Carbonyldiimidazole
  • DCM for methylene chloride
  • PE for petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF for N, N-dimethylformamide
  • DMSO dimethylsulfoxide
  • EtOAc for ethyl acetate Ester
  • EtOH for ethanol
  • MeOH for methanol
  • CBz benzyloxycarbony
  • the compounds of the present invention exhibit good inhibitory activity against wild-type and V804M mutant RET.
  • intermediate 001-3 (3.0g, 8.42mmol, 1eq) to a 100mL single-necked bottle, add N, N-dimethylformamide (3mL), and add sodium hydrogen (1.01g, 25.26mmol, 0 ° C under magnetic stirring) 60% content, 3eq), after the addition is completed, the temperature is raised to 25 ° C for 0.5h, and then the temperature is raised to 90 ° C for 0.5h.
  • the reaction solution was cooled to 25 ° C, 50 mL of water was added to the reaction solution, filtered, and the filter cake was dissolved in 40 mL of water to be slurried, filtered and dried in vacuo to obtain intermediate 001-4.
  • Raney nickel (76.42 mg, 891.95 ⁇ mol, 0.2 eq) was added to a stainless steel hydrogenation flask, followed by methanol (80 mL) and tetrahydrofuran (80 mL), followed by intermediate 001-4 (1.5 g, 4.46 mmol, 1 eq). Under a pressure of 30 psi of hydrogen (8.99 mg, 4.46 mmol, 1 eq), the reaction was performed at 25 ° C. for 24 h. The reaction solution was cooled to 25 ° C, filtered and concentrated with celite to obtain intermediate 001-5.
  • One-necked bottle 1 Dissolve intermediate 001-5 (200mg, 652.83 ⁇ mol, 1eq) in acetic acid (1mL), dropwise add 48% hydrobromic acid (1mL), then react at 70 ° C for 0.5h, then move to room temperature After stirring for 1 h, the reaction was cooled to 0 ° C., and an aqueous solution (0.5 ml of water) of sodium nitrite (54.05 mg, 783.39 ⁇ mol, 1.2 eq) was added dropwise to react for 0.5 h.
  • Single-necked bottle 2 Dissolve cuprous bromide (140.47mg, 979.24 ⁇ mol, 29.82 ⁇ L, 1.5eq) in 48% hydrobromic acid (1mL), stir at 70 ° C, and add the reaction solution in single-necked bottle 1 dropwise , Continue to react at 70 °C for 1h. The reaction was cooled to room temperature, adjusted to pH-9 with 1M sodium bicarbonate solution (50 mL), followed by extraction with ethyl acetate and concentration to obtain intermediate 001-6.
  • Step 7 Synthesis of 001/002
  • Step 1 Synthesis of intermediate 001-12
  • Step 1 Synthesis of 005/006
  • the crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150 * 25mm * 5 ⁇ m; mobile phase: [water (0.225% formic acid) -acetonitrile]; acetonitrile%: 22% -52%, 8min), and then chiral separation ( Chromatography column: YMC CHIRAL Amylose-C (250mm * 30mm, 10 ⁇ m; mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) to separate compounds 005 and 006.
  • Step 1 Synthesis of intermediate 001-19
  • Step 4 Synthesis of 007/008
  • Step 1 Synthesis of 009/010
  • the crude product was separated by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150 * 30mm 5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid) -acetonitrile]; acetonitrile%: 25% -55%, 7min) and then separated by chiral separation (Chromatographic column: DAICEL CHIRALCEL OJ-H (250mm * 30mm, 5 ⁇ m); mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) separated 011 and 012.
  • 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 bovine serum albumin, 0.1 mM Na 3 VO 4 , 2 mM dithiothreitol (DTT), 1% DMSO.
  • Hepes 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 bovine serum albumin, 0.1
  • 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 acoustic technology (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, 0.1 ⁇ 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, Mie constant concentration) was added to start the reaction.
  • Echo 550 acoustic technology
  • 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), and the IC 50 value is 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

L'invention concerne un composé ayant une structure tricyclique et une application dudit composé dans la préparation d'un inhibiteur de kinase RET. L'invention concerne plus précisément un composé représenté par la formule (II), des isomères ou des sels pharmaceutiquement acceptables dudit composé.
PCT/CN2019/116167 2018-11-07 2019-11-07 Dérivé tricyclique utilisé comme inhibiteur de ret WO2020094084A1 (fr)

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