WO2020078360A1 - 一类蛋白受体激酶抑制剂的制备和应用 - Google Patents

一类蛋白受体激酶抑制剂的制备和应用 Download PDF

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WO2020078360A1
WO2020078360A1 PCT/CN2019/111334 CN2019111334W WO2020078360A1 WO 2020078360 A1 WO2020078360 A1 WO 2020078360A1 CN 2019111334 W CN2019111334 W CN 2019111334W WO 2020078360 A1 WO2020078360 A1 WO 2020078360A1
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substituted
unsubstituted
ring
group
compound
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PCT/CN2019/111334
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French (fr)
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江磊
冯志勇
路小丽
尚珂
寿建勇
吴淡宜
徐圆
许灵灵
张淑芸
张宇星
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上海轶诺药业有限公司
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Priority to CN201980067895.1A priority Critical patent/CN113242858A/zh
Publication of WO2020078360A1 publication Critical patent/WO2020078360A1/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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the technical field of medicine, and more specifically, to a protein receptor kinase inhibitor.
  • Tropomyosin receptor kinase is a class of nerve growth factor receptors, belonging to the receptor tyrosine kinase family, mainly including three highly homologous members TRKA, TRKB and TRKC, respectively It is encoded by the three genes NTRK1, NTRK2 and NTRK3. These receptor tyrosine kinases are mainly expressed in nerve tissue, and play an important role in the development and physiological functions of the nervous system through the activation of neurotrophins (neurotrophins). TRK acts as a tyrosine kinase receptor, and each TRK has its corresponding ligand to bind and activate its downstream signaling pathway.
  • NGF nerve growth factor
  • TRKB ligands include BDGF (brain-derived growth factor) and NT-4 / 5 (neurotrophin-4 / 5); NT-3 specifically binds and activates TRKC . All three TRK receptors contain an extracellular domain for ligand binding, a transmembrane domain, and an intracellular domain with kinase activity.
  • a specific ligand When a specific ligand binds to the extracellular domain of the corresponding receptor, it will trigger oligomerization of the receptor and phosphorylation of specific tyrosine residues in the intracytoplasmic kinase domain, resulting in downstream signaling pathways such as Ras / The activation of MAPK, PLC ⁇ / PKC and PI3K / AKT signaling pathways, thereby regulating a series of physiological processes such as the proliferation, differentiation and survival of nerve cells.
  • the TRK signaling pathway is usually precisely regulated, and its abnormal activation is closely related to tumorigenesis. The results show that there are many mechanisms that cause abnormal activation of the TRK pathway, including gene fusion, protein overexpression and single nucleotide mutations.
  • NTRK gene fusion has been proven to cause multiple It is an important factor for tumorigenesis and does not depend on the tissue source and type of tumor.
  • NTRK fusion genes have been discovered, such as ETV6-NTRK3, MPRIP–NTRK1, CD74–NTRK1, etc.
  • the results of clinical trials in recent years have shown that these fusion genes are very effective anticancer targets, and tumors containing NTRK fusion genes have a very significant response rate to TRK inhibitors.
  • TRK target inhibitors such as (WO2010048314, WO2011146336, WO2017004342).
  • some patients receiving treatment have developed drug resistance, and it is confirmed that it is caused by some base mutations in the enzyme active region, such as NTRK1 G595R or G667C mutation, NTRK3 G623R or G696A mutation. Therefore, there is still a need in the art to develop a new generation of TRK kinase inhibitors to solve the above problems.
  • the object of the present invention is to provide a new class of TRK kinase inhibitors and the preparation method and use thereof.
  • Ring A has the structure shown in the following formula:
  • Each X 4 is independently C or N;
  • Each X 5 is independently CR 7 or N; wherein, R 7 is hydrogen, deuterium, halogen, NH 2 or OH;
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 6-12 membered fused ring (including bicyclic fused rings, tricyclic fused rings), bridged rings or spiro rings (including substituted or unsubstituted fused rings (including di (Cyclic ring, tricyclic ring), bridge ring or spiro ring); wherein, the ring ring, bridge ring or spiro ring contains 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom;
  • X 1 , X 2 and X 3 are each independently CR 6 or N;
  • R 6 is hydrogen, deuterium, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy base;
  • n 1, 2 or 3;
  • Each R 3 is independently hydrogen, deuterium, hydroxyl, halogen, trifluoromethyl, cyano, amino, amide, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy base;
  • n is 2 and two R 3 together form -O- (CH 2 ) m -O-; m is an integer of 1-4;
  • R B is a substituted or unsubstituted 4-7 membered heterocyclic ring (the heterocyclic ring contains 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom);-(CH 2 ) m1- , -O- (CH 2 ) m2 -O-; where m1 and m2 are each independently an integer of 1-4
  • R B is -substituted or unsubstituted -C1-C10 alkylene-L 2- (wherein L 2 is NH, O, S or S (O) 2 ), substituted or unsubstituted C1-C6 alkyl , Substituted or unsubstituted C1-C6 alkoxy, -O- (CH 2 ) m -O-; m is an integer of 1-4;
  • the compound of formula I has the structure represented by the following formula I-1:
  • ring A is a bicyclic 9-10 membered heteroaromatic ring; wherein the heteroaromatic ring contains 1-3 nitrogen atoms.
  • ring A is selected from the group:
  • the ring A is selected from the group consisting of:
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 6-12 membered fused ring, bridged ring or spiro ring; said fused ring, bridged ring or spiro ring Contains 1-3 nitrogen atoms.
  • the fused ring is selected from the group consisting of 3 fused 5, 4 fused 5, 5 fused 5, 6 fused 5, 7 fused 5, 6 fused 6, 6 fused 7.
  • the spiro ring is a spiro ring selected from the group consisting of spiro [4 ⁇ 5] ring, spiro [5 ⁇ 5] ring, spiro [5 ⁇ 6] ring, spiro [5 ⁇ 7 ]ring.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted group selected from the group consisting of:
  • the substitution refers to being substituted by one or more groups selected from the group consisting of C1-C6 alkyl, oxo, and C1-C6 alkyl cyano.
  • substituted include:
  • the substituted include
  • the substituted include
  • the substituted include
  • the substituted include
  • the substituted include
  • R A is selected from the group:
  • X 1 and X 2 are as defined above;
  • n is 1, 2 or 3; and R 3 is hydrogen, deuterium, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy; or n Is 2 and two R 3 together form -O- (CH 2 ) m -O-; m is an integer of 1-4;
  • R 3 , R 4 , and R 5 in other places are each independently hydrogen, deuterium, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.
  • R A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X 1 is CR 6 or N;
  • X 2 and X 3 are each independently CR 6 ;
  • n 1, 2 or 3; and R 3 is hydrogen, deuterium, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy; or n is 2 and Two R 3 together form -O- (CH 2 ) m -O-; m is an integer of 1-4.
  • the compound of formula I is selected from the following group:
  • the compound of formula I is selected from the following group:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described in the first aspect of the present invention or a stereoisomer or a racemate or a pharmaceutically acceptable salt thereof , And pharmaceutically acceptable excipients.
  • a compound according to the first aspect of the present invention or a stereoisomer or a racemate or a pharmaceutically acceptable salt thereof, or according to the second aspect of the present invention The use of the pharmaceutical composition, which is used in medicine for preventing and treating diseases related to TRK.
  • the TRK-related diseases are selected from the group consisting of cancer, proliferative diseases, pain, skin diseases or disorders, metabolic diseases, muscle diseases, neurological diseases, autoimmune diseases, pruritus caused by dermatitis, Inflammation-related diseases, bone-related diseases.
  • the cancer is selected from cancers (including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • cancers including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • a compound as described in the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or The use of the pharmaceutical composition according to the second aspect of the present invention for the preparation and prevention of and / or treatment of TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or gene fusion dysfunction activation) Pharmaceutical composition of related diseases.
  • TRK dysfunction TRK gene amplification, or overexpression, or mutation, or gene fusion dysfunction activation
  • the pharmaceutical composition can be used in combination with other therapeutic agents.
  • the drug combination includes, but is not limited to, other first-line kinase inhibitors, immunomodulators (tumor immune checkpoint inhibitors), cell division blockers and other conventional first-line chemotherapy drugs.
  • the disease is selected from the group consisting of cancer, proliferative diseases, pain, skin diseases or disorders, metabolic diseases, muscle diseases, neurological diseases, autoimmune diseases, and pruritus caused by dermatitis.
  • the cancer is selected from cancers (including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • cancers including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • a TRK inhibitor comprising the compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof Salt, hydrate or solvate.
  • the TRK inhibitor selectively inhibits one or more TRK kinases selected from the group consisting of TRKA, TRKB or TRKC.
  • a method for preparing a compound according to the first aspect of the present invention or its stereoisomer or racemate or a pharmaceutically acceptable salt thereof characterized in that The method includes steps:
  • the compound of formula Ia is reacted with the compound of formula Ib to form the compound of formula I;
  • R 1 is C1-C6 alkyl; the remaining groups are as defined in the first aspect of the present invention.
  • this step also includes a step of deprotection.
  • a protecting group for example, an amino protecting group or a hydroxy protecting group, etc.
  • the terms "containing” or “including (including)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl refers to a fully saturated linear or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (Preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule through a single bond, including but not limited to methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3 -Methylhexyl, octyl, nonyl and decyl etc.
  • C1-C6 alkyl refers to an alkyl group containing 1 to 6 carbon
  • 6-10 membered aromatic ring means an aromatic ring having 6-10 ring atoms, the ring atoms being carbon atoms.
  • the aromatic ring may be monocyclic or bicyclic.
  • benzene ring, naphthalene ring and similar groups are examples of aromatic rings having 6-10 ring atoms, the ring atoms being carbon atoms.
  • the term "5-10 membered heteroaromatic ring” means a heteroaromatic ring having 5-10 ring atoms, the ring atom having at least 1 (may Is 1, 2 or 3) is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the heteroaromatic ring may be monocyclic or bicyclic.
  • the term "6-11 membered bridge ring or spiro ring” means a bicyclic ring having 6 to 11 ring atoms, and two of the rings are bridged or spiro connected.
  • the bridge ring or spiro ring contains 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.
  • the compound of the present invention is a compound represented by formula I or a stereoisomer or a racemate or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus can produce enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salts includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .
  • organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesul
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the bioavailability of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piper Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, di
  • reaction scheme exemplarily illustrates the method for preparing the compound represented by formula I or its stereoisomer or racemate or pharmaceutically acceptable salt thereof, wherein each group is as described above. It should be understood that in the following reaction schemes, combinations of substituents and / or variables in the general formula are only permissible if such combinations result in stable compounds. It should also be understood that other general formulas can be prepared by those skilled in the art of organic chemistry by the methods disclosed herein (by applying appropriately substituted starting materials and modifying the synthesis parameters as needed using methods known to those skilled in the art) or known methods.
  • the method includes the steps of:
  • the compound of formula Ia is reacted with the compound of formula Ib to form the compound of formula I;
  • R 1 is C1-C6 alkyl
  • ring B is defined as the first aspect of the present invention.
  • this step also includes a step of deprotection.
  • a protecting group for example, an amino protecting group or a hydroxy protecting group, etc.
  • the intermediate compound functional group may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C (O) -R "(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organis Synthesis, (1999), 4th Ed., Wiley.
  • the protective group may also be a polymer resin.
  • the compounds of the present invention have excellent TRK (eg TRKA, TRKB, TRKC) inhibitory activity, so the compounds of the present invention and its various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing
  • TRK eg TRKA, TRKB, TRKC
  • the pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and / or treat diseases (eg, cancer) related to the activity or expression level of TRK kinase.
  • the term "pharmaceutical composition” refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of organisms, which facilitates the absorption of active ingredients and thus exerts biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing Adverse biological reactions or interact with any components contained in the composition in an undesirable manner.
  • the term "pharmaceutically acceptable excipients” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, or Sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor includes but is not limited to glioma, sarcoma, melanoma, articular chondroma, cholangiocarcinoma, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small Cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer , Melanoma, kidney cancer, oral cancer and other diseases.
  • preventive include reducing the likelihood that a patient will develop or worsen a disease or disorder.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease relief effect. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administer refers to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and transrectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and transrectal administration.
  • transrectal administration including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • Those skilled in the art are familiar with application techniques that can be used in the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. Pergamon; and Remington's, Pharmaceutical Sciences (current Sciences), Mack Publishing, Co., The ones discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination drug”, “administration of other treatments”, “administration of other therapeutic agents”, etc. refer to medicines obtained by mixing or combining more than one active ingredient Treatment, which includes fixed and unfixed combinations of active ingredients.
  • the term “fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • the term “unfixed combination” refers to simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the compound of the present invention can effectively inhibit the proliferation of KM12-LUC cells.
  • the compounds of the present invention can effectively inhibit the phosphorylation levels of TRKA, TRKB and TRKC at the cytological level.
  • reaction solution was continuously stirred for 2 hours, and liquid quality monitoring showed The product was generated, concentrated, hydrochloric acid / 1-4 dioxane solution (4 ml, 4N) was added, stirred overnight, concentrated, and the residue was purified by preparative high performance liquid chromatography to obtain the target product (27.7 mg, 62%), which was yellow solid.
  • the target compound was prepared under conditions similar to Example 1
  • the target compound was prepared under conditions similar to Example 1
  • Recombinant human-derived TRKA, TRKB, and TRKC proteins were purchased from Carna Biosciences.
  • the HTRFkinEASETK kit was purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to a three-fold concentration gradient dilution with a final concentration of 1 ⁇ M to 0.05 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA protein kinase 1 ⁇ M TK substrate-biotin (Substrate-biotin) peptide substrate, 14.68 ⁇ M ATP, 1 ⁇ enzyme buffer, 5 mM MgCl 2 , 1 mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • TRKB protein kinase 1 ⁇ M TK Substrate - Biotin (Substrate-biotin) peptide substrate, 4.77 ⁇ M ATP, 1 ⁇ ligase buffer, 5mM MgCl 2, 1mMMnCl 2, 1mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 50 minutes, and the reaction system was 10 ⁇ l.
  • TRKC protein kinase 0.037 ng / ⁇ l TRKC protein kinase, 1 ⁇ M TK substrate-biotin (Substrate-biotin) peptide substrate, 25.64 ⁇ M ATP, 1 ⁇ enzyme buffer, 5 mM MgCl 2 , 1 mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 Parameter curve fitting measured IC50 (nM) data, see Table 1 for details.
  • +++ means IC 50 ⁇ 10 nm
  • ++ means 10 nm ⁇ IC 50 ⁇ 100 nm
  • + means 100 nm ⁇ IC 50 ⁇ 500 nm
  • ⁇ means IC 50 > 500 nm
  • the NIH-3T3 cell line stably expressing normal TRKA or TRKB or TRKC was constructed by plasmid transfection.
  • Human colon cancer cell line KM12-LUC (LUC, stably expressing Luciferace) containing the TPM3-NTRK1 fusion gene was used as a model for evaluating the pharmacological efficacy of test compounds.
  • the TRK fusion gene in KM12-LUC cells makes it independent of the stimulation of extracellular growth factors, and can continue to spontaneously activate and activate its downstream signaling pathways MAPK-ERK, PI3K-AKT and other signaling pathways closely related to cell proliferation. Therefore, inhibition of TRK activity in KM12-LUC cells can significantly inhibit cell proliferation.
  • the method is as follows: On the first day, cells are seeded in a 384-well plate at 2000 cells / well; on the second day, different concentrations of the test compound are added; on the fifth day, CellTiter-Glo (Promega) is added to detect cell viability and the cells are counted for 72 hours Proliferation inhibition rate. The prism5 was used for statistical analysis and the IC 50 value of the test compound was obtained.
  • TRKA G595R
  • TRKA G667C
  • TRKC G623R
  • HTRFkinEASETK is purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to 4-fold concentration gradient dilution, with a final concentration of 1 ⁇ M to 0.004 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA TRKA (G595R) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate
  • 4.5 ⁇ M ATP 1 ⁇ enzymatic buffer
  • 5 mM MgCl 2 1 mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • TRKA TRKA (G667C) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate, 5.5 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5 mM MgCl 2 , 1 mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 IC50 (nM) data measured by parameter curve fitting, see Table 4 for details.

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Abstract

本发明提供了一种蛋白受体激酶抑制剂的制备方法。具体地，本发明公开了一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐，其中，各基团的定义如说明书中所述。本发明还公开了上述化合物作为TRK激酶抑制剂的用途。 (I)

Description

一类蛋白受体激酶抑制剂的制备和应用 技术领域
本发明涉及医药技术领域，更具体而言，涉及一种蛋白受体激酶抑制剂。
背景技术
原肌球蛋白受体激酶(tropomyosin-receptor kinase,TRK)是一类神经生长因子受体，隶属于受体酪氨酸激酶家族，主要包括高度同源的TRKA、TRKB和TRKC三个成员，分别由NTRK1、NTRK2和NTRK3三个基因编码而成。这些受体酪氨酸激酶主要在神经组织中表达，并通过神经营养因子NTs(neurotrophins)的激活在神经系统的发育和生理功能中发挥重要作用。TRK作为酪氨酸激酶受体，每个TRK都有与其相对应的配体结合并激活其下游的信号通路。NGF(nerve growth factor)特异性结合并激活TRKA；TRKB的配体包括有BDGF(brain-derived growth factor)和NT-4/5(neurotrophin-4/5)；NT-3特异性结合并激活TRKC。三种TRK受体均含有用于配体结合的细胞外结构域、跨膜结构域和具有激酶活性的胞内结构域。
当特定配体与相应受体的胞外结构域相结合，会引发受体的寡聚化和胞质内激酶结构域中特定酪氨酸残基的磷酸化，从而引起下游信号通路如Ras/MAPK、PLCγ/PKC和PI3K/AKT信号通路的激活，进而调控神经细胞的增殖、分化和存活等一系列生理过程。TRK信号通路通常被精确调控，而它的异常激活则与肿瘤发生密切相关。研究结果表明，引起TRK通路异常激活的机制有很多，包括基因融合、蛋白质过度表达和单核苷酸突变，这些异常与肿瘤的发病机制密切相关，特别是NTRK基因融合已被证实是导致多种肿瘤发生的重要因素，且不依赖于肿瘤的组织来源和类型。在当前二代测序技术和精准医疗的迅猛发展下，越来越多的NTRK融合基因被发现，例如ETV6-NTRK3、MPRIP–NTRK1、CD74–NTRK1等。近年来的临床试验结果表明，这些融合基因是非常有效的抗癌靶点，且含有NTRK融合基因的肿瘤对TRK抑制剂有非常显著的响应率。
因此，越来越多的TRK靶点抑制剂被报道，如(WO2010048314、WO2011146336、WO2017004342)。同时，在临床试验阶段，已经发现有部分接受治疗的患者出现了耐药现象，并被证实是由酶活区域的部分碱基突变引起，例如NTRK1 G595R或G667C突变，NTRK3的G623R或G696A突变。因此，本领域仍然需要开发新一代TRK激酶抑制剂，以解决上述问题。
发明内容
本发明的目的在于提供一类新的TRK激酶抑制剂及其制备方法和用途。
本发明第一方面，提供了一种式I所示的化合物，或其立体异构体或外消旋体，或其药学上可接受的盐：
Figure PCTCN2019111334-appb-000001
其中，
环A具有如下式所示的结构：
Figure PCTCN2019111334-appb-000002
各个X 4各自独立地为C或N；
各个X 5各自独立地为CR 7或N；其中，R 7为氢、氘，卤素，NH 2或OH；
R 1、R 2与和他们相连的氮原子共同形成6-12元并环(包括二环并环、三环并环)、桥环或螺环(包括取代或未取代的并环(包括二环并环、三环并环)、桥环或螺环)；其中，所述的并环、桥环或螺环含有1-3个选自氮原子、氧原子和硫原子的杂原子；
R A为
Figure PCTCN2019111334-appb-000003
其中，
X 1、X 2、X 3各自独立地为CR 6或N；R 6为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
n为1、2或3；
各个R 3各自独立地为氢、氘、羟基、卤素、三氟甲基，氰基，氨基，酰胺基，取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数；
R B为取代或未取代的4-7元杂环(所述杂环含有1-3个选自氮原子、氧原子和硫原子的杂原子)；-(CH 2) m1-、-O-(CH 2) m2-O-；其中，m1、m2各自独立地为1-4的整数
或者R B为-取代或未取代的-C1-C10亚烷基-L 2-(其中，L 2为NH、O、S或S(O) 2)、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、-O-(CH 2) m-O-；m为1-4的整数；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘、卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基 -(C1-C6酰胺基)、
Figure PCTCN2019111334-appb-000004
或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
虚线表示化学键或无。
在另一优选例中，所述的式I化合物具有如下式I-1所示的结构：
Figure PCTCN2019111334-appb-000005
在另一优选例中，环A为双环的9-10元杂芳环；其中，所述的杂芳环含有1-3个氮原子。
在另一优选例中，环A选自下组：
Figure PCTCN2019111334-appb-000006
在另一优选例中，所述的环A选自下组：
Figure PCTCN2019111334-appb-000007
在另一优选例中，R 1、R 2与和他们相连的氮原子共同形成取代或未取代的6-12元并环、桥环或螺环；所述的并环、桥环或螺环含有1-3个氮原子。
在另一优选例中，所述的并环为选自下组的并环：3并5、4并5、5并5、6并5、7并5、6并6、6并7。
在另一优选例中，所述的螺环为选自下组的螺环：螺[4·5]环、螺[5·5]环、螺[5·6]环、螺[5·7]环。
在另一优选例中，R 1、R 2与和他们相连的氮原子共同形成取代或未取代的选自下组的基团：
Figure PCTCN2019111334-appb-000008
Figure PCTCN2019111334-appb-000009
在另一优选例中，所述取代是指被选自下组的一个或多个基团所取代：C1-C6烷基、氧代、C1-C6烷基氰基。
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000010
包括：
Figure PCTCN2019111334-appb-000011
Figure PCTCN2019111334-appb-000012
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000013
包括
Figure PCTCN2019111334-appb-000014
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000015
包括
Figure PCTCN2019111334-appb-000016
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000017
包括
Figure PCTCN2019111334-appb-000018
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000019
包括
Figure PCTCN2019111334-appb-000020
在另一优选例中，取代的
Figure PCTCN2019111334-appb-000021
包括
Figure PCTCN2019111334-appb-000022
Figure PCTCN2019111334-appb-000023
在另一优选例中，R A选自下组：
Figure PCTCN2019111334-appb-000024
各式中，X 1、X 2定义同前；
芳香环上，n为1、2或3；且R 3为氢、氘、羟基、卤素、取代或未取代的C1-C6 烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数；
其它地方的R 3、R 4、R 5各自独立地为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基。
在另一优选例中，R A为
Figure PCTCN2019111334-appb-000025
其中，X 1为CR 6或N；X 2、X 3各自独立地为CR 6；
n为1、2或3；且R 3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；；或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数。
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2019111334-appb-000026
Figure PCTCN2019111334-appb-000027
Figure PCTCN2019111334-appb-000028
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2019111334-appb-000029
Figure PCTCN2019111334-appb-000030
本发明的第二方面，提供了一种药物组合物，其包含治疗有效量的如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，或如本发明第二方面所述的药物组合物的用途，其用于预防和治疗与TRK相关的疾病的药物中的用途。
在另一优选例中，所述TRK相关的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒，炎症相关疾病，骨相关的疾病。
在另一优选例中，所述的癌症选自TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的癌症(包括但不仅限于)：神经母细胞瘤， 前列腺癌，甲状腺癌，肺癌卵巢癌，胰腺癌、结直肠癌症、非小细胞肺癌、纤维肉瘤等。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如本发明第二方面所述的药物组合物的用途，其用于制备预防和/或治疗与TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的疾病的药物组合物。
在另一优选例中，所述的药物组合物可以与其他治疗剂进行联合用药。
在另一优选例中，所述的药物组合包括但不仅限于其他靶点的激酶抑制剂、免疫调节剂(肿瘤免疫检查点抑制剂)、细胞分裂阻滞剂等常规一线化疗药物。
在另一优选例中，所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒。
在另一优选例中，所述的癌症选自TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的癌症(包括但不仅限于)：神经母细胞瘤，前列腺癌，甲状腺癌，肺癌卵巢癌，胰腺癌、结直肠癌症、非小细胞肺癌、纤维肉瘤等。
本发明的第五方面，提供了一种TRK抑制剂，所述抑制剂包含如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
在另一优选例中，所述的TRK抑制剂选择性抑制选自下组的一种或多种TRK激酶：TRKA、TRKB或TRKC。
本发明的第六方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐的制备方法，其特征在于，所述方法包括步骤：
Figure PCTCN2019111334-appb-000031
在惰性溶剂中，将式Ia化合物与式Ib化合物反应，从而形成式I化合物；
其中，R 1为C1-C6烷基；其余各基团定义同本发明第一方面。
在另一优选例中，当式Ib化合物中还含有保护基团(例如，氨基保护基或羟基保护基等)，则该步骤中还含有脱保护基的步骤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次发现了一类新颖、有效的TRK激酶小分子抑制剂。在此基础上完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“C1-C6烷基”指含有1至6个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“6-10元芳环”意指具有6-10个环原子的芳环，所述环原子为碳原子。所述芳环可以单环或双环。例如苯环、萘环等类似基团。
在本申请中，作为基团或是其它基团的一部分，术语“5-10元杂芳环”意指具有5-10个环原子的杂芳环，所述环原子至少有1个(可以是1个、2个或3个)是选自氮、氧和硫的杂原子。所述杂芳环可以单环或双环。例如，嘧啶并吡唑环、吡嗪并咪唑环、吡啶并吡唑环、吡啶并咪唑环、吡啶并嘧啶环、吡啶并吡啶环。
在本申请中，作为基团或是其它基团的一部分，术语“6-11元桥环或螺环”意指具有6-11个环原子的双环，且其中两个环桥接或螺接。所述桥环或螺环含有1-3个选自氮原子、氧原子和硫原子的杂原子。例如，
Figure PCTCN2019111334-appb-000032
Figure PCTCN2019111334-appb-000033
本发明化合物
本发明的化合物为式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐。
本发明的化合物可能含有一个或多个手性碳原子，因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见 Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
制备方法
下列反应方案示例性的说明了制备式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐的方法，其中各基团均如在上所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
所述方法包括步骤：
Figure PCTCN2019111334-appb-000034
在惰性溶剂中，将式Ia化合物与式Ib化合物反应，从而形成式I化合物；
其中，R 1为C1-C6烷基；环B定义同本发明第一方面。
在另一优选例中，当式Ib化合物中还含有保护基团(例如，氨基保护基或羟基保护基等)，则该步骤中还含有脱保护基的步骤。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
应用
本发明的化合物具有优异的TRK(例如TRKA、TRKB、TRKC)抑制活性，，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与TRK激酶活性或表达量相关的疾病(例如，癌症)。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“肿瘤”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软 骨瘤、胆管瘤、白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本发明的主要优点在于：
本发明化合物能够有效的抑制KM12-LUC细胞的增殖。
本发明化合物能够在细胞学水平有效抑制TRKA、TRKB和TRKC的磷酸化水平。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发 明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
中间体1的合成
Figure PCTCN2019111334-appb-000035
(R,E)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019111334-appb-000036
将2,5-二氟苯(甲)醛(5g,35.2mmol)与(R)-2-甲基丙烷-2-亚磺酰胺(4.47g,36.9mmol)溶于二氯甲烷(50ml)中，室温下加入碳酸铯(8.0g,24.6mmol),然后升温至50℃反应3h，TLC显示反应完毕，过滤，滤饼用二氯甲烷洗涤，滤液用盐水洗涤，Na 2SO 4干燥，旋干得(R,E)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺，为黄色油状液体(9g)。
(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019111334-appb-000037
将镁屑(2g,83.3mmol)溶于四氢呋喃(72ml)中，氮气保护，于40℃下将Dibal-H(0.1ml,1.5M,0.15mmol)滴加入体系，40℃反应0.5h,然后将2-(2-溴乙 基)-1,3-二噁烷(14.3g,73.47mmol)的四氢呋喃(40ml)溶液缓慢滴加入体系并控制温度在40-50℃，滴完后保持40℃搅拌1h。撤掉加热，将反应体系冷却至-30℃，然后将(R,E)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(9g,36.73mmol)的四氢呋喃(40ml)溶液滴加入体系，控制其温度在-30℃-20℃，滴完后，于-30℃搅拌2h,TLC显示反应完毕,用10％的柠檬酸水溶液淬灭并控制温度在10℃，用二氯甲烷萃取，有机相用饱盐水洗涤，Na 2SO 4干燥，旋干得(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺，无色油状液体(15.8g)。
(R)-2-(2,5-二氟苯基)吡咯烷
Figure PCTCN2019111334-appb-000038
室温下将(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺(15.8g,43.76mmol)加入到三氟乙酸(32ml)与水(8ml)的混合溶液中，室温搅拌1h,然后将三氟乙酸(60ml)加入到体系，三乙基硅烷(15.2g,131.1mmol)滴加入体系，反应室温过夜，LCMS监测反应完毕，旋掉大部分三氟乙酸,剩余溶于盐酸(1N,100ml)并搅拌0.5h,用甲基叔丁基醚萃取，有机相用盐酸(1N,50ml)洗涤，合并水相，水相用40％氢氧化钠水溶液调节pH＝11,然后用二氯甲烷萃取，合并有机相，饱盐水洗涤，无水硫酸钠干燥，旋干得(R)-2-(2,5-二氟苯基)吡咯烷，油状液体(6.7g)。
吡唑并[1,5-a]嘧啶-5(4H)-酮
Figure PCTCN2019111334-appb-000039
将1H-吡唑-5-胺(20克,0.24摩尔)与1,3-二甲基嘧啶-2,4(1H,3H)-二酮(35克0.25摩尔)溶于乙醇(200毫升)中，室温下降乙醇钠(34克,0.50摩尔)分批加入反应体系中，加热到70℃反应3小时，LCMS监测反应完毕，待反应体系冷却至室温，过滤，滤饼用乙醇洗涤，正己烷洗涤，干燥得吡唑并[1,5-a]嘧啶-5(4H)-酮，黄色固体(36g,收率：94％)。
3-硝基吡唑并[1,5-a]嘧啶-5(4H)-酮
Figure PCTCN2019111334-appb-000040
室温下将吡唑并[1,5-a]嘧啶-5(4H)-酮(30克,191.1摩尔)分批加入到硝酸(68％)(150毫升)中，加热到80℃反应3小时，LCMS监测反应完毕，待反应体系冷却至室温，过滤，滤饼用水洗涤,甲醇洗涤，干燥得3-硝基吡唑并[1,5-a]嘧啶-5(4H)-酮，红色固体(28g,收率：82％)。
5-氯-3-硝基吡唑并[1,5-a]嘧啶
Figure PCTCN2019111334-appb-000041
将3-硝基吡唑并[1,5-a]嘧啶-5(4H)-酮(15克,83.3毫摩尔)与2,6-二甲基吡啶(17.8克,166.7毫摩尔)溶于乙腈(150毫升)中，室温下将POCl 3(51克,333.2毫摩尔)滴加入体系，然后升温至80℃搅拌过夜，LCMS监测反应完毕，将溶剂旋掉，剩余溶于二氯甲烷(200毫升)中，有机相用水洗涤，饱盐水洗涤，无水硫酸钠干燥，旋干得5-氯-3-硝基吡唑并[1,5-a]嘧啶，灰色固体(15g,收率：91％)。
(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-3-硝基吡唑并[1,5-a]嘧啶
Figure PCTCN2019111334-appb-000042
将5-氯-3-硝基吡唑并[1,5-a]嘧啶(2.38克,12.02毫摩尔)与(R)-2-(2,5-二氟苯基)吡咯烷(4克,12.62毫摩尔)溶于乙醇(40毫升)与四氢呋喃(10毫升)中，室温下加入三乙胺(4.2克,42毫摩尔),反应体系加热到50℃反应2小时，LCMS监测反应完毕，旋掉溶剂，剩余溶于二氯甲烷中，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干得(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-3-硝基吡唑并[1,5-a]嘧啶，黄色固体(3.7g,收率：90％)。
(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-胺
Figure PCTCN2019111334-appb-000043
将(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-3-硝基吡唑并[1,5-a]嘧啶(3.7克,10.72毫摩尔)溶于二氯甲烷(50毫升),甲醇(50毫升)与饱和氯化铵溶液(50毫升)的混合溶液中，室温下加入锌粉(6.8克，107.2毫摩尔),然后室温反应过夜，LCMS监测反应完毕，过滤，滤液用饱盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷/甲醇＝150/1-50/1)得(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-胺，黄色固体(3.2g,收率：94％)
1H NMR(400MHz,CDCl3):δ(ppm)8.06(d,J＝7.6Hz,1H),7.62(s,1H),7.06-7.00(m,1H),6.91-6.87(m,1H),6.77-6.73(m,1H),5.88(d,J＝1.6Hz,1H),5.32-5.29(m,1H),3.92(d,J＝7.2Hz,1H),3.75(d,J＝7.2Hz,1H),2.78(s,2H),2.48-2.44(m,1H),2.08-2.01(m,3H).
19F NMR(400MHz,CDCl3):δ(ppm)-124.30,-124.35.
中间体2的合成
Figure PCTCN2019111334-appb-000044
1)合成化合物2-3
Figure PCTCN2019111334-appb-000045
在单口瓶(100mL)中将化合物1-1(0.58g，2.0mmol)及化合物1-2(0.70g，4.0mmol)溶于EtOH(10.0mL)中，然后加入AcOH(0.24g，4.0mmol)。反应在室温下搅拌3小时。然后，加入NaBH 3CN(0.50g，8.0mmol)。所得反应液在75度下搅拌17小时。减压下将反应液浓缩至干，所得残余物溶于30mL二氯甲烷和30mL饱和氯化铵溶液。分离出有机相后，水相用二氯甲烷萃取两次。合并的有机相浓缩至干后所得残余物用石油醚和乙酸乙酯过柱，得无色油状物1-3(0.72g，80％收率)。LC-MS(ESI+)m/z:[M+H]450.32
2)合成化合物2-4
Figure PCTCN2019111334-appb-000046
在单口瓶(50mL)中加入化合物1-3(0.72g，1.6mmol)，CH 2Cl 2(8.0mL)及TFA(1.1g，9.6mmol)。反应在室温下搅拌17小时。反应液浓缩至干后所得粗产品1-4(1.2g，超过100％收率)直接用于下一步反应。LC-MS(ESI+)m/z:[M+H]350.20
3)合成化合物2-5
Figure PCTCN2019111334-appb-000047
在单口瓶(100mL)中加入化合物1-4(0.49g，1.4mmol)，MeOH(28mL)及NaOMe的甲醇溶液(浓度5.4mol/L,0.39mL，2.1mmol)。反应液在80度下搅拌3小时。反应液浓缩至干后所得残余物溶于20mL二氯甲烷和20mL水。分离出有机相后，水相用二氯甲烷萃取两次。合并的有机相浓缩至干后所得粗产品1-5(0.37g，87％收率)。LC-MS(ESI+)m/z:[M+Na]326.14
4)合成化合物2
Figure PCTCN2019111334-appb-000048
在单口瓶(50mL)中加入化合物1-5(0.37g，1.24mmol)，Boc 2O(0.35g，1.61mmol)，Et 3N(0.13g，1.24mmol)及CH 2Cl 2(2.5mL)。反应液在室温下搅拌12小时。反应液浓缩至干所得残余物用石油醚和乙酸乙酯过柱，得黄色油状物1-6(0.33g，66％收率)。LC-MS(ESI+)m/z:[M+Na]426.36
中间体化合物3的合成
Figure PCTCN2019111334-appb-000049
1)合成化合物3-2
Figure PCTCN2019111334-appb-000050
在单口瓶(100毫升)中加入化合物1(630mg，2.69mmol)，化合物2(698mg，4.03mmol),甲醇(15mL),反应在室温反应1小时，加入氰基硼氢化钠(253mg，4.03mmol)，反应在室温反应16小时。反应液旋干，用二氯甲烷和甲醇过柱，得黄色油状物3(960mg，收率91％)。LC-MS(ESI):m/z(M+H) +392.31。
2)合成化合物3-3
Figure PCTCN2019111334-appb-000051
在单口瓶(100毫升)中加入化合物3(960mg，2.45mmol)，盐酸二氧六环(15mL,60mmol),反应在室温反应2小时。反应液旋干，得黄色油状物4(980mg,收率100％)。LC-MS(ESI):m/z(M+H) +292.24.
3)合成化合物3
Figure PCTCN2019111334-appb-000052
在单口瓶(100毫升)中加入化合物4(980mg，2.45mmol)，碳酸钾(1.014g，7.35mmol),甲醇(15mL),反应在75度回流反应3小时。反应液冷却至室温，过滤，滤液旋干，用二氯甲烷和甲醇过柱，得黄色油状物5(390mg，收率61％)。LC-MS(ESI):m/z(M+H) +260.24。1H NMR(400MHz,DMSO)δ7.26(m,5H),3.59(m,2H),3.22(m,2H),2.80(m,5H),2.65(dd,J＝24.8,9.1Hz,2H),2.40(dd,J＝15.9,7.9Hz,1H),2.18(ddd,J＝12.4,7.8,4.6Hz,1H),1.67(dt,J＝12.4,7.3Hz,1H).
实施例1:N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-1,7-二氮杂螺[4.4]壬烷-7-甲酰胺
Figure PCTCN2019111334-appb-000053
向(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-胺(40毫克,0.126毫摩尔)的二氯甲烷溶液(4毫升)中加入CDI(41毫克,0.253毫摩尔)，室温搅拌2个小时，再加入叔-丁基1,7-二氮杂螺[4.4]壬烷-1-羧酸酯(143毫克,0.632毫摩尔)和N,N-二异丙基乙胺(163毫克,1.265毫摩尔)的二氯甲烷溶液(2ml).反应液继续搅拌2小时，液质监控显示有产物生成，浓缩，加入盐酸/1-4二氧六环溶液(4毫升，4N)，搅拌过夜，浓缩，残渣通过制备型高效液相色谱纯化获得目标产物(27.7毫克,62％)，为黄色固体。
MS-ESI:m/z 468[M+H]+.
1H NMR(400MHz,CD 3OD)δ(ppm)8.24(s,1H),7.87(s,1H),7.16-7.07(m,1H),7.02-6.93(m,1H),6.84-6.80(m,1H),6.40-6.10(m,1H),5.41(s,1H),4.59-4.57(m,1H),4.01-3.91(m,1H),3.80-3.66(m,1H),3.62-3.50(m,2H),3.45-3.32(m,2H),3.05–2.82(m,2H),2.55-2.40(m,1H),2.12-1.96(m,4H),1.94–1.72(m,4H).
实施例2 7-氨基-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-2-氮杂螺[4.5]癸烷-2-甲酰胺
Figure PCTCN2019111334-appb-000054
将N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-7-羰基-2-氮杂螺[4.5]癸烷-2-甲酰胺(30毫克，0.06毫摩尔),乙酸铵(23毫克，0.30毫摩尔)溶解在甲醇(4毫升)，室温搅拌2小时，加入氰基硼氢化钠(11毫克，0.18毫摩尔)，室温搅拌2小时，浓缩，残渣通过制备型高效液相色谱纯化获得目标产物(27.7毫克,62％)，为黄色固体。
MS-ESI:m/z 496[M+H]+.
1H NMR(400MHz,CD 3OD)δ(ppm)8.25(d,J＝4.0Hz,1H),7.87(s,1H),7.14-7.08(m,1H),7.01-6.93(m,1H),6.84-6.80(m,1H),6.15(brs,1H),5.41(s,1H),4.00-3.91(m,1H),3.75-3.73(m,1H),3.49-3.45(m,2H),3.22-3.15(m,1H),2.88-2.77(m,1H),2.51-2.41(m,1H),2.07-1.11(m,16H).
实施例3:N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-1,4-二甲基-5-羰基八氢吡咯并[3,4-e][1,4]二氮杂卓-7(1H)-甲酰胺
Figure PCTCN2019111334-appb-000055
将N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-4-甲基-5-羰基八氢吡咯并[3,4-e][1,4]二氮杂卓-7(1H)-甲酰胺(14毫克，0.027毫摩尔),甲醛水溶液(1毫升)和醋酸(2滴)溶解在甲醇(3毫升)，室温搅拌2小时，加入氰基硼氢化钠(5毫克，0.082毫摩尔)，室温搅拌1小时，浓缩，残渣通过制备型高效液相色谱纯化获得目标产物(27.7毫克,62％)，为黄色固体。
MS-ESI:m/z 525[M+H]+.
1H NMR(400MHz,CD 3OD)δ(ppm)8.25(d,J＝6.4Hz,1H),7.87(d,J＝4.8Hz, 1H),7.16-7.10(m,1H),6.99-6.93(m,1H),6.84-6.79(m,1H),6.14(brs,1H),5.39(brs,1H),4.00-3.87(m,4H),3.80-3.71(m,2H),3.45-3.33(m,2H),3.01(s,3H),3.01-2.95(m,2H),2.67-2.59(m,1H),2.49-2.36(m,2H),2.32(s,3H),2.07-1.96(m,3H).
采用类似于实施例1-3的条件，替换相应的起始原料，得到如下表中所示化合物：
Figure PCTCN2019111334-appb-000056
Figure PCTCN2019111334-appb-000057
对比例1:2-(1-(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-羰基)-3-羟基吡咯烷-3-基)-N-甲基乙酰胺
Figure PCTCN2019111334-appb-000058
目标化合物在类似于实施例1的条件下制备
MS(ESI):m/z＝485[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm)7.75-7.70(m,1H),7.65(t,J＝5.5Hz,1H),7.18–7.04(m,1H),7.04–6.78(m,3H),5.38-5.32(m,1H),4.08–3.43(m,6H),2.78–2.60(m,3H),2.58-2.40(m,2H),2.35-2.15(m,1H),2.14–1.69(m,5H).
对比例2:(6-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)(3-((二甲氨基)甲基)-4-羟基吡咯烷-1-基)甲酮
Figure PCTCN2019111334-appb-000059
目标化合物在类似于实施例1的条件下制备
MS(ESI):m/z＝471[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm)7.77-7.70(m,1H),7.67-7.65(m,1H),7.18–7.08(m,1H),7.00-6.80(m,2H),5.34(t,J＝9.4Hz,1H),4.56(s,1H),4.15-4.05(m,1H),4.00-3.63(m,4H),3.60-3.45(m,1H),3.44–3.33(m,1H),3.15-2.88(m,1H),2.56–2.40(m,2H),2.39–1.92(m,9H).
生物实施例1：TRKA，TRKB，TRKC激酶体外活性测试
实验材料
重组人源TRKA，TRKB，TRKC蛋白购自Carna Biosciences。HTRF kinEASE TK试剂盒购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行3倍浓度梯度稀释，终浓度为1μM到0.05nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA酶反应：
0.2ng/μl TRKA蛋白激酶，1μM TK底物-生物素(Substrate-biotin)多肽底物，14.68μM ATP，1×酶缓冲液，5mM MgCl 2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
TRKB酶反应：
0.037ng/μl TRKB蛋白激酶，1μM TK底物-生物素(Substrate-biotin)多肽底物，4.77μM ATP，1×酶缓冲液，5mM MgCl 2，1mMMnCl 2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
TRKC酶反应：
0.037ng/μl TRKC蛋白激酶，1μM TK底物-生物素(Substrate-biotin)多肽底物，25.64μM ATP，1×酶缓冲液，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-抗体，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值通过下列公式将读数转化成抑制率(％)＝(1-Ratio test/Ratio max)×100％。Ratio max为不含检测化合物的阳性对照，Ratio test为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表1。
表1
化合物 TRKA(nm) TRKB(nm) TRKC(nm)
实施例1 ++ + ++
实施例2 +++ +++ +++
实施例3 +++ +++ +++
实施例4 ++ ++ ++
实施例5 +++ ++ +++
实施例6 +++ ++ +++
实施例7 ++ + ++
实施例8 ++ ++ ++
实施例9 +++ +++ +++
对比例1 + - -
对比例2 - - -
其中，+++表示IC 50＜10nm，++表示10nm＜IC 50＜100nm，+表示100nm＜IC 50＜500nm、-表示IC 50＞500nm
生物测试例2:用elisa方法检测细胞学水平TRK激酶活性
通过质粒转染构建稳定表达正常TRKA或TRKB或TRKC的NIH-3T3细胞株。
第一天接种细胞于96孔细胞培养板，10000细胞/孔于正常培养基中(DMEM+10％FBS)。第二天换含有0.5％FBS的培养基饥饿过夜。第三天加不同浓度的待测化合物处理细胞1个小时,然后用100ng/ul生长因子刺激10分钟(NGF用于激活TRKA，BDNF用于激活TRKB，NT-3用于激活TRKC)。将细胞培养板置于冰上；去掉上清，用预冷的PBS润洗一次。用双蒸水稀释elisa试剂盒中附带的裂解液(Cellsignaling Technology)并加入蛋白酶和磷酸酶抑制剂。将配置好的细胞裂解液加入孔板中，冰上静置20分钟。排枪吹打细胞裂解液数次，并将其转移至抗体预包被的板条中，封板并4度过夜孵育。剩余步骤参照elisa试剂盒中提供的方法进行(例如Cellsignaling Technology#7212C中所描述)。
结果显示，本发明化合物能够在细胞学水平有效的抑制TRKA、TRKB磷酸化水平，具体见表2。
表2
化合物 TRKA(nm) TRKB(nm)
实施例2 ++ ++
生物测试例3:KM12-LUC细胞增殖实验
含有TPM3-NTRK1融合基因的人结肠癌细胞株KM12-LUC(LUC,稳定表达Luciferace)用于待测化合物细胞学水平药效评估的模型。KM12-LUC细胞中的TRK融合基因使其不依赖于胞外生长因子的刺激，可以持续自发激活并激活其下游信号通路MAPK-ERK、PI3K-AKT等与细胞增殖密切相关的信号通路。因此，在KM12-LUC细胞中抑制TRK活性可显著抑制细胞的增殖。
方法如下：第一天，在384孔板中接种细胞，2000细胞/孔；第二天加不同浓度的待测化合物；第五天，加CellTiter-Glo(Promega)检测细胞活性，计算细胞72小时增殖抑制率。用prism5来进行统计分析并得出待测化合物的IC 50值。
结果显示，本发明化合物能够有效的抑制KM12-LUC细胞的增殖，具体见表3
表3
化合物 KM12-LUC(nm)
实施例2 ++
生物测试例4突变的TRKA(G595R),TRKA(G667C)and TRKC(G623R)激酶体外活性测试
实验材料
重组人源TRKA(G595R)，TRKA(G667C)，TRKC(G623R)蛋白购自SignalChem。HTRF kinEASE TK kit购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行4倍浓度梯度稀释，终浓度为1μM到0.004nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA(G595R)酶反应：
0.12ng/μlTRKA(G595R)蛋白激酶，1μM TK Substrate-biotin多肽底物，4.5μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKA(G667C)酶反应：
0.026ng/μlTRKA(G667C)蛋白激酶，1μM TK Substrate-biotin多肽底物，5.5μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKC(G623R)酶反应：
1.0ng/μlTRKC(G623R)蛋白激酶，1μM TK Substrate-biotin多肽底物，62.9μM ATP，1×enzymatic buffer，5mM MgCl 2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值减去不含酶的阴性对照孔数值后通过下列公式将读数转化成抑制率(％)＝(1-Ratio test/Ratio max)×100％。Ratio max为不含检测化合物的阳性对照，Ratio test为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表4。
表4
化合物 TRKA(G595R)(nm)
实施例1 ++
实施例2 ++
实施例3 ++
实施例4 ++
实施例5 +
实施例6 ++
实施例7 ++
实施例8 +
实施例9 ++
对比例1 ++
对比例2 ++
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐：
    Figure PCTCN2019111334-appb-100001
    其中，
    环A具有如下式所示的结构：
    Figure PCTCN2019111334-appb-100002
    各个X 4各自独立地为C或N；
    各个X 5各自独立地为CR 7或N；其中，R 7为氢、氘，卤素，NH 2或OH；
    R 1、R 2与和他们相连的氮原子共同形成取代或未取代的6-12元并环(包括二环并环、三环并环)、桥环或螺环；其中，所述的并环、桥环或螺环含有1-3个选自氮原子、氧原子和硫原子的杂原子；
    R A为
    Figure PCTCN2019111334-appb-100003
    其中，
    X 1、X 2、X 3各自独立地为CR 6或N；R 6为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
    n为1、2或3；
    各个R 3各自独立地为氢、氘、羟基、卤素、三氟甲基，氰基，氨基，酰胺基，取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
    或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数；
    R B为取代或未取代的4-7元杂环(所述杂环含有1-3个选自氮原子、氧原子和硫原子的杂原子)；-(CH 2) m1-、-O-(CH 2) m2-O-；其中，m1、m2各自独立地为1-4的整数；
    或者R B为-取代或未取代的-C1-C10亚烷基-L 2-(其中，L 2为NH、O、S或S(O) 2)、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘、卤素、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6 烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O) 2NH 2、氧代(＝O)、-CN、羟基、-NH 2、羧基、C1-C6酰胺基(-C(＝O)-N(Rc) 2或-NH-C(＝O)(Rc)，Rc为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
    Figure PCTCN2019111334-appb-100004
    或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-12元杂环基、-(CH 2)-C6-C10芳基、-(CH 2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH 2、-OH、C6-C10芳基、C1-C6胺基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
    虚线表示化学键或无。
  2. 如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，环A为双环的9-10元杂芳环；其中，所述的杂芳环含有1-3个氮原子。
  3. 如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，R 1、R 2与和他们相连的氮原子共同形成取代或未取代的6-12元并环、桥环或螺环；所述的并环、桥环或螺环含有1-3个氮原子。
  4. 如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，R A选自下组：
    Figure PCTCN2019111334-appb-100005
    各式中，X 1、X 2定义同前；
    芳香环上，n为1、2或3；且R 3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数；
    其它位置的R 3、R 4、R 5各自独立地为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基。
  5. 如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，R A为
    Figure PCTCN2019111334-appb-100006
    其中，X 1为CR 6或N；X 2、X 3各自独立地为CR 6；
    n为1、2或3；且R 3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；；或者n为2且两个R 3共同形成-O-(CH 2) m-O-；m为1-4的整数。
  6. 如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，选自下组：
    Figure PCTCN2019111334-appb-100007
    Figure PCTCN2019111334-appb-100008
  7. 一种药物组合物，其包含治疗有效量的权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
  8. 权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐或权利要求7所述的药物组合物的用途，其特征在于，用于预防和治疗与TRK功能异常相关的疾病的药物中的用途。
  9. 一种TRK抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
  10. 权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐的制备方法，其特征在于，所述方法包括步骤：
    Figure PCTCN2019111334-appb-100009
    在惰性溶剂中，将式Ia化合物与式Ib化合物反应，从而形成式I化合物；
    其中，R 1为C1-C6烷基；其余各基团定义同权利要求1。
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