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WO2021043209A1 - 一种ret抑制剂、其药物组合物及其用途 - Google Patents

一种ret抑制剂、其药物组合物及其用途 Download PDF

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Publication number
WO2021043209A1
WO2021043209A1 PCT/CN2020/113240 CN2020113240W WO2021043209A1 WO 2021043209 A1 WO2021043209 A1 WO 2021043209A1 CN 2020113240 W CN2020113240 W CN 2020113240W WO 2021043209 A1 WO2021043209 A1 WO 2021043209A1
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alkyl
group
membered
independently
compound
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PCT/CN2020/113240
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English (en)
French (fr)
Inventor
谢洪明
罗明
张英俊
杨桂珍
王凯
何锦
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广东东阳光药业有限公司
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Publication of WO2021043209A1 publication Critical patent/WO2021043209A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/4985—Pyrazines or piperazines 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • 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

Definitions

  • the present invention belongs to the field of medicine. Specifically, the present invention relates to a novel compound exhibiting transfection-period rearrangement (RET) kinase inhibition, a pharmaceutical composition containing the compound, the use of the compound or the pharmaceutical composition thereof in the preparation of medicines.
  • the drugs are particularly useful for the treatment and prevention of RET-related diseases and disorders, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
  • RET Re-arranged during transfection is one of the receptor tyrosine kinases belonging to the cadherin superfamily, which activates multiple downstream pathways involved in cell proliferation and survival.
  • RET fusion protein is associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer.
  • the identification of RET fusion protein as a driving factor for certain cancers has prompted the use of multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion protein.
  • multi-kinase inhibitors such as Sorafenib, sunitinib, vandetanib, and punatinib exhibit cell proliferation inhibitory effects on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012 ,suppl; Abstract no:7510).
  • the multi-kinase inhibitor cabozantinib showed partial efficacy in two non-small cell lung cancer patients with positive RET fusion gene (Cancer Discov, 3(6), Jun2013, p.630-5).
  • these drugs cannot always be administered at a level sufficient to inhibit RET due to toxicity due to the inhibition of targets other than RET.
  • one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Reactivation of kinases through mutations is a common resistance mechanism. When drug resistance occurs, the patient's treatment options are usually very limited, and cancer progression is not inhibited in most cases.
  • WO 2017011776 discloses a single-target RET kinase inhibitor, which has a good preventive or therapeutic effect on RET and mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to deal with cancers related to abnormal RET genes.
  • the present invention provides a new compound that exhibits the inhibition of transfection-period rearrangement (RET) kinase.
  • the compound has a good inhibitory effect on RET wild-type and RET gene mutants, and has a better effect on RET wild-type and RET gene mutants. Good inhibition selectivity.
  • the present invention provides a compound represented by formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, Metabolites, pharmaceutically acceptable salts or prodrugs,
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently CR 4 or N;
  • Y is O, NH or S
  • T is a bond, alkylene, alkylene-O- or alkylene-NH-, and the T is optionally selected from D, OH, F, Cl, Br by 1, 2, 3, or 4 , I, CN, NH 2 , CF 3 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino substituents;
  • Ring G is a spirocarbocyclyl or spiroheterocyclic group
  • q 0, 1, 2, 3 or 4;
  • E is a bond, -NR 6 -, or -O-;
  • Each f is independently 1, 2, 3, or 4;
  • Each t is independently 0, 1, 2, 3, or 4;
  • M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, CF 3 , OH, Substituted by substituents of NR 5 R 6 , OR 7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclyl, cycloalkyl ;
  • R 1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected from F, Substituted by Cl, Br, CN, NH 2 , OH and NO 2 substituents;
  • Each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkane Group, cycloalkylalkyl, aryl, heteroaryl;
  • R 2 , R 3 and the same C atom connected to them form a carbocyclic or heterocyclic ring;
  • R 4 is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from F, Cl, Replaced by substituents of Br, CN, NH 2 , OH and NO 2;
  • R 5 is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optional Ground is substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH 2 , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl ;
  • R 6 is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally selected from F, Cl, Br, CN , NH 2 , OH and NO 2 substituents;
  • R 7 is OH, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl.
  • T is a bond, C 1-6 alkylene, C 1-6 alkylene-O- or C 1-6 alkylene-NH-, and T is optionally substituted by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF 3 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, C 6-10 aryl, 5-12 membered heteroaryl, or C 1-6 alkylamino substituents are substituted.
  • T is a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -( CH 2 ) 6 -, -(CH 2 ) 2 -O- or -(CH 2 ) 2 -NH-, and the T is optionally selected from 1, 2, 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF 3 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidine Substituents are substituted by substituents of phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy
  • G is a 6-12 membered spiro carbocyclic group or a 6-12 membered spiro heterocyclic group
  • R 5 is H, D, C 1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group are each independently optionally selected by 1, 2, 3 or 4 Substituted by a substituent selected from F, Cl, Br, OH, NH 2 , C 1-6 alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
  • R 6 is H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkane
  • the groups are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 ;
  • R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl.
  • G is the following sub-structure:
  • each ring T1 is independently a 4-7 membered carbon monocyclic ring or heteromonocyclic ring;
  • Z 1 and Z 2 are independently -CH 2 -, -O-, -S-, -NH-;
  • Z 3 is -O-, -S-, -NH-;
  • n1 0, 1 or 2;
  • n2 is 1, 2 or 3;
  • n3 is 0 or 1.
  • G is the following sub-structure:
  • R 6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl Group, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl each independently optionally selected from F, Cl, Br, CN, NH 2 , Substituted by OH and NO 2 substituents;
  • R 7 is OH, methyl, ethyl, NH 2 , N(CH 3 ) 2 , n-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
  • A is the following sub-structure:
  • Z 1a and Z 2a are each independently -CH 2 -or -NH-;
  • Z 3a is -CH- or -N-;
  • Z 4a is -O-, -S- or -NH-;
  • n and t are each independently 0, 1 or 2;
  • n and t1 are each independently 0 or 1;
  • A is the following sub-structure:
  • M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted by 1 , 2, 3 or 4 selected from D, F, Cl, CN, OH, CF 3 , NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxy alkane Group, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkyl acyl, 3-7 membered heterocyclic group, C 3-7 cycloalkyl substituents are substituted.
  • M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclo Hexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydro Pyridyl, 7-azabicyclo[2.2.1]heptyl, hexahydrofuran[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptanyl; and M is optional
  • R 1 is H, D, CN, F, Cl, Br, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl and cyclopropyl can be independently optionally 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 ;
  • R 4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethyl group may be optionally independently substituted with 1,2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2, OH , NO 2 substituted by a substituent.
  • each R 2 and R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
  • R 2 , R 3 and the same C atom connected to them form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
  • each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl , Methyl, ethyl, N(CH 3 ) 2 , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl Group, cyclopentyl ethyl, cyclopentyl methyl, phenyl, pyridyl, pyrazinyl;
  • R 2 , R 3 and the same C atom connected to them form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
  • the compound of the present invention has a structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, or nitrogen oxide of the structure of formula (I-1) , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Ring A1 is the following sub-structure:
  • Z 1a and Z 2a are each independently CH 2 or NH;
  • A1 is a sub-structure:
  • the compound described in the present invention has a structure of formula (I-2) or (I-3), or a stereoisomer of a structure of formula (I-2) or (I-3), geometrically different Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Z 1 , Z 2 and Z 3a are each independently CH or N;
  • n and t are each independently 0, 1 or 2;
  • n and t1 are each independently 0 or 1;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of RET-related diseases.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for the prevention or treatment of RET-related diseases.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention also provides a method for preventing or treating RET-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention relates to intermediates for preparing compounds represented by the structures of formula (I), (I-1), (I-2) or (I-3).
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), (I-1), (I-2) or (I-3).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically suitable and related to the other components of the formulation and the mammal used for treatment.
  • the salts of the compounds of the present invention also include intermediates or intermediates for the preparation or purification of compounds represented by formula (I), (I-1), (I-2) or (I-3) or formula (I), (I- 1)
  • subject used in the present invention refers to an animal. Typically the animal is a mammal.
  • the subject also refers to primates (such as humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R and S configurations, (Z) and (E) isomers of the double bond, and (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) belongs to the scope of the present invention.
  • the structural formula and the compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts and prodrug compounds also fall within the scope of the present invention.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the compounds of the present invention can be independently optionally substituted with one or more substituents, such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and subclasses in the examples.
  • a class of compounds A class of compounds.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent.
  • an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in the present invention Replaced. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkyl When an alkyl group is a linking group, and “alkyl” is listed for the Markush group definition, then “alkyl” means the connected alkylene group.
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group.
  • alkylene groups include, but are not limited to: -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, and the like.
  • alkylene-O- means that an alkylene group is connected to other parts of the molecule through an oxygen atom, wherein the alkylene group has the definition as described in the present invention.
  • alkylene-NH- means that an alkylene group is connected to other parts of the molecule through NH, wherein the alkylene group has the definition as described in the present invention.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups.
  • hydroxyalkyl represents an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups.
  • hydroxyalkyl means an alkyl group substituted with 1 or 2 hydroxy groups.
  • hydroxyalkyl represents C 1-6 hydroxyalkyl, that is, C 1-6 alkyl is substituted by one or more hydroxy groups.
  • C 1-6 hydroxyalkyl represents C 1 -6 Alkyl group substituted with 1 hydroxy group.
  • hydroxyalkyl represents C 1-4 hydroxyalkyl.
  • hydroxyalkyl represents C 1-3 hydroxyalkyl.
  • hydroxyalkyl groups include, but are not limited to, OHCH 2 -, CH 2 OHCH 2 CH 2 CH 2 -, CH 2 OHCH 2 -, CH 2 OHCH 2 CHOHCH 2 -, CH(CH 3 )OHCH 2 CHOHCH 2 -, ( CH 3 )OHCH-, etc.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-but Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-(
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, wherein the alkoxy group and the alkyl group have the definitions as described in the present invention.
  • alkoxyalkyl represents C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1-4 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl represents C 1-3 alkoxy C 1-3 alkyl.
  • alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl Group, propoxyethyl, propoxypropyl, etc.
  • halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
  • haloalkyl means that an alkyl group is substituted with one or more halogen atoms.
  • haloalkyl represents C 1-6 haloalkyl, that is, an alkyl in which C 1-6 alkyl is substituted with one or more halogens.
  • haloalkyl represents C 1-4 haloalkyl.
  • haloalkyl represents C 1-3 haloalkyl.
  • Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2, 2-Difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-di Chloroethyl, 1,1-dibromoethyl, etc.
  • cycloalkyl refers to a monovalent saturated monocyclic carbocyclic ring system.
  • the cycloalkyl group contains 3-7 ring carbon atoms, that is, a C3-7 cycloalkyl group.
  • the cycloalkyl group contains 3-6 carbon atoms, that is, C 3-6 cycloalkyl; in another embodiment, the cycloalkyl group contains 3-5 carbon atoms, that is, C 3-5 ring alkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group may be independently optionally substituted with one or more substituents described in the present invention.
  • cycloalkylene refers to a divalent saturated monocyclic carbocyclic ring system.
  • the cycloalkylene group contains 3-7 ring carbon atoms, that is, a C3-7 cycloalkylene group.
  • cycloalkylene containing 3-6 carbon atoms i.e.
  • a cycloalkyl group containing 3-5 carbon atoms i.e., C 3- 5 Cycloalkylene
  • examples of cycloalkylene include but are not limited to 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene , 1,3-cyclopentylidene, etc.
  • the cycloalkylene group may be independently optionally substituted with one or more substituents described in the present invention.
  • monocyclic refers to a saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic ring have the definitions as described in the present invention.
  • the monocyclic carbocyclic ring system is a carbon monocyclic ring
  • the monocyclic heterocyclic ring system is a heteromonocyclic ring.
  • the term "monocyclic group” means a monovalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic ring have the definitions as described in the present invention.
  • a monocyclic group contains 3-7 ring atoms, that is, a monocyclic group is a 3-7 membered monocyclic group; in other embodiments, a monocyclic group contains 3-6 ring atoms, that is, a monocyclic group contains 3-6 ring atoms.
  • the cyclic group is a 3-6 membered monocyclic group.
  • monocyclic groups include, but are not limited to: cyclopropyl, cyclopentyl, cyclohexyl, 1,2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furanyl, and the like.
  • the monocyclic group described in the present invention is a monovalent saturated monocyclic carbocyclic or monocyclic heterocyclic ring system.
  • the monocyclic group may be independently optionally substituted with one or more substituents described in the present invention.
  • the term "monocyclic group” refers to a divalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic ring and heterocyclic ring have the definitions as described in the present invention.
  • the sub-monocyclic group contains 3-7 ring atoms, that is, the sub-monocyclic group is a 3-7 membered monocyclic group; in other embodiments, the sub-monocyclic group contains 3-6 rings.
  • the atom, that is, the monocyclic group is a 3-6 membered monocyclic group.
  • the monocyclic ring group of the present invention is a divalent saturated monocyclic carbocyclic or monocyclic heterocyclic ring system.
  • monocyclic groups include, but are not limited to, cyclopropylene, cyclopentylene, cyclohexylene, 1,2-cyclopentadienylene, pyrrolidinylene, and the like.
  • the monocyclic cyclylene group may be independently optionally substituted with one or more substituents described in the present invention.
  • the term "monoheterocyclylene” refers to a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the definition as described in the present invention.
  • the monoheterocyclylene contains 3-7 ring atoms, that is, the monoheterocyclylene is a 3-7 membered monoheterocyclylene; in other embodiments, the monoheterocyclylene contains 3 -6 ring atoms, that is, monoheterocyclylene is 3-6 membered monoheterocyclylene.
  • the monocyclic heterocyclic group of the present invention is a divalent saturated monocyclic heterocyclic ring system.
  • heterocyclylalkyl means an alkyl group substituted with a heterocyclyl group, wherein the heterocyclyl group and the alkyl group have the definitions as described in the present invention.
  • heterocyclylalkyl is 3-12 membered heterocyclyl C 1-6 alkyl; in other embodiments, heterocyclyl alkyl is 3-6 membered heterocyclyl C 1-6 Alkyl; In some embodiments, heterocyclylalkyl is 3-6 membered heterocyclyl C 1-4 alkyl.
  • heterocyclylalkyl include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, and the like.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definitions described in the present invention.
  • the haloalkoxy group represents a C 1-6 haloalkoxy group, that is, an alkyl group in which the C 1-6 alkoxy group is substituted with one or more halogens.
  • haloalkoxy represents C 1-4 haloalkoxy.
  • haloalkoxy represents C 1-3 haloalkoxy.
  • Such examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, monochloroethoxy, and many more.
  • alkyl acyl represents C 1-6 alkyl acyl; in other embodiments, alkyl acyl represents C 1-4 alkyl acyl.
  • alkyl acyl include, but are not limited to: formyl, acetyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group. Wherein cycloalkyl and alkyl have the definitions as described in the present invention. In some embodiments, cycloalkylalkyl represents C 3-7 cycloalkyl C 1-6 alkyl; in other embodiments, cycloalkyl alkyl represents C 3-6 cycloalkyl C 1-6 Alkyl; In other embodiments, cycloalkylalkyl means C 3-6 cycloalkyl C 1-4 alkyl. Examples of cycloalkylalkyl include, but are not limited to: cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.
  • aromatic ring or "aromatic hydrocarbon” means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, of which at least one The ring system is aromatic, where each ring system contains a ring composed of 3-7 atoms. Examples of aromatic rings may include benzene, naphthalene, and anthracene.
  • aryl refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring carbon atom of an aromatic ring.
  • aryl groups may include phenyl, naphthyl, and anthracenyl.
  • aryl is listed for the Markush group definition, then "aryl” means a linked arylene group.
  • M is an aryl group in the definition of the present invention, it means that M is a linked arylene group.
  • arylene refers to a divalent aromatic ring group formed by removing two hydrogen atoms from the ring carbon atoms of an aromatic ring.
  • Examples of the aryl group represented as an attached arylene group may include a phenylene group, a naphthylene group, and an anthrylene group.
  • the aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • heteromatic ring refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms.
  • heteroaryl refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring atom of a heteroaromatic ring.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group or the 5-10 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the term “heteroaryl” means a heteroaromatic ring group containing 5 ring atoms or a 5-membered heteroaryl group, which contains 1, 2, 3, or 4 heteroaryl groups independently selected from O, S, and N. atom.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroaryl group When a heteroaryl group is a linking group, and a heteroaryl group is listed for the Markush group definition, the heteroaryl group means a connected heteroarylene group.
  • M When M is a heteroaryl group in the definition of the present invention, it means that M is a connected heteroarylene group.
  • heteroarylene refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from the ring atoms of a heteroaryl group.
  • the heteroaryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • bridged ring group refers to a bivalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more non-adjacent ring atoms, including bridged carbocyclyls and bridged heterocycles. Ring base.
  • the bridging ring group is a 5-12 membered bridging ring group.
  • the bridging cyclylene group may be independently optionally substituted with one or more substituents described in the present invention.
  • oxocyclylene refers to a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two adjacent ring atoms, including carbocyclylene and heterocyclylene.
  • the oxocyclylene group is a 5-12 membered oxocyclylene group.
  • the pyrimidine group may be independently optionally substituted with one or more substituents described in the present invention.
  • spirocyclylene refers to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system formed by two rings sharing one carbon atom, including spirocarbocyclylene and spiroheterocyclylene.
  • the spirocyclylene is a 5-12 membered spirocyclylene.
  • the spirocyclylene group may be independently optionally substituted with one or more substituents described in the present invention.
  • carrier group and “carbocyclic ring” can be used interchangeably to indicate a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system in which the ring atoms are all carbon atoms, including monocarbocyclic groups, bridged carbocyclic groups, And carbocyclyl and spirocarbocyclyl.
  • bridged carbocyclic ring and “bridged carbocyclic group” can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring carbon atoms, And the ring atoms are carbon atoms.
  • the bridged carbocyclic ring contains 6-12 ring carbon atoms, which means 6-12 membered carbon ring; in other embodiments, the bridged carbocyclic ring contains 6-10 ring carbon atoms, which means 6 -10 bridged carbon ring.
  • bridged carbocyclic rings include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, Octahydro-1H-indene, etc.
  • a bridged carbocyclic ring or a bridged carbocyclic group is a linking group, and a bridged carbocyclic ring or a bridged carbocyclic group is listed for the Markush group definition, then the bridged carbocyclic ring or bridged carbocyclic group means the connected subbridged carbon Ring base.
  • bridged carbocyclic group means a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged carbocyclic ring.
  • the bridged carbocyclic or bridged carbocyclic group may be independently optionally substituted with one or more substituents described in the present invention.
  • spirocarbocyclic and “spirocarbocyclyl” can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system formed by two carbocyclic rings sharing one carbon atom.
  • the spiro carbocyclic ring contains 7-12 ring carbon atoms, which means 7-12 membered spiro carbocyclic ring; in other embodiments, the spiro carbocyclic ring contains 7-10 ring carbon atoms, which means 7 -10 membered spiro carbon ring.
  • spirocarbocyclic rings include, but are not limited to: spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, and the like.
  • spirocarbocyclic or spirocarbocyclic group is a linking group
  • a spirocarbocyclic or spirocarbocyclic group is listed for the definition of the Markush group
  • the spirocarbocyclic or spirocarbocyclic group means the connected spirocarbocyclic group Ring base.
  • spirocarbocyclylene means a divalent spirocarbocyclic group formed by removing two hydrogen atoms from the ring atoms of a spirocarbocyclic ring.
  • the spirocarbocyclic or spirocarbocyclic group may be independently optionally substituted with one or more substituents described in the present invention.
  • heterocyclic ring or “heterocyclic group” can be used interchangeably, and both refer to a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system with 3-12 ring atoms, and in this system It contains at least one carbon atom and one, two or three heteroatoms selected from O, N, and S.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the heterocyclic group contains 4-7 ring atoms, which means a 4-7 membered heterocyclic group;
  • heterocyclic groups include but are not limited to: oxirane, azetidinyl, oxygen Heterocyclobutyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydro Furanyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl Pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl
  • Examples of the nitrogen atom in the heterocyclic group being oxidized to an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine.
  • heterocyclic ring or a heterocyclic group is a linking group, and a heterocyclic ring or a heterocyclic group is exemplified for the Markush group definition, the heterocyclic ring or a heterocyclic group means a connected heterocyclylene group.
  • heterocyclylene refers to a divalent heterocyclic group formed by removing two hydrogen atoms from the ring atoms of a heterocyclic ring.
  • the heterocyclic ring or heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.
  • bridged heterocyclic ring or “bridged heterocyclic group” can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring atoms, and The system contains at least one carbon atom and one, two or three heteroatoms selected from O, N, and S.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the bridged heterocyclic ring contains 6-12 ring atoms, which means 6-12 membered heterocyclic ring; in other embodiments, the bridged heterocyclic ring contains 6-10 ring atoms, which means 6-10 ring atoms.
  • Member bridge heterocycle Examples of bridged heterocycles include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2.
  • bridged heterocyclic ring or a bridged heterocyclic group is a linking group, and a bridged heterocyclic ring or a bridged heterocyclic group is listed for the definition of the Markush group, the bridged heterocyclic ring or a bridged heterocyclic group means a connected sub-bridged heterocycle. Ring base.
  • bridged heterocyclic group means a bivalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged heterocyclic ring.
  • the bridged heterocyclic ring or bridged heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.
  • spiroheterocycle or “spiroheterocycle” can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing one carbon atom, and the system contains 1, 2 One or three heteroatoms selected from O, N, S.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the spiro heterocyclic ring contains 7-12 ring atoms, which means 7-12 membered spiro heterocyclic ring; in other embodiments, the spiro heterocyclic ring contains 7-10 ring atoms, which means 7-10 ring atoms. Membered spiro heterocyclic ring.
  • spiro heterocycles include, but are not limited to: 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane Alkane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[ 5.5] Undecane, 2,7-diazaspiro[4.4]nonane-1-one, etc.
  • spiro heterocyclic ring or a spiro heterocyclic group is a linking group
  • a spiro heterocyclic ring or a spiro heterocyclic group is listed for the definition of the Markush group
  • the spiro heterocyclic ring or a spiro heterocyclic group represents a connected spiro heterocyclic group.
  • Ring base means a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of the spiroheterocyclic ring.
  • the spiro heterocyclic ring or spiro heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term “aminoalkyl” refers to an alkyl group substituted with one amino group. In some embodiments, the term “aminoalkyl” refers to amino C 1-6 alkyl. In other embodiments, the term “aminoalkyl” refers to amino C 1-4 alkyl. In other embodiments, the term “aminoalkyl” refers to amino C 1-3 alkyl.
  • aminoalkyl examples include, but are not limited to, aminomethyl, aminoethyl, aminon-propyl, aminoisopropyl, aminoisobutyl, aminotert-butyl, 1,2-diaminoethyl, and the like.
  • alkylamino refers to an amino group substituted with one or two alkyl groups.
  • alkylamino means C 1-6 alkylamino, that is, an amino group substituted with one or two C 1-6 alkyl groups.
  • alkylamino means C 1-4 alkylamino.
  • alkylamino refers to C 1-3 alkylamino.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, Propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, etc.
  • alkylsulfonyl represents C 1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 alkylsulfonyl; in other embodiments, alkyl Sulfonyl means C 1-4 alkylsulfonyl.
  • alkylsulfonyl groups include, but are not limited to, methylmethanesulfonyl, ethylmethanesulfonyl, n-propylmethanesulfonyl, isopropylmethanesulfonyl, n-butylmethanesulfonyl, and the like.
  • the left end of Q is connected to ring A, and the right end of Q is connected to M.
  • Means Similarly, the left end of ring A is connected to E, and the right end of A is connected to Q.
  • piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.
  • protecting group refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include acetyl and silyl groups.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a suitable base such as hydroxide, carbonate, bicarbonate, etc.
  • non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of containing their solvents (for example, ethanol, DMSO, etc.), and used for their crystallization.
  • their solvents for example, ethanol, DMSO, etc.
  • the compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the "nitrogen oxide” in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent such as dichloromethane, the amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.
  • LWDeady Syn.Comm.1977, 7,509-514
  • MCPBA m-chloroperoxybenzoic acid
  • treating any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • RET-associated cancer refers to a cancer that is related to or has a disorder in the expression or activity or level of RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them.
  • RET kinase also referred to herein as RET kinase protein or RET kinase
  • This article describes non-limiting examples of RET-related cancers.
  • the disorder of the expression or activity or level of the RET gene, RET kinase, or any one of them is one or more point mutations in the RET gene.
  • the phrase "the expression or activity or level of RET gene, RET kinase, or any one of them is dysregulated” refers to a genetic mutation (for example, a translocation of the RET gene that results in the expression of a fusion protein, resulting in a loss of at least one amino acid compared to the wild-type RET protein Deletion in the RET gene expressed by the RET protein, or mutation in the RET gene that causes the expression of the RET protein with one or more point mutations, or the RET protein resulting in the deletion of at least one amino acid in the RET protein compared with the wild-type RET protein Alternative splicing form of RET mRNA), or RET gene amplification, which leads to overexpression of RET protein or autocrine activity caused by overexpression of cellular RET gene, resulting in the activity of the kinase domain of RET protein in the cell Increased pathogenicity (e.g., constitutive activation of the kinase domain of the RET protein).
  • the expression or activity or level of RET gene, RET kinase, or any one of them may be a mutation in a RET gene encoding a RET protein that is similar to a protein encoded by a RET gene that does not contain the mutation. Ratio, with constitutive activity or with increased activity.
  • the expression or activity or level of RET gene, RET kinase, or any one of them may be the result of gene or chromosomal translocation, which leads to the expression of a fusion protein comprising the first functional kinase domain.
  • the RET part and the second part of the chaperone protein ie not RET).
  • the disorder of RET gene, RET protein, or expression or activity may be the result of gene translation of one RET gene and another RET gene.
  • Disregulation of the expression or activity or level of RET kinase, RET gene, or any (for example, one or more) of them may contribute to tumorigenesis.
  • the disorder of RET kinase, RET gene, or the expression or activity or level of any one of them may be translocation, overexpression, activation, amplification, or mutation of RET kinase, RET gene, or RET kinase domain.
  • the translocation may include a translocation involving the RET kinase domain
  • the mutation may include a mutation involving the RET ligand binding site
  • the amplification may be the RET gene.
  • Other disorders can include RET mRNA splicing variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.
  • the imbalance in the expression or activity or level of RET gene, RET kinase, or any of them includes one or more deletions (for example, deletion of amino acid at position 4), insertions, or point mutations in RET kinase.
  • the dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes the deletion of one or more residues of RET kinase, resulting in constitutive activity of the RET kinase domain.
  • irritable bowel syndrome includes diarrhea-dominated, constipation-dominated or alternating bowel patterns, functional bloating, functional constipation, functional diarrhea, non-specific functional bowel disease, functional abdominal pain syndrome, chronic characteristic Primary constipation, functional esophagus disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, etc.
  • any structural formula given in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds.
  • the isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolism studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients.
  • 18 F-enriched compounds are particularly ideal for PET or SPECT research.
  • the isotope-enriched compound represented by formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation process of the present invention, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.
  • isotopes particularly deuterium (ie, 2 H or D)
  • deuterium in the present invention is regarded as a substituent of the compound of formula (I), (I-1), (I-2), (I-3) or (I-4).
  • the isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium.
  • isotopic enrichment factor used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention provides a new compound that exhibits the inhibition of transfection-period rearrangement (RET) kinase.
  • the compound has a good inhibitory effect on RET wild-type and RET gene mutants, and has a better effect on RET wild-type and RET gene mutants. Good inhibition selectivity.
  • the present invention provides a compound represented by formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, Metabolites, pharmaceutically acceptable salts or prodrugs,
  • R 1, X 1, X 2, X 3, X 4, X 5, E, A, Q, M, T, R a, q have the definitions as described in the present invention.
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently CR 4 or N.
  • Y is O, NH or S.
  • T is a bond, alkylene, alkylene-O- or alkylene-NH-, and the T is optionally selected by 1, 2, 3, or 4 selected from D, OH , F, Cl, Br, I, CN, NH 2 , CF 3 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino Substituents are substituted.
  • Ring G is spirocarbocyclyl or spiroheterocyclyl.
  • q is 0, 1, 2, 3, or 4.
  • E is a bond, -NR 6 -, or -O-.
  • Each f is independently 1, 2, 3, or 4;
  • Each t is independently 0, 1, 2, 3, or 4.
  • M is H, D, heteroaryl, aryl, cycloalkyl, or heterocyclyl, and M is optionally 1, 2, 3, or 4 selected from D, F, Cl, CN , CF 3 , OH, NR 5 R 6 , OR 7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclic, cycloalkane Substituents of the group are substituted.
  • R 1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected by 1, 2, 3 or It is substituted by 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 .
  • each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, Halogenated alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl;
  • R 2 , R 3 and the same C atom connected to them form a carbocyclic or heterocyclic ring;
  • R 4 is H, D, F, Cl, Br, alkyl, or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted by 1, 2, 3, or 4 Substituted by substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2.
  • R 5 is H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl and hetero
  • the aryl groups are each independently optionally selected from F, Cl, Br, OH, NH 2 , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl groups. Substituents of the group are substituted.
  • R 6 is H, D, alkyl, or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally selected from F , Cl, Br, CN, NH 2 , OH and NO 2 substituents.
  • R 7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • T is a bond, C 1-6 alkylene, C 1-6 alkylene-O- or C 1-6 alkylene-NH-, and T is optionally substituted by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF 3 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, C 6-10 aryl, 5-12 membered heteroaryl, or C 1-6 alkylamino substituents are substituted.
  • T is a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -( CH 2 ) 6 -, -(CH 2 ) 2 -O- or -(CH 2 ) 2 -NH-, and the T is optionally selected from 1, 2, 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF 3 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidine Substituents are substituted by substituents of phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy
  • G is 6-12 membered spirocarbocyclyl or 6-12 membered spiroheterocyclyl.
  • R 5 is H, D, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl , wherein the C 1-6 alkyl group, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group are each independently optionally grouped by 1, Replaced by 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH 2 , C 1-6 alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl .
  • R 6 is H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy
  • the C 1-6 alkyl groups are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH, and NO 2 .
  • R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl.
  • G is the following sub-structure:
  • each ring T1 is independently a 4-7 membered carbon monocyclic ring or heteromonocyclic ring;
  • Z 1 and Z 2 are independently -CH 2 -, -O-, -S-, -NH-;
  • Z 3 is -O-, -S-, -NH-;
  • n1 0, 1 or 2;
  • n2 is 1, 2 or 3;
  • n3 is 0 or 1.
  • G is the following sub-structure:
  • R 6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, or methoxyethyl, wherein the methyl , Ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently optionally selected from F, Cl, Br , CN, NH 2 , OH and NO 2 substituents.
  • R 7 is OH, methyl, ethyl, NH 2 , N(CH 3 ) 2 , n-propyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.
  • A is the following sub-structure:
  • Z 1a and Z 2a are each independently -CH 2 -or -NH-;
  • Z 3a is -CH- or -N-;
  • Z 4a is -O-, -S- or -NH-;
  • n and t are each independently 0, 1 or 2;
  • n and t1 are each independently 0 or 1;
  • A is the following sub-structure:
  • M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted by 1 , 2, 3 or 4 selected from D, F, Cl, CN, OH, CF 3 , NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxy alkane Group, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkyl acyl, 3-7 membered heterocyclic group, C 3-7 cycloalkyl substituents are substituted.
  • M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclo Hexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydro Pyridyl, 7-azabicyclo[2.2.1]heptyl, hexahydrofuran[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptanyl; and M is optional
  • M is phenyl
  • M is optionally selected from 1, 2, 3 or 4 selected from D, F, Cl, CN, OH, CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , trifluoromethoxy, 2, 2,2-Trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl , Methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl substituents Replaced.
  • M is N
  • R 1 is H, D, CN, F, Cl, Br, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl and cyclopropyl can be independently optionally It is substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 .
  • R 4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl , Methoxy and ethoxy can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 .
  • each R 2 and R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
  • R 2 , R 3 and the same C atom connected to them form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
  • each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl , Methyl, ethyl, N(CH 3 ) 2 , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl Group, cyclopentyl ethyl, cyclopentyl methyl, phenyl, pyridyl, pyrazinyl;
  • R 2 , R 3 and the same C atom connected to them form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
  • the compound of the present invention has a structure of formula (IA), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, Metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compound of the present invention has a structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, or nitrogen oxide of the structure of formula (I-1) , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Ring A1 is the following sub-structure:
  • Z 1a and Z 2a are each independently CH 2 or NH;
  • A1 is a sub-structure:
  • the compound described in the present invention has a structure of formula (I-2) or (I-3), or a stereoisomer of a structure of formula (I-2) or (I-3), geometrically different Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Z 1 , Z 2 and Z 3a are each independently CH or N;
  • n and t are each independently 0, 1 or 2;
  • n and t1 are each independently 0 or 1;
  • the compound of the present invention has one of the following structures, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable Salt or prodrug of
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of RET-related diseases.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for the prevention or treatment of RET-related diseases.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention also provides a method for preventing or treating RET-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof.
  • RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the present invention relates to intermediates for preparing compounds represented by the structures of formula (I), (I-1), (IA), (I-2) or (I-3).
  • the present invention relates to a method for the preparation, separation and purification of the compound represented by formula (I), (I-1), (IA), (I-2) or (I-3).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of the compound of the present invention or its pharmaceutical composition.
  • Also provided herein is a method of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the compound of the present invention or Its pharmaceutical composition.
  • IBS irritable bowel syndrome
  • the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of irritable bowel syndrome (IBS) and/or pain associated with IBS.
  • IBS irritable bowel syndrome
  • the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for the prevention or treatment of irritable bowel syndrome (IBS) and/or pain associated with IBS.
  • IBS irritable bowel syndrome
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically suitable and related to the other components of the formulation and the mammal used for treatment.
  • the salt of the compound of the present invention also includes intermediates or formula (I) used to prepare or purify the compound represented by formula (I), (IA), (I-1), (I-2) or (I-3) , (I-1), (IA), (I-2) or (I-3), the salt of the separated enantiomers of the compound, but not necessarily a pharmaceutically acceptable salt.
  • the nitrogen oxides of the compounds of the present invention are also included in the scope of the present invention. It can be done by using common oxidants (such as hydrogen peroxide) at elevated temperature, in the presence of acids such as acetic acid, to oxidize the corresponding nitrogen-containing basic substances, or by reacting with peracids in a suitable solvent, such as in dichloromethane , Ethyl acetate or methyl acetate with peracetic acid, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare the nitrogen oxide of the compound of the present invention.
  • common oxidants such as hydrogen peroxide
  • acids such as acetic acid
  • the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acid such as glucuronic acid and galactose Alkyl acid; ⁇ -hydroxy acid, such as citric acid and tartaric acid; amino acid, such as aspartic acid and glutamic acid; aromatic acid, such as benzoic acid and cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
  • the desired salt can be prepared by a suitable method, for example, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxide or alkaline earth Metal hydroxide, etc.
  • suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine Etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compound of the present invention and its pharmaceutical composition, preparation and administration
  • the present invention provides compounds of the present invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, for example, RET mutants that are resistant to current standard care treatments ("RET resistant mutants").
  • the compound of the present invention or its pharmaceutical composition may be selective for wild-type RET, resulting in reduced toxicity associated with the inhibition of other kinases.
  • the pharmaceutical composition of the present invention includes the compounds represented by formula (I), (IA), (I-1), (I-2) or (I-3), the compounds listed in the present invention, or the compounds of the examples Compound.
  • the amount of the compound in the composition of the present invention can effectively treat or alleviate RET-related diseases or disorders in patients, including RET-related cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
  • the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable adjuvants, which, like those used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms.
  • pharmaceutically acceptable adjuvants include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • the active ingredients are usually mixed with excipients, diluted with excipients, or packaged in such carriers in the form of, for example, capsules, sachets, paper or other containers.
  • excipient can be a solid, semi-solid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient.
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low Melting point wax, cocoa butter, etc.
  • the composition can be a tablet, pill, powder, lozenge, sachet, cachet, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in a liquid medium) ,
  • a tablet, pill, powder, lozenge sachet, cachet, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in a liquid medium)
  • ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions and powders in sterile packaging containing up to 10% by weight of the active compound
  • the composition is formulated for oral administration.
  • the composition is formulated as a tablet or capsule.
  • a therapeutically effective amount of the compound of the present invention when used in therapy, a therapeutically effective amount of the compound of the present invention, especially a compound of formula (I), (IA), (I-1), (I-2) or (I-3) and pharmaceutically acceptable compounds thereof
  • the salt can be administered as an unprocessed chemical and can also be provided as an active ingredient in a pharmaceutical composition. Therefore, the content of the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, especially formula (I), (IA), (I-1), (I-2) or (I- 3)
  • the compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, the adjuvants include but are not limited to carriers, diluents or excipients, and the like.
  • terapéuticaally effective amount refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit (e.g., reduction of cancer cells).
  • a separate active ingredient refers only to that ingredient.
  • the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, when administered sequentially or simultaneously.
  • the compounds of the present invention especially the compounds of formula (I), (IA), (I-1), (I-2) or (I-3), and their pharmaceutically acceptable salts are as described above.
  • the carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the recipient.
  • a method for preparing a pharmaceutical preparation comprises combining the compound of the present invention, especially formula (I), (IA), (I-1), (I-2) or (I-3)
  • the compound or its pharmaceutically acceptable salt is mixed with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • pharmaceutically acceptable used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are within the scope of reasonable medical judgment and are suitable for contact with patient tissues without excessive toxicity or irritation. , Allergies, or other problems and complications that are commensurate with a reasonable benefit/risk ratio, and are effectively used for the intended purpose.
  • the amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will have to vary according to the host to be treated and the specific route of administration.
  • the compound of formula (I), (IA), (I-1), (I-2) or (I-3) is mixed with a carrier material to prepare a single dosage form.
  • the amount of active ingredient will depend on the disease to be treated and the severity of the disease. The degree, time of administration, route of administration, excretion rate of the compound used, treatment time, and patient's age, sex, weight and condition vary.
  • a preferred unit dosage form is a unit dosage form containing a daily dose or sub-dose or an appropriate fraction of the above-mentioned active ingredients herein.
  • Treatment can be initiated in small doses that are clearly below the optimal dose of the compound. Thereafter, increase the dose in smaller increments until the best effect is achieved in this case.
  • the most ideal concentration level of the compound administered is usually to provide effective results in anti-tumor without causing any harmful or toxic side effects.
  • composition containing the compound of the present invention can be formulated into a unit dosage form, each dosage containing about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as a single dose for human subjects or other patients, each unit containing a predetermined amount of active material (ie, a compound of general formula I as provided herein) and a suitable drug. With excipients, the predetermined amount is calculated to produce the desired therapeutic effect.
  • compositions provided herein contain about 5 mg to about 50 mg of active ingredient.
  • active ingredient Those of ordinary skill in the art will understand that this embodies the inclusion of about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the compound or composition of the active ingredient.
  • compositions provided herein contain about 50 mg to about 500 mg of active ingredient.
  • Those of ordinary skill in the art will understand that this embodies the inclusion of about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg or about 450 mg to about 500 mg of active ingredient compound or composition.
  • the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient.
  • Those of ordinary skill in the art will understand that this embodies the inclusion of about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 to about 750 mg, about 750 mg to about 800 mg, about 800 mg To about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient compound or composition.
  • the pharmaceutical composition is suitable for administration by any suitable route, such as oral (including oral or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, skin) Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route.
  • suitable route such as oral (including oral or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, skin)
  • Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route can be prepared according to any known method in the field of pharmacy, for example, by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
  • the present invention also provides a method of treating an individual suffering from RET-related cancer, the method comprising administering the compound of the present invention before, during, or after the administration of another anticancer drug (e.g., not the compound of the present invention).
  • the present invention provides a method for treating cancer in a patient in need, the method comprising: (a) determining whether the cancer in the patient is a RET-related cancer (e.g., comprising having one or more RET inhibitors Sexually mutated RET-related cancers, RET-related cancers) (e.g., using regulatory agency approved, such as FDA approved, kits to identify the expression of RET gene, RET kinase, or any of them in a patient or in a patient’s biopsy sample Or an imbalance in activity or level, or by performing any non-limiting example of the assay described herein); and (b) if the cancer is determined to be a RET-related cancer, then administering to the patient a therapeutically effective amount of formula (I), (IA ), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • RET-related cancer e.g., comprising having one or more RET inhibitors Sexually mutated
  • Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., another RET inhibitor, such as a RET inhibitor that is not a compound of the invention).
  • another anti-cancer agent e.g., another RET inhibitor, such as a RET inhibitor that is not a compound of the invention.
  • the subject was previously treated with a compound of formula (I), (IA), (I-1), (I-2), or (I-3) or a pharmaceutically acceptable salt or solvate thereof RET inhibitor treatment, or previously (e.g. after tumor removal or radiation therapy) with other anticancer agents.
  • Non-limiting examples of other therapeutic agents include: other RET targeted therapeutic agents (ie, other RET kinase inhibitors: RET inhibitors that are not the compounds of the present invention), receptor tyrosine kinase targeted therapeutic agents, signal transduction agents Pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (such as Obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeting agents, and radiotherapy.
  • other RET targeted therapeutic agents ie, other RET kinase inhibitors: RET inhibitors that are not the compounds of the present invention
  • receptor tyrosine kinase targeted therapeutic agents include signal transduction agents Pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (such as Obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeting agents, and radiotherapy.
  • the other RET targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.
  • Non-limiting examples of RET targeted therapeutic agents include alatinib, apatinib, cabozantinib (XL-184), dovetinib, levatinib, motesanib, nintedanib, puna Tinib, Regulafenib, Sitravatinib (MGCD516), Sunitinib, Sorafenib, Vataranib, Vandetanib, AUY-922(5-(2,4- Dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide), BLU6864, BLU-667, DCC -2157, NVP-AST487(1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-( Methylamino)pyrimidin-4-yl]
  • RET inhibitors such as those described in, for example, U.S. Patent Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157; 2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; International Publication No.
  • This article also provides a method of treating cancer, including administering to a patient in need a drug combination for treating cancer, which includes (a) a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof, and (b) other treatments Agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of cancer, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • a drug combination for treating cancer which includes (a) a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof, and (b) other treatments Agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of cancer, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • the amount and the amount of other therapeutic agents are jointly effective in the treatment of cancer.
  • the compounds and compositions described herein can be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents.
  • the compound or composition of the present invention may be administered in combination with one or more compounds selected from the group consisting of: cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR) ), sunitinib (SUTENT), regulafenib (STAVARGA), prnatinib (ICLUSIG), bevacizumab (Avastin), crizotinib (XALKORI), or gefitinib (IRESSA) ).
  • the compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents through the same or different administration routes.
  • the compounds of the present invention may be contained in a single formulation or in separate formulations together with other therapeutic agents.
  • the compounds of the present invention can be used to treat irritable bowel syndrome (IBS) in combination with one or more other therapeutic agents or therapies that act through the same or different mechanisms of action.
  • IBS irritable bowel syndrome
  • the at least one other therapeutic agent may be part of the same or separate dosage form as the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, via the same Or different administration routes, and administration according to the same or different administration schedules.
  • other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g. psyllium, methylcellulose), antidiarrheal drugs (e.g.
  • bile Acid binding agents e.g. cholestyramine, colestipol, colesevelam
  • anticholinergics and anticonvulsants e.g. scopolamine, bicyclic amine
  • antidepressants e.g. tricyclic antidepressants
  • imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine
  • antibiotics such as rifaximin
  • alosetron and lubiprostone e.g. imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine
  • antibiotics such as rifaximin
  • alosetron and lubiprostone e.g. alosetron and lubiprostone
  • the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of RET-related diseases or disorders, wherein RET-related diseases or disorders include RET-related cancers , Irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
  • the present invention provides compounds of the present invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, for example, RET mutants that are resistant to current standard care treatments ("RET resistant mutants").
  • the compound of the present invention or its pharmaceutical composition may be selective for wild-type RET, resulting in reduced toxicity associated with the inhibition of other kinases.
  • the present invention provides the use of the compound of the present invention that inhibits wild-type RET and RET mutants or a pharmaceutical composition thereof in the preparation of drugs for preventing or treating wild-type RET and RET mutant-related diseases or disorders.
  • the cancer e.g., RET-related cancer
  • the cancer is a hematological cancer.
  • the cancer e.g., RET-related cancer
  • the cancer eg, RET-related cancer
  • lung cancer eg, small cell lung cancer or non-small cell lung cancer
  • papillary thyroid cancer medullary thyroid cancer
  • differentiated thyroid Carcinoma recurrent thyroid cancer
  • refractory differentiated thyroid cancer lung adenocarcinoma
  • bronchiolar carcinoma multiple endocrine tumors of type 2A or 2B (MEN2A or MEN2B, respectively)
  • pheochromocytoma parathyroid hyperplasia
  • breast Cancer colorectal cancer
  • the cancer eg, RET-related cancer
  • the cancer is selected from: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenal cortical cancer, anal cancer , Appendix cancer, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burki Special lymphoma, carcinoid tumor, unknown primary cancer, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer
  • the RET-related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple type 2A or 2B Endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma and cervical cancer.
  • the RET-related cancer is RET fusion lung cancer or medullary thyroid cancer.
  • the compound of formula (I), (IA), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof can be used to treat patients
  • mutations that are resistant to RET inhibitors which lead to compounds other than formula (I), (IA), (I-1), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates
  • the resistance of the drug is increased, such as the substitution at amino acid position 804, such as V804M, V804L, or V804E).
  • the treatment is administered in combination or as an existing drug treatment (e.g., not of formula (I), ( IA), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof (other RET kinase inhibitor).
  • an existing drug treatment e.g., not of formula (I), ( IA), (I-1), (I-2) or (I-3)
  • a pharmaceutically acceptable salt or solvate thereof other RET kinase inhibitor.
  • RET kinase inhibitors e.g., compounds other than formula (I), (IA), (I-1), (I-2), or (I-3) or a pharmaceutically acceptable salt thereof Or other RET kinase inhibitors of solvates).
  • the RET kinase inhibitor may be selected from cabozantinib, vandetanib, alatinib, sorafenib, levatinib, prnatinib, dovitinib, sunitinib , Foretinib, BLU667 and BLU6864.
  • the irritable bowel syndrome includes diarrhea predominant, constipation predominant or alternating, functional bloating, functional constipation, functional diarrhea, non Specific functional bowel disorders, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain and inflammatory bowel disease.
  • the compounds and compositions can be administered in any amount and any route of administration to effectively treat or reduce the severity of the disease.
  • the exact amount required will vary according to the patient's condition, which depends on race, age, general condition of the patient, severity of infection, special factors, method of administration, and so on.
  • the compound or composition can be used in drug combination with one or more other therapeutic agents, as discussed in the present invention.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, and the substituents are defined as formula (I), (IA), (I-1), (I-2) Or as shown in (I-3).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • the reagents can be purchased from the market.
  • the reagents can be purchased from commodity suppliers such as Lingkai Pharmaceutical, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company. They are used without further purification. Unless otherwise indicated.
  • General reagents are purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran is obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, N,N-dimethylacetamide and petroleum ether are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh
  • NMR spectroscopy uses CDC1 3 or DMSO-d 6 as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, doublet of doublet), dt (doublet of triplets, doublet of doublet). Coupling constant, expressed in Hertz (Hz).
  • MS data is measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C).
  • the G1329A automatic sampler and G1315B DAD detector are used For analysis, the ESI source is applied to the LC-MS spectrometer.
  • MS mass spectrometry
  • the above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1 ⁇ 30mm, 5 ⁇ m.
  • the injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phases are 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B).
  • the purification of the compound was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210nm and 254nm, Zorbax SB-C18 column, specification 2.1 ⁇ 30mm, 4 ⁇ m, 10 minutes, flow rate 0.6mL/min , 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), the column temperature is kept at 40°C.
  • HPLC high performance liquid chromatography
  • the intermediate compound of formula (IA-1a) can be obtained by referring to the synthesis steps of the above intermediate synthesis scheme.
  • ring A is the following sub-structure: Hal 1 and Hal 2 are each independently F, Cl, Br, I, preferably Cl, Br; Pg 1 is an amino protecting group, such as Boc, etc.; Pg 2 is a hydroxyl protecting group, such as benzyl, and the like.
  • the compound of formula (IA-1a-1) and the compound of formula (IA-1a-2) under suitable coupling agent conditions such as palladium coupling agent, preferably PdCl 2 (dppf)CH 2 Cl 2
  • suitable coupling agent conditions such as palladium coupling agent, preferably PdCl 2 (dppf)CH 2 Cl 2
  • the coupling reaction occurs in dioxane, etc.
  • the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) are under suitable coupling agent conditions (Such as a palladium coupling agent, preferably PdCl 2 (dppf)CH 2 Cl 2 ) in a suitable solvent (such as toluene, etc.) to produce a compound of formula (IA-1a-5);
  • suitable reaction conditions for example, in the presence of sodium hydroxide and hydrogen peroxide, in a tetrahydrofuran solvent
  • the intermediate compound of formula (IA-2a) can be obtained by referring to the synthesis steps of the intermediate (IA-2a) synthesis scheme.
  • Hal and Hal 2 are each independently F, Cl, Br, and I, preferably Cl and Br.
  • the compound of formula (IA-1a-6) and the compound of formula (IA-2) under suitable conditions (such as basic conditions, the base is K 2 CO 3 ) in a suitable solvent (such as N,N-dimethylacetamide) The reaction in) yields the compound of formula (IA-2a).
  • the compound of formula (IA) can be obtained by referring to the synthetic steps of Synthetic Scheme 1. Among them, Hal is F, Cl, Br, and I, preferably Cl and Br.
  • the compound of formula (IA-1) and the compound of formula (IA-2) are in a suitable solvent (such as N,N-dimethylacetamide) under suitable conditions (such as basic conditions, the base is K 2 CO 3) The reaction takes place to obtain the compound of formula (IA).
  • the compound of formula (IA1) can be obtained by referring to the synthetic steps of Synthetic Scheme 2.
  • the compound of formula (IA-1) and the compound of formula (IA-3) under suitable conditions (such as basic conditions, the base is K 2 CO 3 ) in a suitable solvent (such as N,N-dimethylformamide amide)
  • suitable conditions such as basic conditions, the base is K 2 CO 3
  • suitable solvent such as N,N-dimethylformamide amide
  • the compound of formula (IA) can be obtained by referring to the synthetic steps of Synthetic Scheme 3.
  • the compound of formula (IA-1) and the compound of formula (IA-4) under suitable conditions (such as basic conditions, the base is K 2 CO 3 ) in a suitable solvent (such as N,N-dimethylformamide amide)
  • suitable conditions such as basic conditions, the base is K 2 CO 3
  • suitable solvent such as N,N-dimethylformamide amide
  • the compound of formula (IA2) can be obtained by referring to the synthetic steps of Synthetic Scheme 4.
  • the compound of formula (IA-2a) and the compound of formula (IA-5) are heated in a suitable solvent (such as DMSO) under suitable conditions (such as basic conditions, the base is K 2 CO 3) to react to obtain formula (IA2) Compound.
  • a suitable solvent such as DMSO
  • suitable conditions such as basic conditions, the base is K 2 CO 3
  • Step 4 4-(6-Fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile
  • Step 5 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 6 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1 .1]Heptane-6-tert-butyl carboxylic acid
  • Step 7 3-(5-(6-(Benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazide Heterobicyclo[3.1.1]heptane-3-tert-butyl-6-carboxylic acid ethyl ester
  • Step 8 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5 -a]pyridine-3-carbonitrile hydrochloride
  • 6-methoxy-3-pyridinecarboxaldehyde 0.4g, 3mmol
  • tetrahydrolithium aluminum 0.06g, 2mmol
  • tetrahydrofuran 10mL
  • Step 11 6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hepta Alkyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 12 6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3- Yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 2 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[ 1,5-a]pyridine-3-carbonitrile
  • Example 1 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile
  • Step 2 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 2 6-(2-(2-oxa-6-azaspiro[3.3]hepta-6-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 8-(2-chloroethyl)-1,4-dioxa-8-azaspiro[4.5]decane
  • Step 2 6-(2-(7-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 4 6-((3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl)oxy)-4-(6-(6-((6 -Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a] Pyridine-3-carbonitrile
  • Step 3 6-((3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl)oxy)-4-(6-(6-((6- (Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile
  • Step 2 6-((2-oxaspiro[3.3]heptane-6-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl) -3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • TLC dot plate shows that the reaction is complete, add 10 mL of saturated ammonium chloride solution to quench the reaction, extract with EA (20 mL ⁇ 2), wash the organic phase with 15 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and spin dry.
  • Silica gel column chromatography eluent pure DCM-DCM/EA ((v/v)4/1-1/4) to obtain 0.103 g (yield 58.7%) of light yellow oil, which is the target product.
  • Step 4 6-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 7 6-((1,4-Dioxaspiro[4.5]decane-8-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl) )Methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 3 6-((1,4-Dioxaspiro[4.5]decane-8-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl) (Methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 8 6-(2-((6-Azaspiro[3.4]heptan-2-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile
  • Step 1 2-(2-Ethoxy-2-oxoethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester
  • Step 3 2-(2-Methylsulfonyloxyethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester
  • Step 4 2-(2-((3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane -6-tert-butyl carboxylate
  • Step 5 6-(2-((6-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile Dihydrochloride
  • Example 10 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine -3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 5 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine- 3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 11 6-((6-hydroxy-6-methylspiro[3.3]heptan-2-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3 -Yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 2 6-((6-hydroxy-6-methylspiro[3.3]heptan-2-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3- (Yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 12 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(4-methoxybenzene Formyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • Step 4 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-6 yl)ethoxy)-4-(6-(5-(4-methoxybenzyl Acyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 13 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(2,3-dimethyl Benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • Step 4 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(2,3-dimethyl Benzoyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 6-(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(6-(4-methoxybenzyl Acyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • Step 3 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methyl Benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 6-(3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • reaction solution was added with 5mL saturated ammonium chloride solution, extracted with DCM (40mL ⁇ 2), the organic phase was washed with water (10mL ⁇ 2), dried over anhydrous sodium sulfate and chromatographed on silica gel column.
  • Step 2 (3-Fluoro-2-methylphenyl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone
  • Step 3 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(6-(3-fluoro-2-methyl Benzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • the target compounds (31)-(33) of Examples 31-33, the target compounds (37)-(38) of Examples 37-38, and the target compounds (40)-( 111), the target compound (224)-(244) of embodiment 224-244, the target compound (211)-(213) of embodiment 210-213, the target compound (215)-(223) of embodiment 215-223 It is prepared by referring to the synthesis route of Example 1 or Synthesis Scheme 1.
  • the specific structure and characterization data are shown in Table 1 below:
  • the target compounds (16)-(17) of Examples 17 and 245 were prepared by referring to the synthetic route of Example 6 or Synthetic Scheme 2.
  • the specific structure and characterization data are described in Table 2 below:
  • the target compounds (18)-(30) of Examples 18-30, the target compounds (34)-(36) of Examples 34-36, the target compounds (39) of Example 39, and the example 114 The target compound (114) of the embodiment, the target compound (117) of the embodiment 117, the target compound (120) of the embodiment 120, the target compound (123) of the embodiment 123, the target compound (125) of the embodiment 125, and the embodiment 129 -131 target compound (129)-(131), embodiment 133-134 target compound (133)-(134), embodiment 144-145 target compound (144)-(145), embodiment 158-160
  • the target compounds (204)-(214) of Examples 204-214 were prepared by referring to the synthetic route of Example 12 or Synthesis Scheme 4. The specific structure and characterization data are described in Table 3 below:
  • the target compounds (208)-(209) of Examples 208-209 can be prepared by referring to the synthetic route of Example 12 or Synthesis Scheme 4. The specific structure and characterization data are described in Table 4 below:
  • the HTRF method was used to test the inhibitory activity of the series of compounds on the two kinases Ret wt and Ret V804M, and the IC 50 value was calculated.
  • CEP-32496 N-[3-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N'-[5-(2,2 ,2-Trifluoro-1,1-dimethylethyl)-3-isoxazolyl]urea.
  • other compounds of the present invention also have good Ret kinase inhibitory activity, wherein the inhibitory activity against Ret wt kinase is 0-20 nM, and the inhibitory activity against Ret wt kinase Ret V804M is 0-300 nM;
  • the inhibitory activity against Ret wt kinase is 0-5 nM, and the inhibitory activity against Ret wt kinase Ret V804M is 0-100 nM, more preferably, the inhibitory activity against Ret wt kinase is 0-1 nM, and the inhibitory activity against Ret wt kinase is Ret V804M.
  • the compounds in Table 1 and Table 3 of the present invention have an inhibitory activity on Ret wt kinase of 0-10 nM, and their inhibitory activity on Ret wt kinase Ret V804M is preferably 0-100 nM. More preferably, the compounds in Table 1 and Table 3 of the present invention have an inhibitory activity against Ret wt kinase.
  • the inhibitory activity against Ret wt kinase is 0-5 nM
  • the inhibitory activity against Ret wt kinase Ret V804M is 0-50 nM.
  • the compounds in Table 1 and Table 3 of the present invention have inhibitory activity against Ret wt kinase of 0-1 nM; the present invention In Table 2, the compound's inhibitory activity on Ret wt kinase is 0-1 nM, and the inhibitory activity of Ret wt kinase Ret V804M is 0-20 nM.

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Abstract

涉及一种药物领域中RET抑制剂、其药物组合物及其用途。具体地，涉及一种式(I)所示的化合物，或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，还涉及包含所述这些化合物的药物组合物、以及所述这些化合物及其药物组合物在制备药物中的用途，该药物尤其用于治疗和预防可用RET相关的疾病和病症，包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。

Description

一种RET抑制剂、其药物组合物及其用途
相关申请
本申请要求中国专利申请号为201910831591.X的优先权，该申请于2019年09月04日递交至国家知识产权局，其所有内容在此作为引用并入本文。
技术领域
本发明属于药物领域，具体的，本发明涉及呈现转染期重排(RET)激酶抑制的新化合物、包含所述化合物的药物组合物、化合物或其药物组合物在制备药物中的用途，该药物尤其用于治疗和预防RET相关的疾病和病症，包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
背景技术
转染重排(Re-arranged during transfection，RET)是属于钙黏蛋白超家族的受体型酪氨酸激酶之一，其激活涉及细胞增殖和存活的多个下游途径。
据报道RET基因产生异常(点突变、染色体易位、染色体逆位、基因扩增)的结果涉及癌化。RET融合蛋白与若干癌症有关，包括乳头状甲状腺癌和非小细胞肺癌。RET融合蛋白鉴定为某些癌症的驱动因素，这推动了使用具有RET抑制活性的多激酶抑制剂来治疗其肿瘤表达RET融合蛋白的患者。据报道索拉非尼(Sorafenib)、舒尼替尼、凡德他尼、普纳替尼等多激酶抑制剂对表达KIF5B-RET的细胞株表现出细胞增殖抑制作用(J Clin Oncol 30,2012,suppl；Abstract no:7510)。另外，据报道多激酶抑制剂卡博替尼对两名RET融合基因阳性的非小细胞肺癌患者表现出部分疗效(Cancer Discov,3(6),Jun2013,p.630-5)。然而，这些药物不能总是以足以抑制RET所需的水平给药，这是由于除RET以外的靶标的抑制所致的毒性。此外，治疗癌症的最大挑战之一是肿瘤细胞对治疗产生抗性的能力。激酶经由突变被重新激活是一种常见的耐药机制。当发生耐药时，患者的治疗选择通常非常有限，并且在大多数情况下癌症进展不受抑制。WO 2017011776公开了单靶点的RET激酶抑制剂，对RET及其突变相关的癌症具有好的预防或治疗作用。目前仍需要进一步研发抑制RET以及其抗性突变体的化合物，来应对RET基因异常相关的癌症。
发明内容
本发明提供了一种呈现转染期重排(RET)激酶抑制的新化合物，该化合物对RET野生型和RET基因突变体具有良好的抑制作用，且对RET野生型和RET基因突变体具有较好的抑制选择性。
本发明化合物某些参数的优良特性，如半衰期、清除率、选择性、生物利用度、化学稳定性、代谢稳定性、膜的渗透性、溶解性等的优良特性，能够促使副作用的降低、治疗指数的扩大或耐受性的改进等。
一方面，本发明提供了一种式(I)所示的化合物，或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000001
其中，
X 1、X 2、X 3、X 4和X 5各自独立地为CR 4或N；
Y为O、NH或S；
T是一个键、亚烷基、亚烷基-O-或亚烷基-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、NH 2、CF 3、烷基、羟基烷基、卤代烷基、环烷基、杂环基、烷氧基、芳基、杂芳基或烷基氨基的取代基所取代；
环G为螺碳环基或螺杂环基；
q为0、1、2、3或4；
R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、-S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、烷基、烷氧基、环烷基、烷氧基烷基或羟基烷基；
E为一个键、-NR 6-、或-O-；
环A为亚桥环基、亚并环基或亚螺环基，且A任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基烷基、烷基、烷氧基、卤代烷基、羟基烷基、碳环基、杂环基、杂环基烷基、烷氧基烷基、亚环烷基和亚单杂环基的取代基所取代；
Q为一个键、-(CR 2R 3) tO-、-(CR 2R 3) f-、-(CR 2R 3) t-NR 6-、-(C＝O)(CR 2R 3) t、-(C＝O)(CR 2R 3) t-(S＝O) 2(CR 2R 3) f、-(C＝O)(CR 2R 3) t-NR 6(CR 2R 3) f-、-(C＝O)(CR 2R 3) t-O(CR 2R 3) f-、-(C＝O)NR 6O(CR 2R 3) f-、-(S＝O) 2-NR 6-(CR 2R 3) t-、(CR 2R 3) f-(C＝O)-、(CR 2R 3) t-(C＝O)-NR 6-(CR 2R 3) t-、-(S＝O) 2(CR 2R 3) t-、-(CR 2R 3) f-(S＝O) 2(CR 2R 3) t、-(S＝O) 2O-、-O(C＝O)-、-(C＝O)NR 6-或-NR 6(C＝O)-；
各f独立地为1、2、3或4；
各t独立地为0、1、2、3或4；
M为H、D、杂芳基、芳基、环烷基或杂环基，且M任选地被1、2、3或4个选自D、F、Cl、CN、CF 3、OH、NR 5R 6、OR 7、烷基、卤代烷基、羟基烷基、卤代烷氧基、芳基、烷氧基烷基、氧代、烷基酰基、杂环基、环烷基的取代基所取代；
R 1为H、D、CN、F、Cl、Br、烷基或环烷基，其中所述的烷基和环烷基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基烷基、烷基、烷基氨基、烷氧 基、卤代烷氧基、环烷基、环烷基烷基、芳基、杂芳基；
或，R 2、R 3和与之相连的同一个C原子成碳环或杂环；
R 4为H、D、F、Cl、Br、烷基或烷氧基，其中所述的烷基和烷氧基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
R 5为H、D、烷基、碳环基、杂环基、芳基或杂芳基，其中所述的烷基、碳环基、杂环基、芳基和杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代；
R 6为H、D、烷基或烷氧基烷基，其中所述烷基和烷氧基烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
R 7为OH、烷基、环烷基、杂环基、芳基、杂芳基。
在一些实施方案中，T是一个键、C 1-6亚烷基、C 1-6亚烷基-O-或C 1-6亚烷基-NH-，且T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 3-7环烷基、3-7元杂环基、C 1-6烷氧基、C 6-10芳基、5-12元杂芳基或C 1-6烷基氨基的取代基所取代。
在一些实施方案中，T是一个键、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-(CH 2) 4-、-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 2-O-或-(CH 2) 2-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、甲基、乙基、丙基、2-羟基乙基、1-羟基乙基、环丙基、环丁基、环戊基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、氧杂环丁烷基、甲氧基、乙氧基、丙氧基、丁氧基、苯基、甲氨基和二甲氨基的取代基所取代。
在一些实施方案中，
G为6-12元螺碳环基或6-12元螺杂环基；
R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、-S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、C 1-6烷氧基C 1-6烷基、C 1-6羟基烷基；
R 5为H、D、C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基或5-10元杂芳基，其中所述的C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基和5-10元杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、C 1-6烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代；
R 6为H、D、C 1-6烷基或C 1-6烷氧基C 1-6烷基，其中所述C 1-6烷基和C 1-6烷氧基C 1-6烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
R 7为OH、C 1-6烷基、C 3-6环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基。
在一些实施方案中，G为以下子结构式：
Figure PCTCN2020113240-appb-000002
其中，各环T1独立地为4-7元的碳单环或杂单环；
Z 1和Z 2独立为-CH 2-、-O-、-S-、-NH-；
Z 3为-O-、-S-、-NH-；
n1为0、1或2；
n2为1、2或3；
n3为0或1。
在一些实施方案中，G为以下子结构式：
Figure PCTCN2020113240-appb-000003
Figure PCTCN2020113240-appb-000004
R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NH 2、NHCH 3、-NHC(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)CH 3、-C(＝O)CH 3、-C(＝O)OH、氧代、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基、环戊基、甲氧基甲基、乙氧基甲基、羟基甲基、2-羟基乙基、1-羟基乙基、2-羟基丙基、2-羟基-2-甲基丙基；
R 5为H、D、甲基、乙基、正丙基、异丙基、正丁基、环丙基、环戊基、吡咯烷基、苯基或吡唑基；其中所述的甲基、乙基、正丙基、环丙基、环戊基、吡咯烷基、苯基和吡唑基各自独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、甲基、-S(＝O) 2CH 3、甲氧基、乙氧基和苯基的取代基所取代；
R 6为H、D、甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基或甲氧基乙基，其中所述甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基和甲氧基乙基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
R 7为OH、甲基、乙基、NH 2、N(CH 3) 2、正丙基、异丙基、叔丁基、环丙基或苯基。
在一些实施方案中，A为5-12元亚桥环基、5-12元亚并环基或5-12元亚螺环基，且A任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-6烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 3-6亚环烷基和3-6元亚单杂基的取代基所取代。
在一些实施方案中，A为以下子结构式：
Figure PCTCN2020113240-appb-000005
其中，Z 1a和Z 2a各独立地为-CH 2-或-NH-；
Z 3a为-CH-或-N-；
Z 4a为-O-、-S-或-NH-；
各Z 5a、Z 6a独立地为-CH 2-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或-NH-；
m和t各独立地为0、1或2；
n和t1各独立地为0或1；
其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，A为以下子结构式：
Figure PCTCN2020113240-appb-000006
其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
在一些实施方案中，M为H、D、5-10元杂芳基、C 6-10芳基、C 3-7环烷基或3-12元杂环基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NR 5R 6、OR 7、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6卤代烷氧基、C 6-10芳基、C 1-6烷氧基C 1-6烷基、氧代、C 1-6烷基酰基、3-7元杂环基、C 3-7环烷基的取代基所取代。
在一些实施方案中，M为H、D、吡啶基、嘧啶基、吡唑基、咪唑基、恶唑基、异恶唑基、吡嗪基、苯基、环戊基、环丙基、环己基、环丁基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、吗啉基、四氢噻喃基、氧杂环丁烷基、1,2-二氢吡啶基、7-氮杂双环[2.2.1]庚烷基、六氢呋喃[3,4-c]并吡咯基、3-氮杂双环[3.1.0]己烷基、八氢吡咯并[1,2-a]吡嗪基或5-氮杂螺[2.4]庚烷基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NH 2、NHCH 3、N(CH 3) 2、三氟甲氧基、2,2,2-三氟乙氧基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲基、乙基、正丙基、异丙基、苯基、甲氧基甲基、甲氧基乙基、氧代、甲酰基、乙酰基、吗啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、环丙基和环己基的取代基所取代；
在一些实施方案中，R 1为H、D、CN、F、Cl、Br、甲基、乙基或环丙基，其中所述的甲基、乙基和环丙基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
R 4为H、D、F、Cl、Br、甲基、乙基、正丙基、甲氧基或乙氧基，其中所述的甲基、乙基、正丙基、甲氧基和乙氧基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、C 1-6羟基烷基、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-7环烷基、C 3-7环烷基C 1-6烷基、C 6-10芳基或5-10元杂芳基；
或，R 2、R 3和与之相连的同一个C原子成3-7元碳环或3-7元杂环。
在一些实施方案中，各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基甲基、2-羟基乙基、1-羟基乙基、甲基、乙基、N(CH 3) 2、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲氧基、环丙基、环戊基、环丙基甲基、环戊基乙基、环戊基甲基、苯基、吡啶基、吡嗪基；
或，R 2、R 3和与之相连的同一个C原子成环戊烷、环丙烷、环丁烷、四氢吡喃、四氢呋喃、哌啶或吡咯烷。
在一些实施方案中，Q为一个键、-O-、-(CH 2) 2O-、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-CH 2CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2NHCH 2-、-(C＝O)OC(CH 3) 2CH 2-、-(C＝O)(CH 2) 2(S＝O) 2CH 2-、-(C＝O)CH(OH)CH 2-、 -(C＝O)CH(OH)-、-(C＝O)CH(OH)CH 2-、-(C＝O)-、-(S＝O) 2-、-(C＝O)CH 2CH(OH)-、-(C＝O)CH 2-、-(C＝O)CH(CH 2OH)-、-(C＝O)C(CH 3) 2-、-(C＝O)CH 2NHC(CH 3) 2CH 2-、-(C＝O)CH 2CH(N(CH 3) 2)-、-(C＝O)(CH 2) 2N(CH 3)CH 2-、-(C＝O)C(CH 3) 2CH 2-、-(C＝O)C(OH)(CH 3)CH 2-、-(C＝O)CH 2OCH 2-、-(C＝O)(CH 2) 3-、-(C＝O)CH(NH 2)-、-(C＝O)(CH 2) 3N(CH 3)CH 2-、-(C＝O)(CH 2) 2-、-(C＝O)CH 2CH(OH)CH 2-、-(C＝O)CF 2CH 2-、-(C＝O)CH(OH)C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3)(OH)CH 2-、-(S＝O) 2CH 2-、-(S＝O) 2CH 2C(CH 3) 2CH 2-、-(C＝O)CH(OCH 3)-、-(C＝O)NHCH(CH 2OH)(CH 2) 2-、-(C＝O)NH-、-(C＝O)N(CH 3)-、-(C＝O)N(CH 2CH 2CH 2CH 3)-、-(C＝O)N(CH 2CH 3)(CH 2) 2-、-(C＝O)NHC(CH 3) 2CH 2-、-(C＝O)N(CH 3)(CH 2) 2-、-(C＝O)NHCH 2CH(CH 3)CH 2-、-(C＝O)NHCH 2-、-(C＝O)NH(CH 2) 2OCH 2-、-(C＝O)N(CH 3)(CH 2) 2OCH 2-、-(S＝O) 2NHC(CH 3) 2CH 2-、-CH 2CH(OH)C(CH 3) 2CH 2-、-CH(CH 3)CH(OH)-、-CH 2(C＝O)NHCH(CH 3)CH 2-、-CH 2(C＝O)-、-(CH 2) 2(C＝O)N(CH 3)CH 2-、-CH 2CH(OH)-、-CH 2CH(OH)CH 2-、-CH 2CH(OH)CH(CH 3)CH 2-、-(C＝O)CH(N(CH 3) 2)-、-(C＝O)C(CH 3) 2CH 2OCH 2-、-(C＝O)C(OCH 3)(CF 3)-、-(C＝O)N(CH 2CH 2OCH 3)CH 2CH(OCH 3)-、-CH 2CH(OCF 3)-、-CH 2CH(OCH(CH 3) 2)-、-CH 2CH(OC(CH 3) 3)-、-CH 2CF 2-、-CH(CH 3)-、-CH 2CH(OCH 3)C(CH 3) 2-、-CH 2CH(N(CH 3) 2)-、-NH-、-(C＝O)NHOCH 2-、-(C＝O)NHOCH 2(CHOH)-、-(S＝O) 2(CH 2CH 3)-、-(S＝O) 2O-、-(S＝O) 2-NHC(CH 3) 2-、-(CH 2) 2(S＝O) 2-、
Figure PCTCN2020113240-appb-000007
Figure PCTCN2020113240-appb-000008
在一些实施方案中，本发明所述的化合物具有式(I-1)的结构，或式(I-1)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000009
其中，
环A1为以下子结构式：
Figure PCTCN2020113240-appb-000010
其中Z 1a和Z 2a各独立地为CH 2或NH；
且A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、 氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，A1为子结构式：
Figure PCTCN2020113240-appb-000011
其中A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
在一些实施方案中，本发明所述的化合物具有式(I-2)或(I-3)的结构，或式(I-2)或(I-3)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000012
其中，Z 1、Z 2和Z 3a各独立地为CH或N；
m和t各独立地为0、1或2；
n和t1各独立地为0或1；
其中
Figure PCTCN2020113240-appb-000013
独立任选地被1、2、3或4个选自F、Cl、 Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，
Figure PCTCN2020113240-appb-000014
为以下子结构式：
Figure PCTCN2020113240-appb-000015
Figure PCTCN2020113240-appb-000016
为以下子结构式：
Figure PCTCN2020113240-appb-000017
其中
Figure PCTCN2020113240-appb-000018
的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚 环丙基、亚环己基和亚吡咯烷基的取代基所取代。
另一方面，本发明提供了一种药物组合物，包含本发明所述的化合物，和药学上可接受的辅剂。
另一方面，本发明还提供了本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗RET相关疾病的药物中的用途。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明还提供了本发明所述的化合物或本发明所述的药物组合物用于预防或治疗RET相关疾病。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明还提供了预防或治疗RET相关疾病的方法，所述方法包括向患者施用治疗有效量的本发明所述的化合物或其药物组合物。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明涉及制备式(I)、(I-1)、(I-2)或(I-3)结构所示化合物的中间体。
另一方面，本发明涉及式(I)、(I-1)、(I-2)或(I-3)示的化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物及其药学上可接受的辅剂。在一些实施方案中，本发明所述的辅剂包括但不限于，载体，赋形剂，稀释剂，溶媒，或它们的组合。在一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
除非其他方面表明，本发明的化合物所有的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学，与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)、(I-1)、(I-2)或(I-3)所示化合物的中间体或式(I)、(I-1)、(I-2)或(I-3)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。
本发明的详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。
除非其他方面表明，本发明所描述的结构式和所述的化合物包括所有的同分异构形式(如对映异构，非对映异构，几何异构或构象异构)、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药。因此，本发明的化合物的单个立体化学异构体、对映异构体、非对映异构体、几何异构体、构象异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药的化合物也属于本发明的范围。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“独立任选地被……取代”这个术语与“取代或非取代”这个术语可以交换使用。一般而言，术语“取代”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个 可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“烷基”表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
当烷基为连接基团时，且针对该马库什基团定义列举了“烷基”，则“烷基”表示连接的亚烷基基团。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括但不限于：-CH 2-、-CH 2CH 2-、-CH(CH 3)CH 2-，等等。
术语“亚烷基-O-”表示亚烷基通过氧原子与分子其他部分相连，其中亚烷基具有如本发明所述的定义。
术语“亚烷基-NH-”表示亚烷基通过NH与分子其他部分相连，其中亚烷基具有如本发明所述的定义。
术语“氧代”，即＝O，表示碳原子上的两个氢被＝O取代的情况，即-CH 2-被＝O取代后成为了-C(＝O)-。
术语“羟基烷基”表示被一个或多个羟基取代的烷基。在一些实施方案中，羟基烷基表示被1、2、3或4个羟基取代的烷基。在一些实施方案中，羟基烷基表示被1或2个羟基取代的烷基。在一些实施方案中，羟基烷基表示C 1-6羟基烷基，即C 1-6烷基被1个或多个羟基取代的烷基，优选的，C 1-6羟基烷基表示C 1-6烷基被1个羟基取代的烷基。在一些实施方案中，羟基烷基表示C 1-4羟基烷基。在一些实施方案中，羟基烷基表示C 1-3羟基烷基。羟基烷基的实例包括但不限于，OHCH 2-、CH 2OHCH 2CH 2CH 2-、CH 2OHCH 2-、CH 2OHCH 2CHOHCH 2-、CH(CH 3)OHCH 2CHOHCH 2-、(CH 3)OHCH-，等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。
术语“烷氧基烷基”表示被一个烷氧基取代的烷基，其中，烷氧基和烷基具有如本发明所述的定义。在一些实施方案中，烷氧基烷基表示C 1-6烷氧基C 1-6烷基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-4烷基；在另一些实施方案中，烷氧基烷基表示C 1-4烷氧基C 1-3烷基；在一些实施方案中，烷氧基烷基表示C 1-3烷氧基C 1-3烷基。烷氧基的实例包括但不限于，甲氧基甲基、乙氧基甲基、丙氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、丙氧基乙基、丙氧基丙基，等。
术语“卤素”表示F(氟)、Cl(氯)、Br(溴)或I(碘)。
术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代。在一些实施方案中，卤代烷基表示C 1-6卤代烷基，即C 1-6烷基被1个或多个卤素取代的烷基。在一些实施方案中，卤代烷基表示C 1-4卤代烷基。在一些实施方案中，卤代烷基表示C 1-3卤代烷基。这样的实例包含，但并不限于，单氟甲基、二氟甲基、三氟甲基、单氟乙基、1,2-二氟乙基、1,1-二氟乙基、2,2-二氟乙基、单氯甲基、二氯甲基、三氯甲基、单氯乙基、1,2-二氯乙基、1,1-二氯乙基、2,2-二氯乙基、1,1-二溴乙基，等等。
术语“环烷基”表示单价的饱和单环碳环体系。环烷基中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，环烷基包含3-7个环碳原子，即C 3-7环烷基。在一实施方案中，环烷基包含3-6个碳原子，即C 3-6环烷基；在另一实施方案中，环烷基包含3-5个碳原子，即C 3-5环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基，等。碳环中-CH 2-基团可被-C(＝O)-替代的实例包括但不限于：环戊酮、环丁酮，等。所述环烷基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚环烷基”表示二价的饱和单环碳环体系。亚环烷基中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，亚环烷基包含3-7个环碳原子，即C 3-7亚环烷基。在一实施方案中，亚环烷基 包含3-6个碳原子，即C 3-6亚环烷基；在另一实施方案中，环烷基包含3-5个碳原子,即C 3-5亚环烷基，亚环烷基的实例包括但不限于1,1-亚环丙基、1,2-亚环丙基、1,1-亚环戊基、1,1-亚环己基，1,3-亚环戊基，等。所述亚环烷基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“单环”表示饱和的或不饱和的单环碳环或单环杂环体系，其中碳环和杂环具有如本发明所述的定义。其中单环碳环体系为碳单环，单环杂环体系为杂单环。
术语“单环基”表示单价的饱和的或不饱和的单环碳环或单环杂环体系，其中碳环和杂环具有如本发明所述的定义。单环基中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，单环基包含3-7个环原子，即单环基为3-7元单环基；在另外一些实施方案中，单环基包含3-6个环原子，即单环基为3-6元单环基。单环基的例子包括但不限于：环丙基、环戊基、环己基、1,2-环戊二烯基、吡咯烷基、四氢呋喃基、吗啉基、呋喃基，等。优选地，本发明所述的单环基为单价的饱和单环碳环或单环杂环体系。所述单环基可独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚单环基”表示二价的饱和的或不饱和的单环碳环或单环杂环体系，其中碳环和杂环具有如本发明所述的定义。亚单环基中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，亚单环基包含3-7个环原子，即亚单环基为3-7元亚单环基；在另外一些实施方案中，亚单环基包含3-6个环原子，即亚单环基为3-6元亚单环基。优选地，本发明所述的亚单环基为二价的饱和单环碳环或单环杂环体系。亚单环基的例子包括但不限于：亚环丙基、亚环戊基、亚环己基、1,2-亚环戊二烯基、亚吡咯烷基，等。所述亚单环基可独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚单杂环基”表示二价的饱和的或不饱和的单环杂环体系，其中杂环具有如本发明所述的定义。亚单杂环基中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，亚单杂环基包含3-7个环原子，即亚单杂环基为3-7元亚单杂环基；在另外一些实施方案中，亚单杂环基包含3-6个环原子，即亚单杂环基为3-6元亚单杂环基。优选地，本发明所述的亚单杂环基为二价的饱和单环杂环体系。
术语“杂环基烷基”表示被杂环基取代的烷基，其中杂环基和烷基具有如本发明所述的定义。在一些实施方案中，杂环基烷基为3-12元杂环基C 1-6烷基；在另外一些实施方案中，杂环基烷基为3-6元杂环基C 1-6烷基；在一些实施方案中，杂环基烷基为3-6元杂环基C 1-4烷基。杂环基烷基的实例包括但不限于：吡咯烷基甲基、哌啶基甲基等。
术语“卤代烷氧基”表示被一个或多个卤素原子取代的烷氧基基团，其中卤素和烷氧基具有如本发明所述的定义。在一些实施方案中，卤代烷氧基基表示C 1-6卤代烷氧基，即C 1-6烷氧基被1个或多个卤素取代的烷基。在一些实施方案中，卤代烷氧基表示C 1-4卤代烷氧基。在一些实施方案中，卤代烷氧基表示C 1-3卤代烷氧基。这样的实例包含，但并不限于，单氟甲氧基、二氟甲氧基、三氟甲氧基、单氟乙氧基、1,2-二氟乙氧基、单氯乙氧基，等等。
术语“烷基酰基”表示烷基基团通过羰基与分子其余部分相连，其中烷基具有如本发明所述的定义，羰基表示-C(＝O)-。在一些实施方案中，烷基酰基表示C 1-6烷基酰基；在另外一些实施方案中，烷基酰基表示C 1-4烷基酰基。烷基酰基的例子包括但不限于：甲酰基、乙酰基，等。
术语“环烷基烷基”表示被一个环烷基取代的烷基。其中环烷基和烷基具有如本发明所述的定义。在一些实施方案中，环烷基烷基表示C 3-7环烷基C 1-6烷基；在另外一些实施方案中，环烷基烷基表示C 3-6环烷基C 1-6烷基；在另外一些实施方案中，环烷基烷基表示C 3-6环烷基C 1-4烷基。环烷基烷基的例 子包括但不限于：环丙基甲基、环戊基乙基、环己基甲基，等。
术语“芳环”或“芳烃”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环。芳环的实例可以包括苯、萘和蒽。
术语“芳基”表示芳环的环碳原子上去掉一个氢原子后形成的一价芳环基团。芳基基团的实例可以包括苯基、萘基和蒽基。当芳基为连接基团时，且针对该马库什基团定义列举了“芳基”，则“芳基”表示连接的亚芳基基团。如本发明定义中M为芳基时，则表示M为连接的亚芳基基团。术语“亚芳基”表示芳环的环碳原子上去掉两个氢原子后形成的二价芳环基团。芳基表示为连接的亚芳基基团的实例可以包括亚苯基、亚萘基和亚蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳环”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环。
术语“杂芳基”表示杂芳环的环原子上去掉一个氢原子后形成的一价芳环基团。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基或5-10元杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。在一些实施方案中，术语“杂芳基”表示含有5个环原子的杂芳环基或5元杂芳基，其中包含1，2，3或4个独立选自O，S和N的杂原子。杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。当杂芳基为连接基团时，且针对该马库什基团定义列举了杂芳基，则杂芳基表示连接的亚杂芳基。如本发明定义中M为杂芳基时，则表示M为连接的亚杂芳基基团。术语“亚杂芳基”表示杂芳基的环原子上去掉两个氢原子后形成的二价杂芳环基团。所述杂芳基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚桥环基”表示二价的共用两个或两个以上不相邻环原子的非芳香性的饱和或部分不饱和的双环或多环体系，包括亚桥碳环基和亚桥杂环基。在一些实施方案中，亚桥环基为5-12元亚桥环基。所述亚桥环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚并环基”表示二价的共用两个相邻环原子的非芳香性的饱和或部分不饱和的双环或多环体系，包括亚并碳环基和亚并杂环基。在一些实施方案中，亚并环基为5-12元亚并环基。所述亚并环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“亚螺环基”表示两个环共有一个碳原子形成的非芳香性的饱和或部分不饱和的双环或多环体系，包括亚螺碳环基和亚螺杂环基。在一些实施方案中，亚螺环基为5-12元亚螺环基。所述亚螺环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“碳环基”和“碳环”可互换使用，表示环原子均为碳原子的饱和或部分不饱和的单环、双环或多环体系，包括单碳环基、桥碳环基、并碳环基和螺碳环基。
术语“桥碳环”和“桥碳环基”可以互换使用，都表示共用两个或两个以上不相邻环碳原子的非芳香性的饱和或部分不饱和的双环或多环体系，且环原子为碳原子。桥碳环中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，桥碳环含有6-12个环碳原子，即表示6-12元桥碳环；在另外一些实施方案中，桥碳环含有6-10个环碳原子，即表示6-10元桥碳环。桥碳环的实例包括但不限于：二环[3.1.1]庚烷、二环[3.2.1]辛烷、二环[2.2.2]辛烷、二环[2.2.0]己烷、八氢-1H-茚，等。当桥碳环或桥碳环基为连接基团时，且针对该马库什基团定义列举了桥碳环或桥碳环基，则桥碳环或桥碳环基表示连接的亚桥碳环基。术语“亚桥碳环基”表示桥碳环的环原子上去掉两个氢原子后形成的二价桥碳环基团。所述桥碳环或桥碳环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“螺碳环”和“螺碳环基”可以互换使用，都表示两个碳环共有一个碳原子形成的非芳香性的饱和或部分不饱和双环或多环体系。螺碳环中-CH 2-基团可以任选地被-C(＝O)-替代。在一些实施方案中，螺碳环含有7-12个环碳原子，即表示7-12元螺碳环；在另外一些实施方案中，螺碳环含有7-10个环碳原子，即表示7-10元螺碳环。螺碳环的实例包括但不限于：螺[4.4]壬烷、螺[3.4]辛烷、螺[4.5]癸烷，等。当螺碳环或螺碳环基为连接基团时，且针对该马库什基团定义列举了螺碳环或螺碳环基，则螺碳环或螺碳环基表示连接的亚螺碳环基。术语“亚螺碳环基”表示螺碳环的环原子上去掉两个氢原子后形成的二价螺碳环基团。所述螺碳环或螺碳环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环”或“杂环基”可以互换使用，都表示有3-12个环原子的单价的非芳香性的饱和或部分不饱和单环、双环或多环体系，且该体系中至少包含1个碳原子，包含1个、2个或3个选自O、N、S的杂原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，杂环基含有4-7个环原子，即表示4-7元杂环基；杂环基的实例包括但不限于：环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基、1,1-二氧代-1,3-硫代吗啉，等。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基。杂环基中氮原子被氧化成N-氧化合物的实例包括但不限于1,1-二氧代-1,3-硫代吗啉。当杂环或杂环基为连接基团时，且针对该马库什基团定义列举了杂环或杂环基，则杂环或杂环基表示连接的亚杂环基。术语“亚杂环基”表示杂环的环原子上去掉两个氢原子后形成的二价杂环基团。所述杂环或杂环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“桥杂环”或“桥杂环基”可以互换使用，都表示共用两个或两个以上不相邻环原子的非芳香性的饱和或部分不饱和的双环或多环体系，且该体系中至少包含1个碳原子，包含1个、2个或3个选 自O、N、S的杂原子。桥杂环中-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，桥杂环含有6-12个环原子，即表示6-12元桥杂环；在另外一些实施方案中，桥杂环含有6-10个环原子，即表示6-10元桥杂环。桥杂环的实例包括但不限于：3,6-二氮杂双环[3.1.1]庚烷、3,8-二氮杂双环[3.2.1]辛烷、2-氮杂双环[2.2.1]庚烷、6-氮杂双环[3.1.1]庚烷、3-氮杂双环[3.1.1]庚烷、8-氮杂双环[3.2.1]辛烷、3--氮杂双环[3.2.1]辛烷、2-二氮杂双环[2.2.2]辛烷、，等。当桥杂环或桥杂环基为连接基团时，且针对该马库什基团定义列举了桥杂环或桥杂环基，则桥杂环或桥杂环基表示连接的亚桥杂环基。术语“亚桥杂环基”表示桥杂环的环原子上去掉两个氢原子后形成的二价桥杂环基团。所述桥杂环或桥杂环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“螺杂环”或“螺杂环基”可以互换使用，都表示两个环共有一个碳原子形成的非芳香性的饱和或部分不饱和环体系，且该体系中包含1个、2个或3个选自O、N、S的杂原子。螺杂环中-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，螺杂环含有7-12个环原子，即表示7-12元螺杂环；在另外一些实施方案中，螺杂环含有7-10个环原子，即表示7-10元螺杂环。螺杂环的实例包括但不限于：4,7-二氮杂螺[2.5]辛烷、2,8-二氮杂螺[4.5]癸烷、2,7-二氮杂螺[4.5]癸烷、2,7-二氮杂螺[3.5]癸烷、2,6-二氮杂螺[3.3]庚烷、2,7-二氮杂螺[4.4]壬烷、3-氮杂螺[5.5]十一烷、2,7-二氮杂螺[4.4]壬烷-1-酮，等。当螺杂环或螺杂环基为连接基团时，且针对该马库什基团定义列举了螺杂环或螺杂环基，则螺杂环或螺杂环基表示连接的亚螺杂环基。术语“亚螺杂环基”表示螺杂环的环原子上去掉两个氢原子后形成的二价螺杂环基团。所述螺杂环或螺杂环基可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“氨基烷基”表示被一个或多个氨基取代的烷基。在一些实施方案中，术语“氨基烷基”表示被一个氨基取代的烷基。在一些实施方案中，术语“氨基烷基”表示氨基C 1-6烷基。在另一些实施方案中，术语“氨基烷基”表示氨基C 1-4烷基。在另一些实施方案中，术语“氨基烷基”表示氨基C 1-3烷基。氨基烷基的实例包括但不限于，氨基甲基、氨基乙基、氨基正丙基、氨基异丙基、氨基异丁基、氨基叔丁基、1,2-二氨基乙基，等。
术语“烷基氨基”表示被一个或两个烷基取代的氨基。在一些实施方案中，术语“烷基氨基”表示C 1-6烷基氨基，即表示被一个或两个C 1-6烷基取代的氨基。在另一些实施方案中，术语“烷基氨基”表示C 1-4烷基氨基。在另一些实施方案中，术语“烷基氨基”表示C 1-3烷基氨基。烷基氨基的实例包括但不限于，甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、异丁基氨基、叔丁基氨基、二甲基氨基、二乙基氨基、二正丙基氨基、二异丙基氨基、二异丁基氨基、二叔丁基氨基，等。
术语“烷基磺酰基”表示烷基-S(＝O) 2-，即烷基通过-S(＝O) 2-与分子其余部分相连。在一些实施方案中，烷基磺酰基表示C 1-6烷基磺酰基；在另一些实施方案中，烷基磺酰基表示C 1-4烷基磺酰基；在另一些实施方案中，烷基磺酰基表示C 1-4烷基磺酰基。烷基磺酰基的实例包括但不限于，甲基甲磺酰基、乙基甲磺酰基、正丙基甲磺酰基、异丙基甲磺酰基、正丁基甲磺酰基，等。
本发明化合物通式中，Q的左端连接环A，Q的右端连接M，例如，当Q为-(S＝O) 2NR 6-时，则
Figure PCTCN2020113240-appb-000019
表示
Figure PCTCN2020113240-appb-000020
同样，环A的左端连接E，A的右端连接Q。
本发明化合物通式中，当T是亚烷基-O-或亚烷基-NH-时，
Figure PCTCN2020113240-appb-000021
表示
Figure PCTCN2020113240-appb-000022
如本发明所描述的，除非另外详细说明，环取代基可以通过环上的任何可连接的位置与分子其余部分相连。例如，哌啶基包含哌啶-1-基、哌啶-2-基、哌啶-3-基和哌啶-4-基。
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有 机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施 方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本文使用的术语“RET相关癌症”是指与RET基因、RET激酶(在本文中也称为RET激酶蛋白或RET激酶)或其中任何一者的表达或活性或水平相关或具有失调的癌症。本文描述了RET相关癌症的非限制性示例。所述RET基因、RET激酶或者其中任何一者的表达或活性或水平的失调是RET基因中的一个或多个点突变。
短语“RET基因、RET激酶或其中任何一者的表达或活性或水平失调”是指基因突变(例如导致融合蛋白表达的RET基因易位，导致与野生型RET蛋白相比包含至少一个氨基酸缺失的RET蛋白表达的RET基因中的缺失，或导致具有一个或多个点突变的RET蛋白表达的RET基因中的突变，或导致与野生型RET蛋白相比RET蛋白中的至少一个氨基酸缺失的RET蛋白的RET mRNA的可变剪接形式)，或RET基因扩增，所述基因扩增导致RET蛋白过表达或由细胞RET基因过表达导致的自分泌活性，导致细胞中RET蛋白的激酶结构域的活性的致病性增加(例如，RET蛋白的激酶结构域的组成性激活)。作为另一个示例，RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是编码RET蛋白的RET基因中的突变，所述RET蛋白与不包含该突变的RET基因编码的蛋白质相比，具有组成型活性或具有增加的活性。例如，RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是基因或染色体易位的结果，其导致融合蛋白的表达，所述融合蛋白包含第一包含功能性激酶结构域的RET部分和伴侣蛋白的第二部分(即不是RET)。在一些示例中，RET基因、RET蛋白或表达或活性的失调可以是一个RET基因与另一个RET基因的基因翻译的结果。
RET激酶、RET基因或其中任何(例如一种或多种)的表达或活性或水平的失调可能有助于肿瘤发生。例如，RET激酶、RET基因失调或者其中任何一者的表达或活性或水平的失调可以是RET激酶、RET基因或RET激酶结构域的易位、过表达、激活、扩增或突变。易位可以包括涉及RET激酶结构域的易位，突变可以包括涉及RET配体结合位点的突变，并且扩增可以是RET基因。其他失调可包括RET mRNA剪接变体和RET自分泌/旁分泌信号传导，这也可能有助于肿瘤发生。
在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶中的一个或多个缺失(例如4位氨基酸的缺失)、插入或点突变。在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶的一个或多个残基的缺失，导致RET激酶结构域的组成型活性。
术语“肠易激综合征”包括腹泻主导型、便秘主导型或交替排便模式、功能性胃气胀、功能性便秘、功能性腹泻、非特异性功能性肠病、功能性腹痛综合征、慢性特发性便秘、功能性食管病、功能性胃十二指肠病、功能性肛门直肠疼痛、炎性肠病，等。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正 电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)、(I-1)、(I-2)、(I-3)或(I-4)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
本发明化合物的描述
本发明提供了一种呈现转染期重排(RET)激酶抑制的新化合物，该化合物对RET野生型和RET基因突变体具有良好的抑制作用，且对RET野生型和RET基因突变体具有较好的抑制选择性。
一方面，本发明提供了一种式(I)所示的化合物，或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000023
其中，R 1、X 1、X 2、X 3、X 4、X 5、E、A、Q、M、T、R a、q具有如本发明所述的定义。
在一些实施方案中，X 1、X 2、X 3、X 4和X 5各自独立地为CR 4或N。
在一些实施方案中，Y为O、NH或S。
在一些实施方案中，T是一个键、亚烷基、亚烷基-O-或亚烷基-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、NH 2、CF 3、烷基、羟基烷基、卤代烷基、环烷基、杂环基、烷氧基、芳基、杂芳基或烷基氨基的取代基所取代。
在一些实施方案中，环G为螺碳环基或螺杂环基。
在一些实施方案中，q为0、1、2、3或4。
在一些实施方案中，R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、 -S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、烷基、烷氧基、环烷基、烷氧基烷基或羟基烷基。
在一些实施方案中，E为一个键、-NR 6-、或-O-。
在一些实施方案中，环A为亚桥环基、亚并环基或亚螺环基，且A任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基烷基、烷基、烷氧基、卤代烷基、羟基烷基、碳环基、杂环基、杂环基烷基、烷氧基烷基、亚环烷基和亚单杂环基的取代基所取代。
在一些实施方案中，Q为一个键、-(CR 2R 3) tO-、-(CR 2R 3) f-、-(CR 2R 3) t-NR 6-、-(C＝O)(CR 2R 3) t、-(C＝O)(CR 2R 3) t-(S＝O) 2(CR 2R 3) f、-(C＝O)(CR 2R 3) t-NR 6(CR 2R 3) f-、-(C＝O)(CR 2R 3) t-O(CR 2R 3) f-、-(C＝O)NR 6O(CR 2R 3) f-、-(S＝O) 2-NR 6-(CR 2R 3) t-、(CR 2R 3) f-(C＝O)-、(CR 2R 3) t-(C＝O)-NR 6-(CR 2R 3) t-、-(S＝O) 2(CR 2R 3) t-、-(CR 2R 3) f-(S＝O) 2(CR 2R 3) t、-(S＝O) 2O-、-O(C＝O)-、-(C＝O)NR 6-或-NR 6(C＝O)-；
各f独立地为1、2、3或4；
各t独立地为0、1、2、3或4。
在一些实施方案中，M为H、D、杂芳基、芳基、环烷基或杂环基，且M任选地被1、2、3或4个选自D、F、Cl、CN、CF 3、OH、NR 5R 6、OR 7、烷基、卤代烷基、羟基烷基、卤代烷氧基、芳基、烷氧基烷基、氧代、烷基酰基、杂环基、环烷基的取代基所取代。
在一些实施方案中，R 1为H、D、CN、F、Cl、Br、烷基或环烷基，其中所述的烷基和环烷基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基烷基、烷基、烷基氨基、烷氧基、卤代烷氧基、环烷基、环烷基烷基、芳基、杂芳基；
或，R 2、R 3和与之相连的同一个C原子成碳环或杂环；
在一些实施方案中，R 4为H、D、F、Cl、Br、烷基或烷氧基，其中所述的烷基和烷氧基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，R 5为H、D、烷基、碳环基、杂环基、芳基或杂芳基，其中所述的烷基、碳环基、杂环基、芳基和杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代。
在一些实施方案中，R 6为H、D、烷基或烷氧基烷基，其中所述烷基和烷氧基烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，R 7为OH、烷基、环烷基、杂环基、芳基、杂芳基。
在一些实施方案中，T是一个键、C 1-6亚烷基、C 1-6亚烷基-O-或C 1-6亚烷基-NH-，且T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 3-7环烷基、3-7元杂环基、C 1-6烷氧基、C 6-10芳基、5-12元杂芳基或C 1-6烷基氨基的取代基所取代。
在一些实施方案中，T是一个键、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-(CH 2) 4-、-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 2-O- 或-(CH 2) 2-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、甲基、乙基、丙基、2-羟基乙基、1-羟基乙基、环丙基、环丁基、环戊基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、氧杂环丁烷基、甲氧基、乙氧基、丙氧基、丁氧基、苯基、甲氨基和二甲氨基的取代基所取代。
在一些实施方案中，G为6-12元螺碳环基或6-12元螺杂环基。
在一些实施方案中，R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、-S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、C 1-6烷氧基C 1-6烷基、C 1-6羟基烷基。
在一些实施方案中，R 5为H、D、C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基或5-10元杂芳基，其中所述的C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基和5-10元杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、C 1-6烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代。
在一些实施方案中，R 6为H、D、C 1-6烷基或C 1-6烷氧基C 1-6烷基，其中所述C 1-6烷基和C 1-6烷氧基C 1-6烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
R 7为OH、C 1-6烷基、C 3-6环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基。
在一些实施方案中，G为以下子结构式：
Figure PCTCN2020113240-appb-000024
其中，各环T1独立地为4-7元的碳单环或杂单环；
Z 1和Z 2独立为-CH 2-、-O-、-S-、-NH-；
Z 3为-O-、-S-、-NH-；
n1为0、1或2；
n2为1、2或3；
n3为0或1。
在一些实施方案中，G为以下子结构式：
Figure PCTCN2020113240-appb-000025
Figure PCTCN2020113240-appb-000026
在一些实施方案中，R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NH 2、NHCH 3、-NHC(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)CH 3、-C(＝O)CH 3、-C(＝O)OH、氧代、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基、环戊基、甲氧基甲基、乙氧基甲基、羟基甲基、2-羟基乙基、1-羟基乙基、2-羟基丙基、2-羟基-2-甲基丙基。
在一些实施方案中，R 5为H、D、甲基、乙基、正丙基、异丙基、正丁基、环丙基、环戊基、吡咯烷基、苯基或吡唑基；其中所述的甲基、乙基、正丙基、环丙基、环戊基、吡咯烷基、苯基和吡唑基各自独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、甲基、-S(＝O) 2CH 3、甲氧基、乙氧基和苯基的取代基所取代。
在一些实施方案中，R 6为H、D、甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基或甲氧基乙基，其中所述甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基和甲氧基乙基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，R 7为OH、甲基、乙基、NH 2、N(CH 3) 2、正丙基、异丙基、叔丁基、环丙基或苯基。
在一些实施方案中，A为5-12元亚桥环基、5-12元亚并环基或5-12元亚螺环基，且A任选地被1、 2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-6烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 3-6亚环烷基和3-6元单杂环基的取代基所取代。
在一些实施方案中，A为以下子结构式：
Figure PCTCN2020113240-appb-000027
其中，Z 1a和Z 2a各独立地为-CH 2-或-NH-；
Z 3a为-CH-或-N-；
Z 4a为-O-、-S-或-NH-；
各Z 5a、Z 6a独立地为-CH 2-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或-NH-；
m和t各独立地为0、1或2；
n和t1各独立地为0或1；
其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，A为以下子结构式：
Figure PCTCN2020113240-appb-000028
Figure PCTCN2020113240-appb-000029
其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
在一些实施方案中，M为H、D、5-10元杂芳基、C 6-10芳基、C 3-7环烷基或3-12元杂环基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NR 5R 6、OR 7、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6卤代烷氧基、C 6-10芳基、C 1-6烷氧基C 1-6烷基、氧代、C 1-6烷基酰基、3-7元杂环基、C 3-7环烷基的取代基所取代。
在一些实施方案中，M为H、D、吡啶基、嘧啶基、吡唑基、咪唑基、恶唑基、异恶唑基、吡嗪基、苯基、环戊基、环丙基、环己基、环丁基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、吗啉基、四氢噻喃基、氧杂环丁烷基、1,2-二氢吡啶基、7-氮杂双环[2.2.1]庚烷基、六氢呋喃[3,4-c]并吡咯基、3-氮杂双环[3.1.0]己烷基、八氢吡咯并[1,2-a]吡嗪基或5-氮杂螺[2.4]庚烷基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NH 2、NHCH 3、N(CH 3) 2、三氟甲氧基、2,2,2-三氟乙氧基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲基、乙基、正丙基、异丙基、苯基、甲氧基甲基、甲氧基乙基、氧代、甲酰基、乙酰基、吗啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、环丙基 和环己基的取代基所取代。
在一些实施方案中，M为苯基、
Figure PCTCN2020113240-appb-000030
Figure PCTCN2020113240-appb-000031
且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NH 2、NHCH 3、N(CH 3) 2、三氟甲氧基、2,2,2-三氟乙氧基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲基、乙基、正丙基、异丙基、苯基、甲氧基甲基、甲氧基乙基、氧代、甲酰基、乙酰基、吗啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、环丙基和环己基的取代基所取代。
在一些实施方案中，M为
Figure PCTCN2020113240-appb-000032
在一些实施方案中，R 1为H、D、CN、F、Cl、Br、甲基、乙基或环丙基，其中所述的甲基、乙基和环丙基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，R 4为H、D、F、Cl、Br、甲基、乙基、正丙基、甲氧基或乙氧基，其中所述的甲基、乙基、正丙基、甲氧基和乙氧基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
在一些实施方案中，各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、C 1-6羟基烷基、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-7环烷基、C 3-7环烷基C 1-6烷基、C 6-10芳基或5-10元杂芳基；
或，R 2、R 3和与之相连的同一个C原子成3-7元碳环或3-7元杂环。
在一些实施方案中，各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基甲基、2-羟基乙基、1-羟基乙基、甲基、乙基、N(CH 3) 2、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲氧基、环丙基、环戊基、环丙基甲基、环戊基乙基、环戊基甲基、苯基、吡啶基、吡嗪基；
或，R 2、R 3和与之相连的同一个C原子成环戊烷、环丙烷、环丁烷、四氢吡喃、四氢呋喃、哌啶或吡咯烷。
在一些实施方案中，Q为一个键、-O-、-(CH 2) 2O-、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-CH 2CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2NHCH 2-、-(C＝O)OC(CH 3) 2CH 2-、-(C＝O)(CH 2) 2(S＝O) 2CH 2-、-(C＝O)CH(OH)CH 2-、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH 2-、-(C＝O)-、-(S＝O) 2-、-(C＝O)CH 2CH(OH)-、-(C＝O)CH 2-、-(C＝O)CH(CH 2OH)-、-(C＝O)C(CH 3) 2-、-(C＝O)CH 2NHC(CH 3) 2CH 2-、-(C＝O)CH 2CH(N(CH 3) 2)-、 -(C＝O)(CH 2) 2N(CH 3)CH 2-、-(C＝O)C(CH 3) 2CH 2-、-(C＝O)C(OH)(CH 3)CH 2-、-(C＝O)CH 2OCH 2-、-(C＝O)(CH 2) 3-、-(C＝O)CH(NH 2)-、-(C＝O)(CH 2) 3N(CH 3)CH 2-、-(C＝O)(CH 2) 2-、-(C＝O)CH 2CH(OH)CH 2-、-(C＝O)CF 2CH 2-、-(C＝O)CH(OH)C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3)(OH)CH 2-、-(S＝O) 2CH 2-、-(S＝O) 2CH 2C(CH 3) 2CH 2-、-(C＝O)CH(OCH 3)-、-(C＝O)NHCH(CH 2OH)(CH 2) 2-、-(C＝O)NH-、-(C＝O)N(CH 3)-、-(C＝O)N(CH 2CH 2CH 2CH 3)-、-(C＝O)N(CH 2CH 3)(CH 2) 2-、-(C＝O)NHC(CH 3) 2CH 2-、-(C＝O)N(CH 3)(CH 2) 2-、-(C＝O)NHCH 2CH(CH 3)CH 2-、-(C＝O)NHCH 2-、-(C＝O)NH(CH 2) 2OCH 2-、-(C＝O)N(CH 3)(CH 2) 2OCH 2-、-(S＝O) 2NHC(CH 3) 2CH 2-、-CH 2CH(OH)C(CH 3) 2CH 2-、-CH(CH 3)CH(OH)-、-CH 2(C＝O)NHCH(CH 3)CH 2-、-CH 2(C＝O)-、-(CH 2) 2(C＝O)N(CH 3)CH 2-、-CH 2CH(OH)-、-CH 2CH(OH)CH 2-、-CH 2CH(OH)CH(CH 3)CH 2-、-(C＝O)CH(N(CH 3) 2)-、-(C＝O)C(CH 3) 2CH 2OCH 2-、-(C＝O)C(OCH 3)(CF 3)-、-(C＝O)N(CH 2CH 2OCH 3)CH 2CH(OCH 3)-、-CH 2CH(OCF 3)-、-CH 2CH(OCH(CH 3) 2)-、-CH 2CH(OC(CH 3) 3)-、-CH 2CF 2-、-CH(CH 3)-、-CH 2CH(OCH 3)C(CH 3) 2-、-CH 2CH(N(CH 3) 2)-、-NH-、-(C＝O)NHOCH 2-、-(C＝O)NHOCH 2(CHOH)-、-(S＝O) 2(CH 2CH 3)-、-(S＝O) 2O-、-(S＝O) 2-NHC(CH 3) 2-、-(CH 2) 2(S＝O) 2-、
Figure PCTCN2020113240-appb-000033
Figure PCTCN2020113240-appb-000034
在一些实施方案中，本发明所述的化合物具有式(IA)的结构，或式(IA)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000035
在一些实施方案中，本发明所述的化合物具有式(I-1)的结构，或式(I-1)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000036
其中，
环A1为以下子结构式：
Figure PCTCN2020113240-appb-000037
其中Z 1a和Z 2a各独立地为CH 2或NH；
且A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，A1为子结构式：
Figure PCTCN2020113240-appb-000038
其中A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
在一些实施方案中，本发明所述的化合物具有式(I-2)或(I-3)的结构，或式(I-2)或(I-3)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000039
Figure PCTCN2020113240-appb-000040
其中，Z 1、Z 2和Z 3a各独立地为CH或N；
m和t各独立地为0、1或2；
n和t1各独立地为0或1；
其中
Figure PCTCN2020113240-appb-000041
独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
在一些实施方案中，
Figure PCTCN2020113240-appb-000042
为以下子结构式：
Figure PCTCN2020113240-appb-000043
Figure PCTCN2020113240-appb-000044
为以下子结构式：
Figure PCTCN2020113240-appb-000045
其中
Figure PCTCN2020113240-appb-000046
的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
在一些实施方案中，本发明所述的化合物具有以下结构之一，或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2020113240-appb-000047
Figure PCTCN2020113240-appb-000048
Figure PCTCN2020113240-appb-000049
Figure PCTCN2020113240-appb-000050
Figure PCTCN2020113240-appb-000051
Figure PCTCN2020113240-appb-000052
Figure PCTCN2020113240-appb-000053
Figure PCTCN2020113240-appb-000054
Figure PCTCN2020113240-appb-000055
Figure PCTCN2020113240-appb-000056
Figure PCTCN2020113240-appb-000057
Figure PCTCN2020113240-appb-000058
Figure PCTCN2020113240-appb-000059
Figure PCTCN2020113240-appb-000060
Figure PCTCN2020113240-appb-000061
Figure PCTCN2020113240-appb-000062
Figure PCTCN2020113240-appb-000063
Figure PCTCN2020113240-appb-000064
Figure PCTCN2020113240-appb-000065
Figure PCTCN2020113240-appb-000066
Figure PCTCN2020113240-appb-000067
Figure PCTCN2020113240-appb-000068
Figure PCTCN2020113240-appb-000069
Figure PCTCN2020113240-appb-000070
Figure PCTCN2020113240-appb-000071
Figure PCTCN2020113240-appb-000072
另一方面，本发明提供了一种药物组合物，包含本发明所述的化合物，和药学上可接受的辅剂。
另一方面，本发明还提供了本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗RET相关疾病的药物中的用途。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明还提供了本发明所述的化合物或本发明所述的药物组合物用于预防或治疗RET相关疾病。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明还提供了预防或治疗RET相关疾病的方法，所述方法包括向患者施用治疗有效量的本发明所述的化合物或其药物组合物。
在一些实施方案中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
另一方面，本发明涉及制备式(I)、(I-1)、(IA)、(I-2)或(I-3)结构所示化合物的中间体。
另一方面，本发明涉及式(I)、(I-1)、(IA)、(I-2)或(I-3)所示的化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物及其药学上可接受的辅剂。在一些实施方案中，本发明所述的辅剂包括但不限于，载体，赋形剂，稀释剂，溶媒，或它们的组合。在一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
本文还提供体外或体内抑制细胞增殖的方法，所述方法包括使细胞与有效量的本发明所述的化合物或其或其药物组合物接触。
本文还提供了在有治疗需要的患者中治疗肠易激综合征(IBS)和/或与IBS相关的疼痛的方法，所述方法包括向所述患者施用治疗有效量的本发明所述化合物或其药物组合物。
本发明还提供了本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗治疗肠易激综合征(IBS)和/或与IBS相关的疼痛的药物中的用途。
本发明还提供了本发明所述的化合物或本发明所述的药物组合物用于预防或治疗治疗肠易激综合征(IBS)和/或与IBS相关的疼痛。
除非其他方面表明，本发明的化合物所有的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学，与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)、(IA)、(I-1)、(I-2)或(I-3)所示化合物的中间体或式(I)、(I-1)、(IA)、(I-2)或(I-3)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。
如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸，氢溴酸，硫酸，硝酸和磷酸等等。或者使用有机酸，如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，丙酮酸，草酸，羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸，乙磺酸，等等。
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯氨，仲氨，叔氨)，碱金属氢氧化物或碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，和环状氨，如哌啶，吗啉和哌嗪等，和从钠，钙，钾，镁，锰，铁，铜，锌，铝和锂得到无机盐。
本发明化合物及其药物组合物、制剂和给药
本发明提供了抑制野生型RET和RET突变体的本发明化合物或其药物组合物，例如，对当前标准护理治疗具有抗性的RET突变体(“RET抗性突变体”)。另外，相对于其它激酶，本发明化合物或其药物组合物对野生型RET可有选择性，从而导致与抑制其它激酶相关的毒性降低。
本发明的药物组合物包括式(I)、(IA)、(I-1)、(I-2)或(I-3)所示的化合物，本发明所列出的化合物，或实施例的化合物。本发明的组合物中化合物的量能有效地治疗或减轻患者RET相关疾病或病症，包括RET相关的癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的辅剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅剂可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅剂与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
在制备本文提供的组合物时，通常将活性成分与赋形剂混合，通过赋形剂稀释或以例如胶囊、小袋、纸或其它容器的形式封装在这种运载体内。如果将赋形剂用作稀释剂，它可以是固体、半固体或液体材料，其用作活性成分的运载体、载体或介质。适宜的载体包括但不限于碳酸镁、硬脂酸镁、滑石粉、 糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。因此，组合物可以是片剂、丸剂、粉末剂、锭剂、囊剂、扁胶囊、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体形式或在液体介质中)、例如最多含有10重量％活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液以及无菌包装的粉末剂。在一个实施方式中，组合物被配制用于口服给药。在一个实施方式中，组合物被配制成片剂或胶囊剂。
当可用于治疗时，治疗有效量的本发明化合物，尤其是式(I)、(IA)、(I-1)、(I-2)或(I-3)化合物及其药学上可接受的盐可作为未加工的化学药品给予，还可作为药物组合物的活性成分提供。因此，本发明内容还提供药物组合物，该药物组合物包括治疗有效量的本本发明化合物，尤其是式(I)、(IA)、(I-1)、(I-2)或(I-3)化合物或其药学上可接受的盐和一种或多种药学上可接受的辅剂，辅剂包括但不限于载体、稀释剂或赋形剂，等。本文所使用的术语“治疗有效量”是指足以显示出有意义的患者益处(例如癌细胞减少)的各活性组分的总量。当使用单独的活性成分单独给药时，该术语仅指该成分。当组合应用时，该术语则是指不论组合，依次或同时给药时，都引起治疗效果的活性成分的组合量。本发明化合物，尤其是式(I)、(IA)、(I-1)、(I-2)或(I-3)化合物及其药学上可接受的盐如上所述。从与制剂其他成分相容以及对其接受者无害的意义上来讲，载体、稀释剂或赋形剂必须是可接受的。根据本发明内容的另一方面，还提供用于制备药物制剂的方法，该方法包括将本发明化合物，尤其是式(I)、(IA)、(I-1)、(I-2)或(I-3)化合物或其药学上可接受的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混匀。本发明所使用的术语“药学上可接受的”是指这样的化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。
与一种或多种辅剂结合以制备单剂型的活性成分的量将必需根据治疗的宿主和具体的给药路径而变化。式(I)、(IA)、(I-1)、(I-2)或(I-3)化合物与载体材料混合以制备单一剂型的活性成分的量将根据待治疗的疾病、疾病的严重程度、给药时间、给药途径、所用化合物的排泄速率、治疗时间和患者年龄、性别、体重和情况而改变。优选的单位剂型是含有本文上述活性成分的日剂量或分剂量或其适宜分数的单位剂型。可用显然低于化合物最佳剂量的小剂量开始治疗。此后，以较小的增量来加大剂量直到在这种情况下达到最佳效果。一般而言，最理想地给予化合物的浓度水平是通常可在抗肿瘤方面提供有效结果而又不至于引起任何有害或有毒的副作用。
包含本发明所述化合物的组合物可以配制成单位剂型，每个剂量包含约5至约1,000mg(1g)，更通常约100mg至约500mg的活性成分。术语“单位剂量形式”指适合作为单一剂量用于人体对象或其他患者的物理上离散的单位，每个单位包含预定量的活性材料(即如本文提供的通式I的化合物)和合适的药用赋形剂，所述预定量经计算能够产生所需的治疗效果。
在一些实施方式中，本文提供的组合物含有约5mg至约50mg的活性成分。本领域普通技术人员将理解，这体现了包含约5mg至约10mg，约10mg至约15mg，约15mg至约20mg，约20mg至约25mg，约25mg mg至约30mg，约30mg至约35mg，约35mg至约40mg，约40mg至约45mg或约45mg至约50mg活性成分的化合物或组合物。
在一些实施方式中，本文提供的组合物含有约50mg至约500mg的活性成分。本领域普通技术人员将会理解，这体现了包含约50mg至约100mg，约100mg至约150mg，约150mg至约200mg，约200mg 至约250mg，约250mg至约300mg，约350mg至约400mg或约450mg至约500mg活性成分的化合物或组合物。
在一些实施方式中，本文提供的组合物含有约500mg至约1,000mg的活性成分。本领域普通技术人员将理解，这体现了包含约500mg至约550mg，约550mg至约600mg，约600mg至约650mg，约650mg至约700mg，约700至约750mg，约750mg至约800mg，约800mg至约850mg，约850mg至约900mg，约900mg至约950mg或约950mg至约1,000mg活性成分的化合物或组合物。
药物组合物适于通过任何合适的途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或者真皮下注射或输注)途径。可按药剂学领域的任何已知方法制备这类制剂，例如通过将活性成分与载体或赋形剂混合。优选口服给药或注射给药。
本发明还提供了治疗患有RET相关癌症的个体的方法，所述方法包括在给予另一种抗癌药物(例如不是本发明所述化合物)之前、期间或之后给予本发明所述化合物。
本发明提供了用于治疗有需要的患者的癌症的方法，所述方法包括：(a)确定所述患者中的癌症是否是RET相关癌症(例如，包括具有一个或多个的RET抑制剂抗性突变的RET相关癌症的RET相关癌症)(例如，使用管理机构批准的，例如FDA批准的，试剂盒来鉴定患者中或患者的活检样品中的RET基因、RET激酶或其中任何一者的表达或活性或水平的失调，或通过进行本文所述测定的任何非限制性示例)；和(b)如果癌症被确定为RET相关癌症，则向患者施用治疗有效量的式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物或其药学上可接受的盐或溶剂合物或其药物组合物。这些方法的一些实施方式进一步包括向对象施用另一种抗癌剂(例如另一种RET抑制剂，例如不是本发明所述化合物的RET抑制剂)。在一些实施方式中，对象先前用不是式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物或其药学上可接受的盐或溶剂合物的RET抑制剂治疗，或先前(例如在切除肿瘤或放射疗法后)用其他抗癌剂治疗。
在本文所述的任何方法的一些实施方式中，式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物(或其药学上可接受的盐或溶剂合物)与治疗有效量的至少一种其他治疗剂联用，所述至少一种其他治疗剂选自一种或多种其他疗法或治疗(例如化学治疗)试剂。
其他治疗剂的非限制性示例包括：其它RET靶向治疗剂(即其他RET激酶抑制剂:不是本发明所述化合物的RET抑制剂)，受体酪氨酸激酶靶向的治疗剂，信号转导途径抑制剂，检查点抑制剂，凋亡途径调节剂(例如Obataclax)；细胞毒性化学治疗剂，血管生成靶向治疗剂，免疫靶向剂和放射疗法。
在一些实施方式中，其他RET靶向治疗剂是显示RET抑制活性的多激酶抑制剂。
RET靶向治疗剂的非限制性示例包括阿拉替尼，阿帕替尼，卡博替尼(XL-184)，多维替尼，乐伐替尼，莫泰沙尼，尼达尼布，普纳替尼，雷格拉非尼，斯塔替尼(sitravatinib)(MGCD516)，舒尼替尼，索拉非尼，瓦他拉尼，凡德他尼，AUY-922(5-(2,4-二羟基-5-异丙基-苯基)-N-乙基-4-[4-(吗啉代甲基)苯基]异噁唑-3-甲酰胺)，BLU6864，BLU-667，DCC-2157，NVP-AST487(1-[4-[(4-乙基哌嗪-1-基)甲基]-3-(三氟甲基)苯基]-3-[4-[6-(甲氨基)嘧啶-4-基]氧苯基]脲)，PZ-1，RPI-1(1,3-二氢-5,6-二甲氧基-3-[(4-羟基苯基)亚甲基]-H-吲哚-2-酮)，RXDX-105(1-(3-(6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-3-(5-(1,1,1-三氟-2-甲基丙-2-基)异噁唑-3-基)脲)，SPP86(1-异丙基-3-(苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺)和TG101209(N-(1,1-二甲基乙 基)-3-[[5-甲基-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-4-嘧啶基]氨基]苯磺酰胺)。
其它治疗剂包括RET抑制剂，如在例如下述中所述的那些：美国专利号7,504,509；8,299,057；8,399,442；8,067,434；8,937,071；9,006,256；和9,035,063；美国公开号2014/0121239；20160176865；2011/0053934；2011/0301157；2010/0324065；2009/0227556；2009/0130229；2009/0099167；2005/0209195；国际公开号WO 2014/184069；WO 2014/072220；WO2012/053606；WO 2009/017838；WO 2008/031551；WO 2007/136103；WO 2007/087245；WO2007/057399；WO 2005/051366；WO 2005/062795；和WO 2005/044835；和J.Med.Chem.2012,55(10),4872-4876,其全部通过引用全文纳入本文。
本文还提供了治疗癌症的方法，包括向有需要的患者给予治疗癌症的药物组合，其包括(a)通式I的化合物或其药学上可接受的盐或溶剂合物，(b)其他治疗剂，和(c)任选的至少一种药学上可接受的运载体，以同时、分开或顺序用于治疗癌症，其中通式I的化合物或其药学上可接受的盐或溶剂合物的量和其他治疗剂的量在治疗癌症方面共同有效。
本文所述的化合物和组合物可单独施用或与其它化合物(包括其它RET调节化合物)或其它治疗剂组合施用。在一些实施方案中，本发明的化合物或组合物可与一种或多种选自以下的化合物组合施用：卡博替尼(COMETRIQ)、凡德他尼(CALPRESA)、索拉非尼(NEXAVAR)、舒尼替尼(SUTENT)、雷格拉非尼(STAVARGA)、普纳替尼(ICLUSIG)、贝伐单抗(阿瓦斯汀)、克唑替尼(XALKORI)或吉非替尼(IRESSA)。本发明的化合物或组合物可通过相同或不同给药途径与其它治疗剂同时或相继施用。本发明的化合物可与其它治疗剂一起包含在单一制剂中或在单独的制剂中。
在一些实施方式中，本发明的化合物可用于与一种或多种其他治疗剂或疗法组合治疗肠易激综合征(IBS)，所述其它治疗剂或疗法通过相同或不同作用机制起作用而在肠易激综合征治疗中有效。根据本领域技术人员已知的标准药学实践，所述至少一种其他治疗剂可以与通式I的化合物或其药学上可接受的盐或溶剂合物作为相同或分开的剂型的一部分、经由相同或不同的给予途径、以及根据相同或不同的给予时间表而给予。用于治疗肠易激综合征(IBS)的其他治疗剂的非限制性示例包括益生菌，纤维增补剂(例如洋车前草，甲基纤维素)，止泻药(例如洛哌丁胺)，胆汁酸结合剂(例如考来烯胺，考来替泊，考来维仑)，抗胆碱能药和抗痉挛药(例如莨菪碱，双环胺)，抗抑郁药(例如三环类抗抑郁药，如丙咪嗪或去甲替林或选择性5-羟色胺再摄取抑制剂(SSRI)如氟西汀或帕罗西汀)，抗生素(例如利福昔明)，阿洛司琼和鲁比前列酮。
本发明化合物和药物组合物的用途
本发明还提供了本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗RET相关疾病或病症的药物中的用途，其中，RET相关疾病或病症包括RET相关的癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
本发明提供了抑制野生型RET和RET突变体的本发明化合物或其药物组合物，例如，对当前标准护理治疗具有抗性的RET突变体(“RET抗性突变体”)。另外，相对于其它激酶，本发明化合物或其药物组合物对野生型RET可有选择性，从而导致与抑制其它激酶相关的毒性降低。
本发明提供了本发明所述的抑制野生型RET和RET突变体的本发明化合物或其药物组合物在制备用于预防或治疗野生型RET和RET突变体相关疾病或病症的药物中的用途。
在本文所述的任何方法或用途的一些实施方式中，癌症(例如RET相关癌症)是血液学癌症。在本 文所述的任何方法或用途的一些实施方式中，癌症(例如RET相关癌症)是实体瘤。在本文所述的任何方法或用途的一些实施方式中，癌症(例如RET相关癌症)是肺癌(例如，小细胞肺癌或非小细胞肺癌)，乳头状甲状腺癌，甲状腺髓样癌，分化型甲状腺癌，复发性甲状腺癌，难治性分化型甲状腺癌，肺腺癌，细支气管肺癌，2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤，甲状旁腺增生，乳腺癌，结直肠癌(例如转移性结肠直肠癌)，乳头状肾细胞癌，胃肠粘膜的神经节细胞瘤病，炎性肌纤维母细胞瘤或宫颈癌。在本文所述的任何方法或用途的一些实施方式中，癌症(例如RET相关癌症)选自：急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，青少年癌症，肾上腺皮质癌，肛门癌、阑尾癌，星形细胞瘤，非典型性畸胎瘤/横纹肌样瘤，基底细胞癌，胆管癌，膀胱癌，骨癌，脑干胶质瘤，脑肿瘤，乳腺癌，支气管肿瘤，伯基特淋巴瘤，类癌瘤，未知原发癌，心脏肿瘤，宫颈癌，儿童癌症，脊索瘤，慢性淋巴细胞白血病(CLL)，慢性骨髓性白血病(CML)，慢性骨髓增殖性肿瘤，结肠癌，结肠直肠癌，颅咽管瘤，皮肤T细胞淋巴瘤，胆管癌，原位导管癌，胚胎性肿瘤，子宫内膜癌，室管膜瘤，食道癌，成感觉神经细胞瘤，尤因肉瘤，颅外生殖细胞肿瘤，性腺外生殖细胞瘤，肝外胆管癌，眼癌，输卵管癌，骨纤维组织细胞瘤，胆囊癌，胃癌，胃肠类癌瘤，胃肠道间质瘤(GIST)，生殖细胞瘤，妊娠滋养细胞疾病，神经胶质瘤，多毛细胞瘤，多毛细胞白血病，头颈癌，心脏癌，肝细胞癌，组织细胞增多症，霍奇金淋巴瘤，下咽癌，眼内黑色素瘤，胰岛细胞瘤，胰腺神经内分泌瘤，卡波西肉瘤，肾癌，朗格汉斯细胞组织细胞增多症，喉癌，白血病，唇和口腔癌，肝癌，肺癌，淋巴瘤，巨球蛋白血症，骨恶性纤维组织细胞瘤，骨癌，黑色素瘤，梅克尔细胞癌，间皮瘤，转移性鳞状颈癌，中线状癌，口癌，多发性内分泌瘤综合征，多发性骨髓瘤，真菌病蕈样肉芽肿，骨髓增生异常综合征，骨髓增生异常/骨髓增殖性肿瘤，髓性白血病，骨髓性白血病，多发性骨髓瘤，骨髓增殖性肿瘤，鼻腔和鼻窦癌，鼻咽癌，成神经细胞瘤，非霍奇金淋巴瘤，非小细胞肺癌，口部癌，口腔癌，唇癌，口咽癌，骨肉瘤，卵巢癌，胰腺癌，乳头状瘤病，副神经节瘤，鼻旁窦和鼻腔癌，甲状旁腺癌，阴茎癌，咽癌，嗜铬细胞瘤，垂体癌，浆细胞瘤，胸膜肺胚细胞瘤，妊娠和乳腺癌，原发性中枢神经系统淋巴瘤，原发腹膜癌，前列腺癌，直肠癌，肾细胞癌，视网膜母细胞瘤，横纹肌肉瘤，唾液腺癌，肉瘤，塞扎里综合征，皮肤癌，小细胞肺癌，小肠癌，软组织肉瘤，鳞状细胞癌，鳞状颈癌，胃癌，T细胞淋巴瘤，睾丸癌，咽喉癌，胸腺瘤和胸腺癌，甲状腺癌症，肾盂和输尿管的移行细胞癌，未知原发癌，尿道癌，子宫癌，子宫肉瘤，阴道癌，外阴癌和威尔姆氏瘤。
在一些实施方案中，本发明所述RET相关癌症选自肺癌，乳头状甲状腺癌，甲状腺髓样癌，分化的甲状腺癌，复发性甲状腺癌，难治性分化型甲状腺癌，2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤，甲状旁腺增生，乳腺癌，结直肠癌，乳头状肾细胞癌，胃肠粘膜神经节细胞瘤和宫颈癌。在一些实施方案中，所述RET相关癌症是RET融合体肺癌或甲状腺髓样癌。
在一些实施方式中，式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物及其药学上可接受的盐和溶剂合物可用于治疗患有RET抑制剂抗性突变(其导致对不是式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物或药学上可接受的盐或溶剂合物的抗性增加，例如在氨基酸位置804处的取代，例如V804M、V804L或V804E)的癌症的患者，所述治疗通过联合给药或作为现有药物治疗(例如，不是式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物或其药学上可接受的盐或溶剂合物的其他RET激酶抑制剂)的后续治疗。本文描述了示例性的RET激酶抑制剂(例如，不是式(I)、(IA)、(I-1)、(I-2)或(I-3)的化合物或其药学上可接受的盐或溶剂合物的其 它RET激酶抑制剂)。在一些实施方式中，RET激酶抑制剂可以选自卡博替尼，凡德他尼，阿拉替尼，索拉非尼，乐伐替尼，普纳替尼，多维替尼，舒尼替尼，福替尼(foretinib)，BLU667和BLU6864。
在本文所述的任何方法或用途的一些实施方式中，所述肠易激综合征(IBS)包括腹泻主导型、便秘主导型或交替型、功能性腹胀、功能性便秘、功能性腹泻、不特异的功能性肠紊乱、功能性腹痛综合征、慢性特发性便秘、功能性食管疾病、功能性胃十二指肠疾病、功能性肛门直肠疼痛和炎性肠病。
根据本发明的方法，化合物和组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度、特殊的因素、给药方式，等等。化合物或组合物可以和一个或多个其他治疗剂进行药物联用，如本发明所讨论的。
本发明化合物的一般合成方法
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、(IA)、(I-1)、(I-2)或(I-3)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。若无其他说明，试剂均可以从市场上购买得到，例如试剂可购买于商品供应商如凌凯医药，Aldrich Chemical Company,Inc.,Arco Chemical Company和Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，N,N-二甲基乙酰胺和石油醚是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC1 3或DMSO-d 6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，双二重峰)，dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。
下面简写词的使用贯穿本发明：
DMAC,DMA        N,N-2-甲基乙酰胺
PdCl 2(dppf)CH 2Cl 2        [1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物
H 2    氢气
Pd/C    钯碳
NaOH    氢氧化钠
NH 4Cl    氯化铵
K 2CO 3    碳酸钾
MeOH    甲醇
PE    石油醚
EA    乙酸乙酯
DCM    二氯甲烷
L    升
mg    毫克
ml,mL    毫升
min    分钟
NaHCO 3
℃    摄氏度，温度
THF    四氢呋喃
g    克
mass％    质量百分比
N,mol/L    摩尔/升
DMF    N,N-二甲基甲酰胺
mmol    毫摩尔
NaH    氢化钠
LiAlH 4    四氢铝锂
TLC    薄层色谱
h    小时
HCl    氯化氢
DMSO    二甲亚砜
下列合成方案描述了制备本发明公开化合物的步骤。除非另外说明，R 1、X 1、X 2、X 3、X 4、X 5、E、A、Q、M、T、R a、q具有如本发明所述的定义。
合成方案1
中间体(IA-1a)合成方案：
Figure PCTCN2020113240-appb-000073
式(IA-1a)中间体化合物可参考上面中间体合成方案的合成步骤得到。其中环A为以下子结构式：
Figure PCTCN2020113240-appb-000074
Hal 1和Hal 2各自独立地为F、Cl、Br、I，优选Cl、Br；Pg 1为氨基保护基团，例如Boc，等；Pg 2为羟基保护基团，例如苄基，等。式(IA-1a-1)化合物与式(IA-1a-2)化合物在合适的偶联剂条件(如钯偶联剂，优选PdCl 2(dppf)CH 2Cl 2)下在合适的溶剂(如二氧六环，等)中发生偶联反应得到式(IA-1a-3)化合物；式(IA-1a-3)化合物与式(IA-1a-4)化合物在合适的偶联剂条件(如钯偶联剂，优选PdCl 2(dppf)CH 2Cl 2)下在合适的溶剂(如 甲苯，等)中发生偶联反应得到式(IA-1a-5)化合物；式(IA-1a-5)化合物在合适的反应条件下(如在氢氧化钠和过氧化氢存在下，在四氢呋喃溶剂中)反应得到式(IA-1a-6)化合物；式(IA-1a-6)化合物与式(IA-1a-7)化合物经过偶联反应得到式(IA-1a-8)化合物；式(IA-1a-8)化合物与式(IA-1a-9)化合物在碱性条件下反应得到式(IA-1a-10)化合物；式(IA-1a-10)化合物在酸性条件下脱氨基保护得到式(IA-1a-11)化合物；式(IA-1a-11)化合物与式(IA-1a-12)化合物在碱性条件下反应得到式(IA-1a-13)化合物；式(IA-1a-13)化合物在合适的条件(如H 2,Pd/C)下还原得到式(IA-1a)化合物。
中间体(IA-2a)合成方案：
Figure PCTCN2020113240-appb-000075
式(IA-2a)中间体化合物可参考中间体(IA-2a)合成方案的合成步骤得到。其中，Hal和Hal 2各自独立地为F、Cl、Br、I，优选Cl、Br。式(IA-1a-6)化合物与式(IA-2)化合物在合适的条件(如碱性条件，碱为K 2CO 3)下在合适的溶剂(如N,N-二甲基乙酰胺)中发生反应得到式(IA-2a)化合物。
合成方案1：
Figure PCTCN2020113240-appb-000076
式(IA)化合物可参考合成方案1的合成步骤得到。其中，Hal为F、Cl、Br、I，优选Cl、Br。式(IA-1)化合物与式(IA-2)化合物在合适的条件(如碱性条件，碱为K 2CO 3)下在合适的溶剂(如N,N-二甲基乙酰胺)中发生反应得到式(IA)化合物。
合成方案2
Figure PCTCN2020113240-appb-000077
式(IA1)化合物可参考合成方案2的合成步骤得到。式(IA-1)化合物与式(IA-3)化合物在合适的条件(如碱性条件，碱为K 2CO 3)下在合适的溶剂(如N,N-二甲基甲酰胺酰胺)中发生反应得到式(IA1)化合物。
合成方案3
Figure PCTCN2020113240-appb-000078
式(IA)化合物可参考合成方案3的合成步骤得到。式(IA-1)化合物与式(IA-4)化合物在合适的条件(如碱性条件，碱为K 2CO 3)下在合适的溶剂(如N,N-二甲基甲酰胺酰胺)中发生反应得到式(IA)化合物。
合成方案4
Figure PCTCN2020113240-appb-000079
式(IA2)化合物可参考合成方案4的合成步骤得到。式(IA-2a)化合物与式(IA-5)化合物在合适的条件(如碱性条件，碱为K 2CO 3)下在合适的溶剂(如DMSO)中加热发生反应得到式(IA2)化合物。
具体实施例
中间体1：6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000080
步骤1：6-溴-4-羟基吡唑并[1,5-a]吡啶-3-甲腈
室温条件下，在1L单口瓶中依次加6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲腈(50g,198.36mmol)，水(16.5mL,916mmol)，氢氧化钠(16.03g,396.8mmol)，DMA(500mL)，室温搅拌5min后转入0℃缓慢加入十二硫醇(97mL,397mmol)，加料结束后，反应转入45℃过夜。将反应液倒入3L冰水中，缓慢加入饱和柠檬酸水调节PH＝5，搅拌半小时后静置，过滤，滤饼用水和石油醚多次洗涤，60℃烘干得到黄色固体44.1g即为目标产物(收率93.4％)。Rf＝0.35(PE/EA＝3：1)；LC-MS：m/z＝239.05[M+H] +。
步骤2：3-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯
1L单口瓶中加入6-溴-4-羟基吡唑并[1,5-a]吡啶-3-甲腈(44.1g,185mmol),吡啶(45mL,559mmol),DCM(800mL)，温度降到-10℃以下，缓慢加入三氟甲磺酸酐(50mL,297.2mmol)，搅拌1h后自然升到室温反应过夜。减压旋干DCM，加水(250ml)稀释，用EA萃取(500ml×3)，收集有机相，饱和食盐水洗涤(250mL)，无水硫酸钠干燥后，过滤，滤液旋干，硅胶柱层析纯化(洗脱剂PE/EA＝50：1 -25：1)得类黄色固体61.5g即为目标产物，收率89.7％。Rf＝0.45(PE/EA＝5：1)。
步骤3：6-溴-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
氮气保护条件下在1L三口瓶中加入3-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(61.5g,166mmol)，2-氟吡啶-5-硼酸酯(44.5g,200mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(6.8g,8.3mmol)，1,4-二氧六环(850mL)，温度降到-10℃下缓慢加入醋酸钾溶液(115mL,345mmol,3mol/L)，此温度下搅拌1h后自然恢复至室温继续反应过夜。过滤，EA(500ml×3)洗涤滤饼，有机相水洗(500ml)，饱和食盐水洗涤(250ml)，无水硫酸钠干燥、过滤，滤液旋干，硅胶柱层析纯化(洗脱剂PE/DCM＝2:1-0:1)，收集目标点，旋干得到白色固体49g即为目标产物，收率93.0％。Rf＝0.50(PE/EA＝1：1)。LC-MS：m/z＝318.10[M+H] +； 1H NMR(400MHz,DMSO):δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H)。
步骤4：4-(6-氟吡啶-3-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-3-甲腈
250mL单口瓶中氮气保护条件下依次加入6-溴-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(8g,25.23mmol)，联硼酸频那醇酯(10g,39.39mmol)，乙酸钾(10g,101.9mmol)，重蒸甲苯(150mL)，氮气置换后再鼓泡10min后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2.1g,2.6mmo)，氮气置换鼓泡10min后120℃加热反应过夜。硅藻土过滤，EA洗涤(50ml×3)滤饼，有机相水洗(250m L)，用饱和食盐水洗(250mL)，无水硫酸钠干燥、过滤、旋干，硅胶柱层析(洗脱剂PE/DCM＝2:1-0:1)，收集旋干得到橘黄色固体8.5g，即为目标产物(收率93.0％)。Rf＝0.15(DCM)。 1H NMR(400MHz,CDCl 3):δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H)。
步骤5：4-(6-氟吡啶-3-基)-6-羟基吡唑并[1,5-a]吡啶-3-甲腈
在250mL的单口瓶中依次加入4-(6-氟吡啶-3-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-3-甲腈(8.5g,23mmol),四氢呋喃(120mL),在冰浴条件下，缓慢加入氢氧化钠溶液(60mL,120mmol,2mol/L)，双氧水(14mL,140mmol,30mass％)，低温搅拌。反应完全后缓慢加入硫代硫酸钠溶液(50mL,150mmol,3mol/L)，恢复室温后，加水(250mL)，EA萃取(250mL×2)，合并有机相用0.1M NaOH溶液洗(500mL×2)。合并所有水相，用稀盐酸将PH调到4,室温搅拌15min，抽滤，得到湿滤饼。母液EA萃取(250ml×3)，合并所有有机相，无水硫酸钠干燥、过滤、旋干，硅胶柱层析(洗脱剂DCM\MeOH(v/v＝100/0-100/1)得到浅黄色固体。合并所有固体，50℃烘干得到浅黄色固体5.1g即为目标产物(收率86.0％)。Rf＝0.25(DCM\MeOH(v/v＝100/1))。LC-MS：m/z＝255.10[M+H] +。
步骤6：3-(5-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-叔丁酯羧酸
30mL的微波管中，依次加入4-(6-氟吡啶-3-基)-6-羟基吡唑并[1,5-a]吡啶-3-甲腈(1.5g,5.9mmol)，6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(2.3g,12mmol)，N,N-二异丙基乙胺(2.0mL,12mmol)，二甲亚砜(15mL)，密封，微波80℃下反应8h。在低温条件下，加水(50mL)稀释，EA萃取(100mL×5)，合并有机相饱和食盐水(250mL)洗涤，无水硫酸钠干燥后，过滤，滤液旋干硅胶层析柱纯化(洗脱剂PE/EA＝5：1-1；1.5)，收集得到黄色产品1.9g即为目标产物(收率74.0％)。Rf＝0.5(PE/EA＝1/1.5)。LC-MS：m/z＝433.10[M+H] +。
步骤7：3-(5-(6-(苄氧基)-3-氰基吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-3-叔丁酯-6-羧酸乙酯
在25mL单口瓶中依次加入3-(5-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-叔丁酯羧酸(1g,2.312mmol)，溴化苄(0.302mL,2.54mmol)，碳酸钾(0.9683g,6.936mmol)，N,N-二甲基甲酰胺(10mL)，80℃搅拌过夜。室温条件下加饱和氯化铵(100mL)淬灭，用DCM(100mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液旋干硅胶层析柱纯化(洗脱剂PE/EA＝5：1-2：1)，得黄色固体1.06g即为目标产物(收率87.7％)。Rf＝0.7(PE/EA＝1：1)。LC-MS：m/z＝523.30[M+H]； 1H NMR(400MHz,CDCl 3)δ8.37(s,1H),8.19(s,1H),8.17(d,J＝1.9Hz,1H),7.74(d,J＝8.7Hz,2H),7.42(dt,J＝11.9,7.4Hz,5H),7.18(d,J＝2.0Hz,1H),5.13(s,2H),4.31(d,J＝4.0Hz,2H),4.16(dd,J＝8.7,4.4Hz,2H),3.55(dd,J＝8.1,3.1Hz,2H),2.24–2.20(m,1H),2.01(d,J＝5.5Hz,1H),1.38(s,9H)。
步骤8：4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(苄氧基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐
3-(5-(6-(苄氧基)-3-氰基吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-3-叔丁酯-6-羧酸乙酯(1.06g,2.03mmol,)，盐酸乙酸乙酯溶液(5mL,20mmol,4mol/L)，室温反应过夜。反应液旋干得到黄色粘稠物，60℃烘干得到黄色固体1.0g，即为目标产物(收率100％)。LC-MS：m/z＝423.30[M-2HCl]。
步骤9：(6-甲氧基吡啶-3-基)甲醇
0℃下，25ml单口瓶中依次加入6-甲氧基-3-吡啶甲醛(0.4g,3mmol)，四氢锂铝(0.06g,2mmol)，四氢呋喃(10mL)，此温度反应过夜。加入EA(50m L)，将反应混合物用水(50mL)稀释，萃取分离后，用饱和NH 4Cl(50mL)溶液洗涤有机层，无水硫酸钠干燥，过滤，滤液旋干，硅胶层析柱纯化(洗脱剂DCM/EA＝4：1)，得淡黄色液体0.38g即为目标产物(收率90.0％)。LC-MS：m/z＝140.15[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.12(d,J＝1.8Hz,1H),7.62(dd,J＝8.5,2.4Hz,1H),6.75(d,J＝8.5Hz,1H),4.62(s,2H),3.93(s,3H)。
步骤10：5-(溴甲基)-2-甲氧基吡啶
在25mL单口瓶中，依次加入(6-甲氧基吡啶-3-基)甲醇(0.38g,2.7mmol)，二氯甲烷(8mL)，三溴化磷(0.31mL,3.3mmol)，0℃反应30min。加入DCM(25ml)稀释，饱和K 2CO 3(25mL)水溶液洗，有机相无水硫酸钠干燥，过滤，滤液旋干，不做进一步纯化直接投下一步。
步骤11：6-(苄氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并并[1,5-a]吡啶-3-甲腈
25ml单口瓶中依次加入4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(苄氧基)吡唑并[1,5-a]吡啶-3-甲腈(400mg,0.8074mmol)，碳酸钾(0.3382g,2.423mmol)，N,N-二甲基甲酰胺(8mL)中，后缓慢加入5-(溴甲基)-2-甲氧基吡啶(0.50g,2.5mmol)，于室温搅拌过夜。反应液加水(25mL)稀释，EA(50mL×3)萃取，有机相饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液旋干硅胶层析柱纯化(洗脱剂DCM/MeOH(v/v＝1/0-20/1)，得到淡黄色固体0.2889g即为目标产物(收率65.82％)。LC-MS：m/z＝544.10[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.39(s,1H),8.22-8.17(m,2H),8.11(s,1H),8.02(s,1H),7.78(d,J＝8.8Hz,1H),7.42(dd,J＝14.9,7.1Hz,5H),7.19(s,1H),6.70(dd,J＝13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H),3.80(s,4H),3.59(s,4H),2.22(s,1H),2.01(s,1H)。
步骤12：6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈
50ml单口瓶中依次加入，6-(苄氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并并[1,5-a]吡啶-3-甲腈(0.288g,0.530mmol)，甲醇(5mL)，钯碳(0.03g，10％mass)，氢气置换数次后于室温搅拌过夜。反应液过滤，甲醇冲洗滤饼，滤液旋干得到淡黄色固体240mg即为目标产物(收率100.0％)。LC-MS：m/z＝454.30[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.39(d,J＝1.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.21(s,1H),8.17-8.12(m,1H),7.81(dd,J＝8.1,2.2Hz,2H),7.14(s,1H),6.78(d,J＝8.6Hz,1H),6.70(d,J＝8.3Hz,1H),5.37(s,1H),4.00-3.90(m,5H),3.73(s,4H),3.51(s,2H),2.27-2.21(m,1H),2.03(d,J＝6.6Hz,1H)。
中间体2：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000081
步骤1：6-(2-氯乙基)-2-氧杂-6-氮杂螺[3.3]庚烷
100mL单口瓶中加入2-氧杂-6-氮杂螺[3.3]庚烷(2.0g,20mmol)，碳酸钾(15g,108.5mmol)，1-溴-2-氯乙烷(8.0mL,97.0mmol)，乙腈(20mL)，加入完毕后室温下反应。反应结束后，抽滤除去不溶性固体，甲醇洗涤滤饼，合并有机相，浓缩硅胶柱层析，得到产物860mg。 1H NMR(400MHz,CDCl 3):δ4.74(s,4H),3.47 3.39(m,6H),2.72(t,J＝6.3Hz,2H)。
步骤2：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
25mL烧瓶中依次加入4-(6-氟吡啶-3-基)-6-羟基吡唑并[1,5-a]吡啶-3-甲腈(500mg,1.97mmol)，碳酸钾(825mg,5.97mmol)，6-(2-氯乙基)-2-氧杂-6-氮杂螺[3.3]庚烷(850mg,5.26mmol)，DMA(6mL)，80℃下反应。TLC检测反应完全后反应液中加水20mL，EA(80mL×2)萃取，有机相水洗(15mL×3)，饱和食盐水洗(15mL×6)，无水硫酸钠干燥后过滤，滤液硅胶柱层析，洗脱剂为EA-EA/MeOH(v/v＝20/1),得到黄色固体210mg即为产物。LC-MS：m/z＝380.20[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.38(d,J＝2.2Hz,1H),8.21(s,1H),8.19(d,J＝2.0Hz,1H),8.01(td,J＝8.4,2.5Hz,1H),7.18(d,J＝2.0Hz,1H),7.13(dd,J＝8.4,2.8Hz,1H),4.75(s,4H),4.03(t,J＝5.2Hz,2H),3.52(s,4H),2.87(t,J＝5.2Hz,2H)。
实施例1：6-(2-(8-氧杂-2-氮杂螺[4.5]癸-2-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000082
步骤1：2-(2-氯乙基)-8-氧杂-2-氮杂螺[4.5]癸烷
10mL烧瓶中依次加入8-氧杂-2-氮杂螺[4.5]癸烷(300mg,2.12mmol)，碳酸钾(882mg,6.38mmol)，乙腈(3mL)，冰浴反应10min后加入1-溴-2-氯乙烷(0.2mL,2.55mmol)，继续冰浴反应10min后室温下反应过夜。反应液直接旋干，硅胶柱层析(洗脱剂为PE:EA＝1:1)，得淡黄色固体41mg即为目标产物(收率9.5％)。 1H NMR(400MHz,CDCl 3):δ3.62(t,J＝5.3Hz,4H),3.55(t,J＝7.0Hz,2H),2.77(t,J＝7.0Hz,2H),2.64(t,J＝6.9Hz,2H),2.47(s,2H),1.68(t,J＝6.9Hz,2H),1.63-1.47(m,4H)。
步骤2：6-(2-(8-氧杂-2-氮杂螺[4.5]癸-2-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL烧瓶中加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(20mg,0.04mmol，参见中间体1的合成)，3-(2-氯乙基)-8-氧杂-3-氮杂螺[4.5]癸烷(28mg,0.14mmol)，碳酸钾(31mg,0.22mmol)，N,N-二甲基乙酰胺(0.8mL)，油浴85℃下反应过夜。反应结束后，乙酸乙酯(30mL×3)萃取，合并有机相无水硫酸钠干燥过，硅胶柱层析(洗脱剂DCM/MeOH(v/v＝30/1-10/1)，得到淡黄色固体16mg即为目标产物(收率：58.4％)。Rf＝0.1(DCM/MeOH＝20/1)。LC-MS(ES-API):m/z＝621.35[M+H] +。 1H NMR(400MHz,CDCl 3):δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.16(d,J＝2.1Hz,1H),8.10(s,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.63(dd, J＝8.5,2.2Hz,1H),7.15(d,J＝1.9Hz,1H),6.70(dd,J＝11.9,8.7Hz,2H),4.17(t,J＝5.5Hz,2H),3.92(s,3H),3.83(d,J＝11.7Hz,2H),3.77(d,J＝5.7Hz,2H),3.65(t,J＝5.2Hz,4H),3.60(s,1H),3.58(s,2H),2.96(t,J＝5.5Hz,2H),2.76(t,J＝6.7Hz,2H),2.69(dd,J＝13.7,6.7Hz,1H),2.59(s,2H),2.03(d,J＝6.3Hz,2H),1.74(t,J＝6.9Hz,2H),1.63-1.54(m,4H)。
实施例2：6-(2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000083
步骤1：6-(2-氯乙基)-2-氧杂-6-氮杂螺[3.3]庚烷
10mL单口瓶中加入2-氧杂-6-氮杂螺[3.3]庚烷(250mg,2.52mmol)，碳酸钾(2.1g,15.1mmol)，1-溴-2-氯乙烷(2.1mL,13.0mmol)，乙腈(2.5mL)，室温下反应。反应结束后，抽滤，甲醇洗涤滤饼，有机相浓缩，硅胶柱层析，得到无色透明液体210mg即为目标产物(收率：51.5％)，Rf＝0.3(EA/MeOH(v/v)＝5/1)。 1H NMR(400MHz,CDCl 3):δ4.74(s,4H),3.47-3.40(m,6H),2.72(t,J＝6.3Hz,2H)。
步骤2：6-(2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL烧瓶中加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(25mg,0.06mmol，参见中间体1的合成)，6-(2-氯乙基)-2-氧杂-6-氮杂螺[3.3]庚烷(5mg,0.34mmol)，碳酸钾(60mg,0.43mmol)，N,N-二甲基乙酰胺(0.8mL)，85℃油浴下反应过夜。反应结束后，乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤滤液旋干硅胶柱层析(洗脱剂为DCM/MeOH＝30/1-10/1)，收集得淡黄色固体6mg即为目标产物(收率：3.0％)。Rf＝0.1(DCM/MeOH(v/v＝20/1)。LC-MS(ES-API):m/z＝579.80[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.41(d,J＝2.1Hz,1H),8.23(s,1H),8.13(s,2H),7.80(dd,J＝8.8,2.5Hz,1H),7.74(s,1H),7.10(dd,J＝8.5,2.5Hz,1H),6.73(dd,J＝16.0,8.7Hz,2H),4.78(s,4H),4.05(t,J＝4.8Hz,2H),3.94(s,3H),3.89(s,2H),3.66(s,4H),3.56(s,4H),2.90(s,2H),2.80(s,1H),2.63(s,1H),2.40-2.29(m,1H),2.28-2.18(m,1H)。
实施例3：6-(2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3，6二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000084
步骤1：8-(2-氯乙基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷
于10mL单口瓶中加入1,4-二氧杂-8-氮杂螺[4.5]癸烷盐酸盐(300mg,1.67mmol)，碳酸钾(693mg,5.01mmol)，丙酮(3.0mL)，加入完毕后冰浴条件下缓慢加入1-溴-2-氯乙烷(0.2mL,2.004mmol)，搅拌10min后恢复至室温反应过夜。反应结束后，旋蒸除去丙酮，二氯甲烷(10ml×2)萃取，有机相合并后水洗(10ml×2)，无水硫酸钠干燥，过滤后硅胶柱层析(洗脱剂为PE/EA(v/v)＝1/1)收集旋干得到白色固体43mg即为目标产物(收率：12.519％，Rf＝0.3(EA/MeOH(v/v)＝5/1))。 1H NMR(400MHz,CDCl 3)：δ＝3.93(s,4H),3.56(t,J＝7.1Hz,2H),2.74(t,J＝7.1Hz,2H),2.63-2.52(m,4H),1.79-1.68(m,4H)。
步骤2：6-(2-(7-氧杂-2-氮杂螺[4.5]癸-2-基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
在5ml单口瓶中依次加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈(20mg,0.04410mmol，参见中间体1的合成)，8-(2-氯乙基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(18.2mg,0.0885mmol)，碳酸钾(30.78mg,0.2205mmol)，DMA(0.5mL)，油浴锅80℃加热过夜。反应完毕后反应液加水(10mL)稀释，用EA萃取(20mL×3)，收集有机相，用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液旋干硅胶层析柱纯化，洗脱剂DCM/MeOH(v/v)＝30/1-15/1，收集旋干得到黄色固体21mg即为目标产物(收率76.47％)(Rf＝0.45，DCM/MeOH(v/v)＝15/1)。LC-MS:m/z＝623.1[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.39(s,1H),8.20(s,1H),8.16(s,1H),8.10(s,1H),7.77(d,J＝7.2Hz,1H),7.63(d,J＝6.8Hz,1H),7.14(s,1H),6.70(dd,J＝12.9,8.7Hz,2H),4.17(t,2H),3.96(s,4H),3.92(s,3H),3.84(d,J＝11.3Hz,2H),3.78(d,J＝4.9Hz,2H),3.66-3.53(m,4H),2.92(t,J＝5.3Hz,2H),2.73-2.67(m,4H),2.10-2.01(m,2H),1.82-1.76(m,4H)。
实施例4：6-((3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000085
步骤1：3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇
在-10℃低温槽中，于25mL双口瓶中加入氢氧化铝锂的THF溶液(2.0mol/L,100mg,3mmol)，氮气保护条件下缓慢加入3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-酮的THF溶液(10mL)，滴加结束后，缓慢恢复至室温继续搅拌2h。低温条件下，加入饱和氯化铵水溶液(10mL)淬灭，倒出用EA萃取(30mL×3),合并有机相，饱和食盐水洗涤(50mL)，有机相无水硫酸钠干燥，过滤旋干，硅胶层析柱(洗脱剂DCM/EA(v/v)＝5/1)，收集目标溶液旋干得到白色固体即为目标产品(收率：90.0％，Rf＝0.5(EA/DCM(v/v)＝1/8))。 1H NMR(400MHz,CDCl 3):δ3.85-3.76(m,1H),3.52(d,J＝3.3Hz,4H),2.12-2.09(m,1H),1.81(dd,J＝11.8,5.6Hz,2H),1.61(d,J＝9.9Hz,6H),0.99(s,6H)。
步骤2：3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基甲磺酸酯
冰浴条件下，在5mL单口瓶中依次加入3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇(100mg,0.4993mmol)，二氯甲烷(1mL)，三乙胺(0.105mL，0.748mmol)，缓慢加入甲磺酰氯(0.05mL，0.649mmol)，滴加结束后，缓慢恢复至室温继续反应2h。在低温条件下，加水(10mL)稀释，用DCM萃取(25mL×3)将合并的有机层分别用饱和NaHCO 3(30mL)洗涤，饱和食盐水盐水(30mL)洗涤，无水硫酸钠干燥后璇干硅胶柱层析纯化(DCM/EA(v/v)＝10/1)，得浅黄色溶液131mg即为目标产品。(收率：94.2％，Rf＝0.8(EA/DCM(v/v)＝1/10))。 1H NMR(400MHz,CDCl3):δ4.86-4.79(m,1H),3.49(d,J＝13.9Hz,4H),3.01(s,3H),1.99(dd,J＝15.4,9.2Hz,2H),1.91(dd,J＝10.9,5.6Hz,4H),1.82(dd,J＝13.1,4.6Hz,2H),0.96(s,6H).
步骤3：6-((3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
在5mL单口瓶中依次加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(25mg,0.05513mmol，中间体1)，3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基甲磺酸酯(30.69mg,0.1102mmol)，碳酸钾(24.06mg,0.1654mmol)，DMF(0.25mL)，油浴锅80℃加热过夜。反应完毕后反应液加水(10mL)稀释，用EA萃取(20mL×3)，收集有机相，用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液旋干，硅胶层析柱纯化(洗脱剂DCM/MeOH(v/v)＝50/1-40/1)，得黄色固体14.3mg，即为目标产物(收率40.8％)，(Rf＝0.4， DCM/MeOH(v/v)＝30/1)。LC-MS:m/z＝636.2[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.40(d,J＝2.2Hz,1H),8.21(s,1H),8.16(d,J＝1.7Hz,1H),8.10(d,J＝1.3Hz,1H),7.77(dd,J＝8.7,2.3Hz,1H),7.63(d,J＝6.3Hz,1H),7.11(d,J＝1.8Hz,1H),6.70(dd,J＝12.9,8.7Hz,2H),4.43-4.34(m,1H),3.92(s,3H),3.84(d,J＝10.8Hz,2H),3.78(d,J＝5.3Hz,2H),3.61(s,2H),3.58(s,2H),3.53(d,J＝9.2Hz,4H),2.69(dd,J＝13.2,7.0Hz,1H),2.04(dd,J＝12.4,5.9Hz,3H),1.94(dd,4H),1.84(dd,J＝12.5,6.0Hz,2H),0.98(s,6H)。
实施例5：6-((2-氧杂螺[3.3]庚烷-6-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000086
步骤1：2-氧杂螺[3.3]庚-6基甲磺酸酯
冰浴条件下，在5mL单口瓶中依次加入2-氧杂螺[3.3]庚-6-醇(100mg,0.9mmol)，二氯甲烷(1mL)，三乙胺(0.2mL，1.0mmol)，缓慢加入甲磺酰氯(0.09mL，1mmol)，滴加结束后，缓慢恢复至室温继续反应2h。在低温条件下，加水(10mL)稀释，用饱和Na 2SO 4水溶液(10mL)淬灭，用EA萃取(30mL×3)合并的有机层分别用饱和NaHCO 3(30mL)洗涤，饱和食盐水(30mL)洗涤，无水硫酸钠干燥后璇干得到浅黄色油状物0.16g即为目标产品。(收率：100％，Rf＝0.8(EA/PE(v/v)＝1/10))。 1H NMR(400MHz,CDCl 3):δ4.83(p,J＝7.2Hz,1H),4.68(d,J＝8.2Hz,4H),2.97(s,3H),2.82–2.74(m,2H),2.52–2.44(m,2H)。
步骤2：6-((2-氧杂螺[3.3]庚烷-6-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
在5mL单口瓶中依次加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈(25mg,0.05513mmol，中间体1)，2-氧杂螺[3.3]庚-6基甲磺酸酯(21.2mg,0.11mmol)，碳酸钾(24.06mg,0.1654mmol)，DMF(0.5mL)，油浴锅80℃加热过夜。反应完毕后反应液加水(10mL)稀释，用EA萃取(25mL×3)，收集有机相，用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液旋干硅胶层析柱纯化，洗脱剂DCM/MeOH(v/v)＝100/1-20/1，收集旋干得到黄色固体11.5mg即为目标产物(收率38％)(Rf＝0.2，DCM/MeOH(v/v)＝30/1)。LC-MS:m/z＝550.30[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.39(d,J＝2.1Hz,1H),8.21(s,1H),8.12(d,J＝1.8Hz,1H),7.95(d,J＝1.9Hz,1H),7.79(dd,J＝8.9,2.4Hz,1H),7.53(d,J＝8.5Hz,1H),7.05(d,J＝2.0Hz,1H),6.93(t,J＝7.4Hz,2H),4.75(d,J＝20.2Hz,4H),4.57–4.52(m,1H),3.97–3.86(m,7H),3.73–3.65(m,4H),2.65–2.56(m,2H),2.48–2.42(m,2H),2.37–2.33(m,1H),2.21(d,J＝7.6Hz,1H)。
实施例6：6-(2-((2-氧杂螺[3.3]庚烷-6-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双 环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000087
步骤1：2-(6-氧杂螺[3.3]庚烷-2-基氧基)乙酸乙酯
25mL双口瓶中，加入NaH(127mg,3.175mmol)，氮气保护下抽真空，0℃下加入无水THF(10mL)溶解，加入液体6-氧杂螺[3.3]庚烷-2-醇(300mg,2.628mmol)，加毕室温搅拌反应2h后转移至0℃，缓慢加入2-溴乙酸乙酯(0.32mL,2.9mmol)，加毕室温搅拌反应。TLC点板，KMnO 4氧化显示反应完毕，加水15mL淬灭，EA(60mL×2)萃取，有机相饱和食盐水30mL洗涤，无水硫酸钠干燥，过滤，旋干，硅胶柱层析(洗脱剂PE/EA(v/v)＝10/1-1/1)，得到油状液体0.222g(收率42.2％)，即为目标产物。 1H NMR(400MHz,CDCl 3):δ4.63(d,J＝12.0Hz,4H),4.19(q,J＝7.1Hz,2H),3.94(s,2H),3.93–3.85(m,1H),2.61–2.52(m,2H),2.23–2.14(m,2H),1.26(t,J＝7.1Hz,3H)。
步骤2：2-(6-氧杂螺[3.3]庚烷-2-基氧基)乙醇
25mL双口瓶中，加入LiAlH 4(0.085g,2.2mmol)和THF 5mL配成溶液，氮气保护下抽真空，将2-(6-氧杂螺[3.3]庚烷-2-基氧基)乙酸乙酯(222mg,1.109mmol)溶解于3mLTHF，0℃下缓慢加入到双口瓶中，保温反应。TLC点板(KMnO 4氧化)显示反应完毕，加入饱和氯化铵溶液10mL淬灭反应，EA(20mL×2)萃取，有机相饱和食盐水15mL洗涤，无水硫酸钠干燥，过滤，旋干，硅胶柱层析(洗脱剂纯DCM-DCM/EA((v/v)4/1-1/4))，得到淡黄色油状物0.103g(收率58.7％)，即为目标产物。 1H NMR(400MHz,CDCl 3):δ4.65(d,J＝16.7Hz,4H),3.83(dd,J＝13.9,7.0Hz,1H),3.73–3.63(m,2H),3.46–3.36(m,2H),2.68–2.47(m,2H),2.15–2.08(m,2H)。
步骤3：2-(6-氧杂螺[3.3]庚烷-2-基氧基)乙基甲磺酸酯
冰浴条件下，在10mL单口瓶中加入2-(6-氧杂螺[3.3]庚-2-基氧基)乙醇(100mg,0.632mmol)，DCM(1.5mL)溶解，加入TEA(0.133mL,0.947mmol)，缓慢滴加甲磺酰氯(0.065mL,0.83mmol)，后自然升至室温反应。TLC显示反应完毕，加水3mL淬灭反应，DCM(15mL×2)萃取，饱和食盐水8mL洗涤，无水硫酸钠干燥，过滤，旋干，抽干，得到理论量黄色液体，直接投入下步反应。
步骤4：6-(2-((2-氧杂螺[3.3]庚烷-6-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶加入2-(6-氧杂螺[3.3]庚烷-2-基氧基)乙基甲磺酸酯(32mg,0.135mmol)，K 2CO 3(37mg,0.265mmol)，6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶 -3-基)吡唑并[1，5-a]吡啶-3-甲腈(30mg,0.066mmol，中间体1)，DMF(1.5mL)溶解，置于60℃搅拌反应8h。TLC点板显示反应完毕，加水10mL洗涤，EA萃取(40mL×2)，合并有机相饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，旋干，硅胶柱层析(洗脱剂纯DCM-DCM/MeOH(v/v＝10/1))，得到淡黄色固体0.011g(收率28％)，即为目标产物。LC-MS:m/z＝594.10[M+H] +； 1H NMR(400MHz,CDCl 3)；δ8.40(s,1H),8.21(s,1H),8.16(s,1H),8.11(s,1H),7.78(dd,J＝8.7,2.1Hz,1H),7.69(d,J＝8.6Hz,1H),7.16(s,1H),6.71(dd,J＝15.4,8.6Hz,2H),4.67(d,J＝18.4Hz,4H),4.17–4.13(m,2H),3.92(s,3H),3.90–3.87(m,1H),3.85(s,3H),3.75–3.72(m,2H),3.66(dd,J＝14.5,7.5Hz,5H),2.76(dd,J＝6.0,3.6Hz,1H),2.65–2.57(m,2H),2.21–2.15(m,2H),2.07–2.00(m,1H)。
实施例7：6-((1,4-二氧杂螺[4.5]癸烷-8-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000088
步骤1：1,4-二氧杂螺[4.5]癸烷-8-醇
冰浴条件下，在100mL单口瓶依次加入1,4-环己二酮单乙二醇缩酮(2.0g,13mmol)，甲醇(40mL)。分批次加入硼氢化钠(1.5g,40mmol)，加料结束后，恢复至室温继续搅拌。2h后TLC显示反应完成。浓缩反应液成固体，加入水(20mL)，用EA萃取(50mL×3)，合并有机相，饱和食盐水洗涤(100mL)，有机相无水硫酸钠干燥，过滤旋干，硅胶层析柱纯化，洗脱剂DCM/EA(v/v)＝5/1，得到无色透明液体1.89g。 1H NMR(400MHz,CDCl 3):δ4.02-3.85(m,4H),3.84-3.73(m,1H),1.93-1.74(m,5H),1.63(ddd,J＝14.2,10.0,6.5Hz,4H)。
步骤2：1,4-二氧杂螺[4.5]癸烷-8-基甲磺酸酯
冰浴条件下，在5mL单口瓶中依次加入1,4-二氧杂螺[4.5]癸烷-8-醇(200mg,1.26mmol)，二氯甲烷(2mL)，三乙胺(0.27mL,1.89mmol)，缓慢加入甲磺酰氯(0.13mL,1.64mmol)，滴加结束后恢复室温搅拌2h。TLC显示反应完成。在低温条件下，加30mL水稀释，用二氯甲烷萃取(50mL×3)，合并的有机相用饱和NaHCO 3洗涤，饱和食盐水水洗涤，有机相无水硫酸钠干燥后旋干，硅胶柱层析(DCM/EA(v/v)＝10/1)，收集得到浅黄色溶液290mg。 1H NMR(400MHz,CDCl 3):δ4.90-4.78(m,1H),3.95(dd,J＝6.0,3.9Hz,4H),3.01(s,3H),2.00(dd,J＝12.2,6.8Hz,4H),1.90-1.81(m,2H),1.68-1.61(m,2H)。
步骤3：6-((1,4-二氧杂螺[4.5]癸烷-8-基)氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶中加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈(40mg,0.09mmol，中间体1)，1,4-二氧杂螺[4.5]癸-8-甲磺酸酯(65mg,0.27mmol)，碳酸铯(115mg,0.35mmol)，DMA(1mL)，60℃反应过夜。将反应液倒入10mL冰水中，EA萃取(30mL×3)，合并有机相用饱食盐水洗(20mL×3)，有机相无水硫酸钠干燥后，过滤，滤液旋干，残余物硅胶柱层析(洗脱剂DCM/MeOH＝25/1)，收集得到白色固体22mg。LC-MS:m/z＝594.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.17(d,J＝1.8Hz,1H),8.11(d,J＝1.5Hz,1H),7.78(dd,J＝8.8,2.3Hz,1H),7.70(d,J＝6.6Hz,1H),7.12(d,J＝1.8Hz,1H),6.70(dd,J＝15.5,8.7Hz,2H),4.43-4.36(m,1H),4.01-3.95(m,4H),3.92(s,3H),3.90-3.80(m,4H),3.70-3.59(m,4H),2.81-2.71(m,1H),2.05-1.98(m,4H),1.96-1.93(m,1H),1.71-1.62(m,4H)。
实施例8：6-(2-((6-氮杂螺[3.4]庚烷-2-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000089
冰浴条件下，在装有6-(2-((6-氮杂螺[3.4]辛烷-2-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈二盐酸盐(10.8mg,0.016mmol,实施例9化合物)的5mL单口瓶中加入饱和碳酸氢钠溶液1mL，调pH为碱性，加入DCM 3mL搅拌5min。分出有机相，再用DCM(5mL×2)萃取，有机相饱和食盐水5mL洗涤，无水硫酸钠干燥，过滤，旋干，抽干。得到淡黄色固体6mg(收率60％)，即为目标产物。LC-MS:m/z＝607.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.41–8.37(m,1H),8.21(s,1H),8.16(d,J＝1.8Hz,1H),8.10(d,J＝1.3Hz,1H),7.78(dd,J＝8.8,2.3Hz,1H),7.62(dd,J＝8.5,2.1Hz,1H),7.17(d,J＝1.7Hz,1H),6.70(dd,J＝12.2,8.7Hz,2H),4.21–4.14(m,2H),4.11–4.02(m,1H),3.92(s,3H),3.83(d,J＝10.9Hz,2H),3.76(d,J＝5.2Hz,4H),3.67–3.58(m,2H),3.57(s,2H),3.14–2.86(m,4H),2.71–2.64(m,1H),2.37–2.29(m,2H),2.24–2.19(m,1H),2.05(dd,J＝11.3,5.7Hz,3H),1.86(d,J＝7.1Hz,2H)。
实施例9：6-(2-((6-氮杂螺[3.4]辛烷-2-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈二盐酸盐
Figure PCTCN2020113240-appb-000090
步骤1：2-(2-乙氧基-2-氧代乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯
25mL双口瓶中，加入NaH(72mg,1.8mmol)，氮气保护下抽真空多次，置于0℃下，加入无水THF(17mL)配成悬浊液，加入2-羟基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(340mg,1.496mmol)，加毕升温至室温搅拌反应2h。转移至0℃，缓慢加入2-溴乙酸乙酯(0.183mL,1.65mmol)，后室温搅拌反应过夜。TLC显示反应完毕，反应液加水15mL淬灭，EA(60mL×2)萃取，有机相饱和食盐水30mL洗涤，无水硫酸钠干燥，过滤，旋干，硅胶柱层析(洗脱剂PE/EA(v/v)＝10/1-2/1)，得到油状液体0.143g(收率31％)，即为目标产物。LC-MS:m/z＝258.1[M-56+H] +。 1H NMR(400MHz,CDCl 3):δ4.21(q,J＝7.1Hz,2H),4.11–4.03(m,1H),4.00–3.95(m,2H),3.37–3.21(m,4H),2.33–2.21(m,2H),2.10–1.97(m,2H),1.88–1.75(m,2H),1.44(s,9H),1.28(t,J＝7.1Hz,3H)。
步骤2：2-(2-羟基乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯
在25mL双口瓶中，加入LiAlH 4(40.5mg,1.07mmol)，加入3mL THF配成悬浊液，氮气保护下抽真空多次，将2-(2-乙氧基-2-氧代乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(134mg,0.428mmol)溶解于3mL THF中，低温槽-40℃下缓慢加入到双口瓶中，保温反应1h。TLC显示反应完毕，加水12mL淬灭反应，EA(25mL×2)萃取，有机相饱和食盐水15mL洗涤，无水硫酸钠干燥，过滤，滤液旋干，硅胶柱层析(洗脱剂PE/EA(v/v)＝4/1-1/4)，得到透明状油状物0.101g(收率87％)，即为目标产物。LC-MS:m/z＝216.3[M-56+H] +； 1H NMR(400MHz,CDCl 3):δ4.04–3.94(m,1H),3.75–3.67(m,2H),3.46–3.41(m,2H),3.37–3.21(m,4H),2.32–2.20(m,2H),2.14(s,1H),2.00–1.89(m,2H),1.85–1.78(m,2H),1.43(s,9H)。
步骤3：2-(2-甲基磺酰氧基乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯
冰浴条件下，在5mL单口瓶中加入2-(2-羟基乙氧基)-6-氮杂螺并[3.4]辛烷-6-羧酸叔丁酯(95mg,0.350mmol)，DCM(1.5mL)溶解，加入TEA(0.074mL,0.53mmol)，缓慢滴加甲磺酰氯(0.036mL,0.46mmol)，后自然升至室温反应1h。TLC显示反应完毕，加水3mL淬灭反应，DCM(10mL×2)萃取，有机相饱和食盐水5mL洗涤，无水硫酸钠干燥，过滤，滤液旋干，快速硅胶柱层析(洗脱剂PE/EA(v/v)＝4/1-1/2)，得到黄色透明油状物0.117g(收率96％)，即为目标产物。 1H NMR(400MHz,CDCl 3):δ4.37–4.31(m,2H),4.01(p,J＝6.8Hz,1H),3.63–3.57(m,2H),3.37–3.21(m,4H),3.05(s,3H),2.33–2.21(m,2H),2.02–1.90(m,2H),1.87–1.77(m,2H),1.44(s,9H)。
步骤4：2-(2-((3-氰基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-6-基)氧基)乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯
5mL单口瓶加入2-(2-甲基磺酰氧基乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(46mg,0.132mmol)，K 2CO 3(37mg,0.265mmol)，6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈(30mg,0.066mmol，中间体1)，用DMF(1.5mL)溶解，置于60℃搅拌反应过夜。TLC显示反应完毕，加水10mL洗涤，EA(40mL×2)萃取，有机相饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液旋干，硅胶柱层析(洗脱剂纯DCM-DCM/MeOH((v/v)＝10/1))，得到淡黄色固体22.6mg(收率48.3％)，即为目标产物。LC-MS:m/z＝707.30[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.16(d,J＝1.5Hz,1H),8.11(d,J＝0.8Hz,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.65(dd,J＝4.4,2.3Hz,1H),7.17(s,1H),6.70(dd,J＝13.4,8.7Hz,2H),4.21–4.13(m,2H),4.12–4.04(m,1H),3.92(s,3H),3.87–3.74(m,6H),3.65–3.54(m,4H),3.38–3.24(m,4H),2.71(s,1H),2.37–2.24(m,2H),2.18–1.89(m,3H),1.87–1.79(m,2H),1.45(s,9H)。
步骤5：6-(2-((6-氮杂螺[3.4]辛烷-2-基)氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈二盐酸盐
10mL单口瓶中，加入2-(2-((3-氰基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-6-基)氧基)乙氧基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(19.2mg,0.027mmol，盐酸乙酸乙酯溶液(2mL,8mmol,4mol/L)，置于室温搅拌反应1h。TLC显示反应完毕，将反应液直接旋干，抽干，得到理论量黄白色固体产物。LC-MS:m/z＝607.2[M+H] +。
实施例10：4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-((6-甲氧基螺[3.3]庚烷-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000091
步骤1：6-羟基螺[3.3]庚烷-2-羧酸甲酯
100mL双口瓶中加入6-氧代螺[3.3]庚烷-2-羧酸甲酯(1.4g,8.3mmol)，置换氮气后加入10mLTHF使其溶解，-78℃下滴加入溶于15Ml THF的三叔丁氧基氢化铝锂(4.6g,17mmol)，滴加完毕后此温度下反应。反应结束后加水15mL淬灭，出现大量白色胶状物，抽滤，水相乙酸乙酯萃取，浓缩硅胶柱层析，洗脱剂PE/EA(v/v)＝10/1，得到无色液体1.2g，即为目标产物。Rf＝0.3(PE/EA(v/v)＝5/1)；LC-MS: m/z＝171.15[M+H] +； 1H NMR(400MHz,CDCl 3):δ4.15(p,J＝7.2Hz,1H),3.64(s,3H),3.01(p,J＝8.5Hz,1H),2.50-2.40(m,1H),2.36-2.24(m,3H),2.23-2.11(m,2H),2.03(s,1H),1.89(m,2H)。
步骤2：6-甲氧基螺[3.3]庚烷-2-羧酸甲酯
100mL单口瓶中加入6-羟基螺[3.3]庚烷-2-羧酸甲酯(1.2g,7.1mmol)，加THF(18mL)使其溶解，-10℃下分两次加入氢化钠(560mg,14.0mmol,60mass％)，15min后加入碘甲烷(1.0mL,16mmol)，室温下反应。反应结束后加水淬灭，乙酸乙酯(20mL×2)萃取，有机相水洗两次后无水硫酸钠干燥，浓缩硅胶柱层析，洗脱剂为PE/EA(v/v)＝20/1-5/1,得到无色液体480mg。Rf＝0.8(PE/EA(v/v)＝5/1)， 1H NMR(400MHz,CDCl 3):δ3.79-3.70(m,1H),3.66(s,3H),3.19(s,3H),3.03(p,J＝8.5Hz,1H),2.44-2.36(m,1H),2.33-2.13(m,5H),1.91(m,2H)。
步骤3：(6-甲氧基螺[3.3]庚烷-2-基)甲醇
25mL双口瓶置换氮气后加入溶于10mLTHF的6-甲氧基螺[3.3]庚烷-2-羧酸甲酯(480mg,2.6mmol)，-10℃下搅拌10min后滴加入二异丁基氢化铝(8.0mL,8.0mmol,1mol/L)，加入完毕后室温下反应。反应结束后加水淬灭反应，反应液出现凝胶状，加入HCl(1N)14mL使其完全溶解，乙酸乙酯(80mL×2)萃取，有机相水洗两次，饱和食盐水洗一次，浓缩硅胶柱层析，洗脱剂为PE/EA(v/v)＝5/1，得到无色液体330mg。Rf＝0.3(PE/EA(v/v)＝5/1)， 1H NMR(400MHz,CDCl 3):δ3.76(p,J＝7.1Hz,1H),3.56(d,J＝6.8Hz,2H),3.21(s,3H),2.46-2.33(m,2H),2.23(dt,J＝11.6,6.0Hz,1H),2.13-2.00(m,2H),1.96-1.84(m,2H),1.78(dd,J＝11.5,5.8Hz,2H)。
:步骤4：(6-甲氧基螺[3.3]庚-2-基)甲基甲磺酸酯
25mL单口瓶中加入(6-甲氧基螺[3.3]庚烷-2-基)甲醇(340mg,2.2mmol)，加4mLDCM使其溶解，加入三乙胺(0.7mL,5mmol)，0℃下滴加入甲基磺酰氯(0.3mL,3mmol)，室温下反应。反应结束后，反应液用DCM(20mL×2)萃取，有机相水洗三次，饱和食盐水洗一次，浓缩柱层析，洗脱剂为PE/EA(v/v)＝5/1，得到液体340mg。Rf＝0.3(PE/EA(v/v)＝5/1)。 1H NMR(400MHz,CDCl 3):δ4.17(d,J＝6.8Hz,2H),3.77(p,J＝7.1Hz,1H),3.21(s,3H),3.01(s,3H),2.70-2.56(m,1H),2.46-2.37(m,1H),2.27(dt,J＝11.6,5.9Hz,1H),2.21-2.08(m,2H),1.91(m,4H)。
步骤5：4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-((6-甲氧基螺[3.3]庚烷-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶中加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(20mg,0.044mmol，中间体1)，碳酸钾(24mg,0.17mmol)，(6-甲氧基螺[3.3]庚-2-基)甲基甲磺酸酯(65mg,0.28mmol)，加入DMF(0.8mL,100mass％)，90℃下反应。过夜反应。反应结束后反应液冷却至室温，加入5mL水，乙酸乙酯(20mL×2)萃取，有机相水洗8次，饱和食盐水洗一次，无水硫酸钠干燥后浓缩柱层析，洗脱剂为DCM/MeOH(v/v)＝40:1，得 到黄色固体13mg。Rf＝0.3(DCM/MeOH(v/v)＝15/1)，LC-MS：m/z＝592.25[M+H] +， 1H NMR(400MHz,CDCl 3)：δ8.40(d,J＝2.1Hz,1H),8.20(s,1H),8.10(d,J＝1.9Hz,2H),7.77(dd,J＝8.8,2.5Hz,1H),7.63(dd,J＝8.5,2.1Hz,1H),7.11(d,J＝2.0Hz,1H),6.69(dd,J＝12.9,8.7Hz,2H),3.95(d,J＝6.5Hz,2H),3.92(s,3H),3.83(d,J＝12.7Hz,2H),3.77(d,J＝6.5Hz,2H),3.60(s,1H),3.58(s,2H),3.21(s,3H),2.76-2.71(m,2H),2.46-2.40(m,1H),2.35-2.10(m,4H),2.08-1.88(m,2H),1.98-1.91(m,4H)。
实施例11：6-((6-羟基-6-甲基螺[3.3]庚烷-2-基)甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000092
步骤1：(6-羟基-6-甲基螺[3.3]庚烷-2-基)甲基甲磺酸酯
10mL单口瓶中加入2-(羟甲基)-6-甲基-螺[3.3]庚烷-6-醇(65mg,0.42mmol)，加入二氯甲烷(0.8mL)使其溶解，加入三乙胺(0.08mL,0.6mmol)，0℃下加入甲磺酰氯(0.06mL,0.7mmol)，室温下反应。TLC检测原料反应完毕，停止反应，反应液加水5mL，DCM(15mL×2)萃取，有机相水洗(5mL×2)，饱和食盐水洗，无水硫酸钠干燥后，滤液浓缩硅胶柱层析，洗脱剂为PE/EA(v/v)＝5/1-2/1，得到无色液体30mg即为产物。 1H NMR(400MHz,CDCl 3)δ4.15(d,J＝6.8Hz,2H),3.00(s,3H),2.66-2.52(m,1H),2.25-2.11(m,4H),2.09(s,2H),1.88(dd,J＝19.5,8.6Hz,2H),1.72(s,1H),1.32(s,3H)。
步骤2：6-((6-羟基-6-甲基螺[3.3]庚烷-2-基)甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶中加入6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1，5-a]吡啶-3-甲腈(23mg,0.05mmol，中间体1)，(6-羟基-6-甲基螺[3.3]庚-2-基)甲基甲磺酸酯(30mg,0.13mmol)，碳酸钾(18mg,0.13mmol)，DMF(0.8mL)，油浴60℃下反应过夜。TLC检测反应结束后反应液冷却至室温，加水5mL，EA(20mL×2)萃取，有机相水洗(5mL×4)，饱和食盐水洗，无水硫酸钠干燥后过滤，滤液浓缩硅胶柱层析，洗脱剂为DCM/MeOH(v/v)＝30/1-20/1，得到黄色固体3mg即为产物。LC-MS：m/z＝592.20[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝1.9Hz,1H),8.21(s,1H),8.11(s,2H),7.78(dd,J＝8.8,2.2Hz,1H),7.69(s,1H),7.11(s,1H),6.71(dd,J＝15.3,8.7Hz,2H),3.95(d,J＝6.4Hz,2H),3.92(s,3H),3.90-3.80(m,4H),3.70-3.60(m,4H),2.76-2.70(m,2H),2.37-2.30(d,J＝13.6Hz,1H),2.27-2.24(m,3H),2.13(s,2H),2.04(s,1H),2.01-1.84(m,3H),1.35(s,3H)。
实施例12：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(5-(4-甲氧基苯甲酰基)六氢吡咯并[3,4-c] 吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000093
步骤1：5-(4-甲氧基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯
25mL单口瓶中加入六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(1.0g,4.7mmol)，4-甲氧基苯甲酸(1.1g,7.2mmol)，加入DCM使其溶解，之后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.8g,9.4mmol)，4-二甲氨基吡啶(1.2g,9.8mmol)，室温下反应20h。反应停止后反应液中加水10mL，水相DCM(30mL)萃取，有机相合并后水洗(10mL×2)，无水硫酸钠干燥后浓缩，硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝50/1)，得到无色液体1.3g即为产物，产率81.25％。LC-MS:m/z＝291.20[M-tBu+H] +； 1H NMR(400MHz,DMSO-d 6):δ7.51(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),3.79(s,3H),3.68(s,2H),3.56–3.33(m,4H),3.20(s,1H),3.05(s,1H),2.85(s,2H),1.39(s,9H)。
步骤2：(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(4-甲氧基苯基)甲酮盐酸盐
25mL单口瓶中加入5-(4-甲氧基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(600mg,1.732mmol)，加入EA(5mL)使其溶解，加入HCl/EA(4mL,4mol/L)，加入完毕后室温反应1h。TLC检测反应结束后反应液直接浓缩，烘干得到固体470mg即为产物，收率95.95％。LC-MS:m/z＝247.25[M+H] +； 1H NMR(400MHz,DMSO-d 6):δ7.50(d,J＝8.7Hz,2H),6.96(d,J＝8.7Hz,2H),3.78(s,3H),3.66(s,2H),3.54(d,J＝3.1Hz,1H),3.52(d,J＝2.6Hz,1H),3.32(s,2H),2.99(s,4H)。
步骤4：6-(2-(2-氧杂-6-氮杂螺[3.3]庚-6-6基)乙氧基)-4-(6-(5-(4-甲氧基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶中加入6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(26mg,0.06853mmol，中间体2)，六氢吡咯并[3,4-c]吡咯-2(1H)-基)(4-甲氧基苯基)甲酮盐酸盐(35mg,0.1096mmol)，碳酸钾(55mg,0.39795mmol)，DMSO(1.5mL)，油浴90℃下反应15h。反应液冷却至室温后加水5mL，EA(20mL×2)萃取，有机相水洗(5mL×3),饱和食盐水洗(5mL×2)，无水硫酸钠干燥后过滤，滤液减压浓缩硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝10/1)，得到类白色固体7mg即为产物，收率：16.86％。LC-MS：m/z＝606.30[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.33(s,1H),8.21(s,1H),8.13(s,1H),7.71(d,J＝7.1Hz,1H),7.54(d,J＝8.4Hz,2H),7.12(s,1H),6.93(d,J＝8.5Hz,2H),6.51(d,J＝8.9Hz,1H),4.78(s,4H),4.06(s,3H),3.91–3.70(m,7H),3.61(s,4H),3.54 (s,3H),3.11(d,J＝18.5Hz,2H),2.93(s,2H)。
实施例13：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(5-(2,3-二甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000094
步骤1：5-(2,3-二甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯
25mL单口瓶中加入六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(500mg,2.3553mmol)，2,3-二甲基苯甲酸(530mg,3.5293mmol,)，加入DCM使其溶解，之后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(903mg,4.710mmol)，4-二甲氨基吡啶(580mg,4.7475mmol)，室温下反应17h。反应液中加水10mL，水相DCM(30mL)萃取，有机相合并后水洗(10mL×2)，无水硫酸钠干燥后浓缩，硅胶柱层析，洗脱剂为PE-PE/EA(v/v＝1/1)，得到无色粘稠状液体660mg即为产物，收率81.37％。LC-MS：m/z＝289.25[M-tBu+H] +；1H NMR(400MHz,DMSO-d 6)：δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H),3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H)。
步骤2：(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2,3-二甲基苯基)甲酮盐酸盐
25mL单口瓶中加入5-(2,3-二甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(330mg,0.9582mmol)，加入EA(3mL)使其溶解，加入HCl/EA(2mL,4mol/L)，加入完毕后室温反应1h。反应过程中有白色固体析出，TLC检测原料反应完毕后反应液直接浓缩，得到白色固体，真空干燥箱内60℃下烘干，得到260mg即为产物，收率85.54％。LC-MS:m/z＝245.30[M+H] +； 1H NMR(400MHz,DMSO-d 6):δ7.18(d,J＝7.3Hz,1H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝7.3Hz,1H),3.73(dd,J＝12.6,7.9Hz,1H),3.54(dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H)。
步骤4：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(5-(2,3-二甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
10mL单口瓶中加入6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(26mg,0.07mmol，中间体2)，(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2,3-二甲基苯基) 甲酮盐酸盐(32mg,0.1009mmol)，碳酸钾(70mg,0.51mmol)，DMSO(1.5mL)，油浴90℃下反应13h。反应液冷却至室温后加水5mL，EA(20mL×2)萃取，有机相水洗(5mL×3)，饱和食盐水洗(5mL×2)，无水硫酸钠干燥后过滤，滤液减压浓缩硅胶柱层析，洗脱剂为DCM/MeOH(v/v＝50/1-10/1)，得到黄色固体7mg即为产物，收率16.92％。LC-MS：m/z＝604.35[M+H] +； 1H NMR(400MHz,CDCl 3)：δ8.31(d,J＝2.1Hz,1H),8.19(s,1H),8.10(d,J＝1.6Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.18–7.12(m,2H),7.10(d,J＝2.0Hz,1H),7.05(d,J＝7.4Hz,1H),6.49(d,J＝8.7Hz,1H),4.76(s,4H),4.07–3.97(m,3H),3.89–3.84(m,1H),3.80–3.70(m,3H),3.60–3.54(m,2H),3.49(dd,J＝9.6,5.3Hz,2H),3.41(dd,J＝11.5,4.6Hz,1H),3.19–3.12(m,2H),3.09–2.99(m,2H),2.95–2.86(m,2H),2.28(s,3H),2.21(s,3H)。
实施例14：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(6-(4-甲氧基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000095
步骤1：6-(4-甲氧基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯
50mL单口瓶中加入2,6-二氮杂螺并[3.3]庚烷-2-羧酸叔丁酯(500mg,2.52mmol)，4-甲氧基苯甲酸(576mg,3.79mmol)，加入DCM，之后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(980mg,5.11mmol)，4-二甲氨基吡啶(636mg,5.2059mmol)，室温下反应18h。停止反应后反应液中加水5mL，水相DCM(20mL)萃取，合并有机相后水洗(5mL×2)，无水硫酸钠干燥后硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝50/1)，得到白色固体270mg即为产物，收率32.21％。LC-MS：m/z＝333.20[M+H] +； 1H NMR(400MHz,CDCl 3):δ7.60(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),4.35(d,J＝28.9Hz,4H),4.10(s,4H),3.84(s,3H),1.44(s,9H)。
步骤2：(4-甲氧基苯基)(2,6-二氮杂螺[3.3]庚-2-基)甲酮
25mL单口瓶中加入6-(4-甲氧基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(200mg,0.6017mmol)，加入DCM(2mL)使其溶解，0℃下加入三氟乙酸(0.9mL,10mmol)，加入完毕后室温反应6h。反应液直接浓缩得到无色液体130mg即为产物，收率93.01％。LC-MS:233.20[M+H] +。
步骤3：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(6-(4-甲氧基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
5mL单口瓶中加入6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡 啶-3-甲腈(26mg,0.06853mmol，中间体2)，(4-甲氧基苯基)(2,6-二氮杂螺[3.3]庚-2-基)甲酮(70mg,0.2605mmol)，碳酸钾(55mg,0.39795mmol)，DMSO(1.5mL)，油浴90℃下反应20.5h。反应液冷却至室温后加水5mL，EA(20mL×2)萃取，有机相水洗(5mL×3),饱和食盐水洗(5mL×2)，无水硫酸钠干燥后过滤，滤液减压浓缩硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝20/1)，得到黄色固体后再次TLC纯化得到类白色固体5mg即为产物，收率12.33％。LC-MS：m/z＝592.30[M+H] +； 1H NMR(400MHz,CDCl 3)：δ8.29(s,1H),8.19(s,1H),8.11(s,1H),7.68(dd,J＝8.7,2.1Hz,1H),7.65(d,2H),7.10(s,1H),6.93(d,J＝8.6Hz,2H),6.43(d,J＝8.6Hz,1H),4.76(s,4H),4.47(d,J＝36.3Hz,4H),4.27(s,4H),4.02(t,J＝4.8Hz,2H),3.86(s,3H),3.55(s,4H),2.92–2.83(m,2H)。
实施例15：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(5-(3-氟-2-甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000096
步骤1：5-(3-氟-2-甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯
100mL单口瓶中加入六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(500mg,2.36mmol,)，3-氟-2-甲基苯甲酸(550mg,3.57mmol)，加入DCM使其溶解，之后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(903mg,4.710mmol)，4-二甲氨基吡啶(580mg,4.75mmol)，室温下反应15h。停止反应后反应液直接浓缩，硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝50/1)，得到无色粘稠状液体620mg即为产物，收率75.56％。LC-MS：m/z＝293.20[M-tBu+H] +； 1H NMR(400MHz,CDCl 3)：δ7.24–7.17(m,1H),7.05(d,J＝9.0Hz,1H),7.02–6.96(m,1H),3.89(dd,J＝12.2,8.0Hz,1H),3.70–3.50(m,3H),3.41(dd,J＝11.3,7.3Hz,1H),3.32(s,1H),3.23–3.08(m,1H),3.08–3.00(m,1H),2.97(d,J＝6.5Hz,1H),2.90–2.81(m,1H),2.23(d,J＝1.4Hz,3H),1.46(s,9H).
步骤2：(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(3-氟-2-甲基苯基)甲酮盐酸盐
25mL单口瓶中加入5-(3-氟-2-甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(620mg,1.780mmol)，加入EA(5mL)使其溶解，加入HCl/EA(11mL,4mol/L)，加入完毕后室温反应2h。反应停止后反应液直接浓缩得到白色固体410mg即为产物，收率71.73％。LC-MS:m/z＝249.20[M+H] +； 1H NMR(400MHz,DMSO-d 6):δ7.30(dd,J＝13.3,7.8Hz,1H),7.20(t,J＝8.9Hz,1H),7.10(d,J＝7.4Hz,1H),3.73(dd,J＝12.6,7.8Hz,1H),3.55(dd,J＝12.7,4.0Hz,1H),3.44–3.21(m,3H),3.16–3.01(m,3H), 3.00–2.87(m,2H),2.15(d,J＝1.6Hz,3H)。
步骤3：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(5-(3-氟-2-甲基苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
10mL单口瓶中加入6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(30mg,0.07907mmol，中间体2)，(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(3-氟-2-甲基苯基)甲酮盐酸盐(40mg,0.1245mmol)，碳酸钾(70mg,0.50648mmol)，DMSO(1.5mL)，油浴90℃下反应12h。停止反应后反应液冷却至室温后加水5mL，EA(30mL×2)萃取，有机相水洗(5mL×3)，饱和食盐水洗(5mL×2)，无水硫酸钠干燥后过滤，滤液减压浓缩硅胶柱层析，洗脱剂为DCM/MeOH(v/v＝50/1-10/1)，得到黄色固体，再次TLC纯化得到类白色固体5mg即为产物，收率10.41％。LC-MS：m/z＝608.35[M+H] +； 1H NMR(400MHz,CDCl 3)：δ8.33(s,1H),8.21(s,1H),8.13(s,1H),7.72(d,J＝6.6Hz,1H),7.24–7.20(m,1H),7.12(s,1H),7.07–7.01(m,2H),6.52(d,J＝8.7Hz,1H),4.78(s,4H),4.08–3.99(m,3H),3.91–3.87(m,1H),3.76(dd,J＝18.8,5.6Hz,2H),3.60(s,3H),3.56–3.48(m,3H),3.45–3.41(m,1H),3.21–3.16(m,2H),3.11–3.05(m,1H),2.93(s,2H),2.26(s,3H)。
实施例16：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(6-(3-氟-2-甲基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2020113240-appb-000097
步骤1：6-(3-氟-2-甲基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯
50mL单口瓶中加入2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(500mg,2.5219mmol)，3-氟-2-甲基苯甲酸(580mg,3.76mmol)，加入DCM，之后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(980mg,5.112mmol)，4-二甲氨基吡啶(636mg,5.2059mmol)，室温下反应15h。停止反应后反应液加入5mL饱和氯化铵溶液，DCM(40mL×2)萃取，有机相水洗(10mL×2)，无水硫酸钠干燥后硅胶柱层析，洗脱剂为DCM-DCM/MeOH(v/v＝50/1)，得到无色液体480mg即为产物，收率56.92％。LC-MS：m/z＝335.20[M+H] +； 1H NMR(400MHz,CDCl 3):δ7.22–7.14(m,1H),7.09–6.98(m,2H),4.29(s,2H),4.11(d,J＝9.3Hz,2H),4.03(d,J＝4.7Hz,4H),2.28(d,J＝2.1Hz,3H),1.43(s,9H)。
步骤2：(3-氟-2-甲基苯基)(2,6-二氮杂螺[3.3]庚烷-2-基)甲酮
25mL单口瓶中加入6-(3-氟-2-甲基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(480mg,1.435 mmol)，加入DCM(5mL)使其溶解，0℃下加入三氟乙酸(1.2mL,16mmol)，完毕后室温反应2.5h。TLC检测反应结束后反应液直接浓缩，得到液体330mg即为产物，收率98.12％。LC-MS:235.15[M+H] +。
步骤3：6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-(6-(3-氟-2-甲基苯甲酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
10mL单口瓶中加入6-(2-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)-4-(6-氟吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈(30mg,0.08mmol，中间体1)，(3-氟-2-甲基苯基)(2,6-二氮杂螺[3.3]庚烷-2-基)甲酮(62mg,0.2646mmol)，碳酸钾(65mg,0.47030mmol)，DMSO(1.5mL)，油浴90℃下反应15h。停止反应后反应液冷却至室温后加水5mL，EA(20mL×2)萃取，有机相水洗(5mL×3)，饱和食盐水洗(5mL×2)，无水硫酸钠干燥后过滤，滤液减压浓缩硅胶柱层析，洗脱剂为DCM/MeOH(v/v＝50/1-10/1)，得到黄色固体27mg即为产物，收率57.52％。LC-MS：m/z＝594.30[M+H] +； 1H NMR(400MHz,CDCl 3):δ8.28(d,J＝2.1Hz,1H),8.19(s,1H),8.10(d,J＝1.9Hz,1H),7.68(dd,J＝8.6,2.3Hz,1H),7.22–7.17(m,1H),7.11–7.04(m,3H),6.42(d,J＝8.6Hz,1H),4.75(s,4H),4.41(s,2H),4.30(d,J＝8.7Hz,2H),4.22(d,J＝8.8Hz,2H),4.14(s,2H),4.00(t,J＝5.1Hz,2H),3.51(s,4H),2.85(t,J＝5.1Hz,2H),2.33(d,J＝1.8Hz,3H)。
采用合适的原料，实施例31-33的目标化合物(31)-(33)、实施例37-38的目标化合物(37)-(38)、实施例40-111的目标化合物(40)-(111)、实施例224-244的目标化合物(224)-(244)、实施例210-213的目标化合物(211)-(213)、实施例215-223的目标化合物(215)-(223)参考实施例1或合成方案1合成路线制备得到，具体结构及表征数据如下表1所述：
表1
Figure PCTCN2020113240-appb-000098
Figure PCTCN2020113240-appb-000099
Figure PCTCN2020113240-appb-000100
Figure PCTCN2020113240-appb-000101
Figure PCTCN2020113240-appb-000102
Figure PCTCN2020113240-appb-000103
Figure PCTCN2020113240-appb-000104
Figure PCTCN2020113240-appb-000105
Figure PCTCN2020113240-appb-000106
Figure PCTCN2020113240-appb-000107
Figure PCTCN2020113240-appb-000108
Figure PCTCN2020113240-appb-000109
Figure PCTCN2020113240-appb-000110
采用合适的原料，实施例17、245的目标化合物(16)-(17)参考实施例6或合成方案2合成路线制备得到，具体结构及表征数据如下表2所述：
表2
Figure PCTCN2020113240-appb-000111
采用合适的原料，实施例18-30的目标化合物(18)-(30)、实施例34-36的目标化合物(34)-(36)、实施例39的目标化合物(39)、实施例114的目标化合物(114)、实施例117的目标化合物(117)、实施例120的目标化合物(120)、实施例123的目标化合物(123)、实施例125的目标化合物(125)、实施例129-131的目标化合 物(129)-(131)、实施例133-134的目标化合物(133)-(134)、实施例144-145的目标化合物(144)-(145)、实施例158-160的目标化合物(158)-(160)、实施例165-171的目标化合物(165)-(171)、实施例191-195的目标化合物(191)-(195)、实施例200的目标化合物(200)、实施例204-214的目标化合物(204)-(214)参考实施例12或合成方案4合成路线制备得到，具体结构及表征数据如下表3所述：
表3
Figure PCTCN2020113240-appb-000112
Figure PCTCN2020113240-appb-000113
Figure PCTCN2020113240-appb-000114
Figure PCTCN2020113240-appb-000115
Figure PCTCN2020113240-appb-000116
Figure PCTCN2020113240-appb-000117
采用合适的原料，实施例112-113的目标化合物(112)-(113)、实施例115-116的目标化合物(115)-(116)、实施例118-119的目标化合物(118)-(119)、实施例121-122的目标化合物(121)-(122)、实施例124的目标化合物(124)、实施例126-128的目标化合物(126)-(128)、实施例132的目标化合物(132)、实施例135-143的目标化合物(135)-(143)、实施例146-157的目标化合物(146)-(157)、实施例161-164的目标化合物(161)-(164)、实施例172-190的目标化合物(172)-(190)、实施例196-199的目标化合物(196)-(199)、实施例201-203的目标化合物(201)-(203)、实施例208-209的目标化合物(208)-(209)可参考实施例12或合成方案4合成路线制备得到，具体结构及表征数据如下表4所述：
表4
Figure PCTCN2020113240-appb-000118
Figure PCTCN2020113240-appb-000119
Figure PCTCN2020113240-appb-000120
Figure PCTCN2020113240-appb-000121
Figure PCTCN2020113240-appb-000122
Figure PCTCN2020113240-appb-000123
Figure PCTCN2020113240-appb-000124
生物学活性测试例：
测试例1：
1、实验目的：
用HTRF方法测试系列化合物对Ret wt、Ret V804M这2个激酶的抑制活性，并求出IC 50值。
2、所用实验试剂及耗材如下：
1)HTRF KinEASE-TK kit(Cisbio，62TK0PEC)
2)Ret wt(Invitrogen，PV3082)
3)Ret V804M(Signalchem，R02-12GG-10)
4)MgCl 2(Sigma，M1028)
5)ATP(Promega，V910B)
6)DTT(Invitrogen，P2325)
7)DMSO(Sigma，D8418)
8)384-well plate,white,low volume,round-bottom(Greiner，784075)
9)384-Well Polypropylene microplate,Clear,Flatt Bottom,Bar Code(Labcyte，P-05525-BC)
10)96-well polypropylene plate(Nunc，249944)
11)Plate shaker(Thermo，4625-1CECN/THZ Q)
12)Centrifuge(Eppendorf，5810R)
13)Envision 2104 multi-label Reader(PerkinElmer，2104-10-1)
14)Echo(Labcyte，550)
3、实验步骤
3.1制备1x激酶反应缓冲液:
1倍体积的5X激酶反应缓冲液和4倍体积的水；5mM MgCl 2；1mM DTT；1mM MnCl 2。
3.2用Echo 550反应板(784075,Greiner)每孔转移10nl稀释好的化合物；
3.3用封板膜封住反应板，1000g离心1分钟。
3.4用1X的酶反应缓冲液配制准备2X激酶。
3.5向反应板中每孔加入5μl激酶(步骤3中配制)。用封板膜封住板子1000g离心30秒，室温放置10分钟。
3.6用1X的酶反应缓冲液配制4x TK-substrate-biotin和4x ATP，混匀，向反应板中加入5μl K-substrate-biotin/ATP混合液。
3.7用封板膜封住板子1000g离心30秒，室温反应40分钟。
3.8用HTRF检测缓冲液配制4X Sa-XL 665(250nM)。
3.9每孔加入5μl Sa-XL 665和5μl TK-antibody-Cryptate，1000g离心30秒，室温反应1小时。
3.10用Envision 2104读615nm(Cryptate)和665nm(XL665)的荧光信号。
4、数据分析
4.1计算每孔的比率(Ratio_665/615nm)
4.2抑制率计算如下:
Figure PCTCN2020113240-appb-000125
Figure PCTCN2020113240-appb-000126
所有阳性对照孔CEP-32496读值的平均值
Figure PCTCN2020113240-appb-000127
所有阴性对照孔DMSO孔读值的平均值
其中，CEP-32496的化学名称为：N-[3-[(6,7-二甲氧基-4-喹唑啉基)氧基]苯基]-N'-[5-(2,2,2-三氟-1,1-二甲基乙基)-3-异恶唑基]脲。
4.3计算IC 50并绘制化合物的抑制曲线：
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：用Graphpad 6.0软件进行数据分析。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值    Y:抑制率(％inhibition)
5、实验结果如表5所示：
表5 本发明化合物的激酶抑制活性
Figure PCTCN2020113240-appb-000128
除表5中本发明化合物的活性外，本发明其他化合物也具有良好的Ret激酶抑制活性，其中，对Ret wt激酶抑制活性为0-20nM，对Ret wt激酶抑制活性Ret V804M为0-300nM；优选地，对Ret wt激酶抑制活性为0-5nM，对Ret wt激酶抑制活性Ret V804M为0-100nM，更优选地，对Ret wt激酶抑制活性为0-1nM，对Ret wt激酶抑制活性Ret V804M为0-50nM。尤其，本发明表1和表3中化合物对Ret wt激酶抑制活性优选为0-10nM，对Ret wt激酶抑制活性Ret V804M优选为0-100nM，更优选地，本发明表1和表3中化合物对Ret wt激酶抑制活性为0-5nM，对Ret wt激酶抑制活性Ret V804M为0-50nM，进一步优选地，本发明表1和表3中化合物对Ret wt激酶抑制活性为0-1nM；本发明表2中化合物对Ret wt激酶抑制活性为0-1nM，对Ret wt激酶抑制活性Ret V804M为0-20nM。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“一些实施方案”、“示例”、 “具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。

Claims (27)

  1. 一种化合物，其为式(I)所述化合物或其立体异构体、几何异构体、互变异构体、氮氧化合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    Figure PCTCN2020113240-appb-100001
    其中，
    X 1、X 2、X 3、X 4和X 5各自独立地为CR 4或N；
    Y为O、NH或S；
    T是一个键、亚烷基、亚烷基-O-或亚烷基-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、NH 2、CF 3、烷基、羟基烷基、卤代烷基、环烷基、杂环基、烷氧基、芳基、杂芳基或烷基氨基的取代基所取代；
    环G为螺碳环基或螺杂环基；
    q为0、1、2、3或4；
    R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、-S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、烷基、烷氧基、环烷基、烷氧基烷基或羟基烷基；
    E为一个键、-NR 6-、或-O-；
    环A为亚桥环基、亚并环基或亚螺环基，且A任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基烷基、烷基、烷氧基、卤代烷基、羟基烷基、碳环基、杂环基、杂环基烷基、烷氧基烷基、亚环烷基和亚单杂环基的取代基所取代；
    Q为一个键、-(CR 2R 3) tO-、-(CR 2R 3) f-、-(CR 2R 3) t-NR 6-、-(C＝O)(CR 2R 3) t、-(C＝O)(CR 2R 3) t-(S＝O) 2(CR 2R 3) f、-(C＝O)(CR 2R 3) t-NR 6(CR 2R 3) f-、-(C＝O)(CR 2R 3) t-O(CR 2R 3) f-、-(C＝O)NR 6O(CR 2R 3) f-、-(S＝O) 2-NR 6-(CR 2R 3) t-、(CR 2R 3) f-(C＝O)-、(CR 2R 3) t-(C＝O)-NR 6-(CR 2R 3) t-、-(S＝O) 2(CR 2R 3) t-、-(CR 2R 3) f-(S＝O) 2(CR 2R 3) t、-(S＝O) 2O-、-O(C＝O)-、-(C＝O)NR 6-或-NR 6(C＝O)-；
    各f独立地为1、2、3或4；
    各t独立地为0、1、2、3或4；
    M为H、D、杂芳基、芳基、环烷基或杂环基，且M任选地被1、2、3或4个选自D、F、Cl、CN、CF 3、OH、NR 5R 6、OR 7、烷基、卤代烷基、羟基烷基、卤代烷氧基、芳基、烷氧基烷基、氧代、烷基酰基、杂环基、环烷基的取代基所取代；
    R 1为H、D、CN、F、Cl、Br、烷基或环烷基，其中所述的烷基和环烷基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基烷基、烷基、烷基氨基、烷氧基、卤代烷氧基、环烷基、环烷基烷基、芳基、杂芳基；
    或，R 2、R 3和与之相连的同一个C原子成碳环或杂环；
    R 4为H、D、F、Cl、Br、烷基或烷氧基，其中所述的烷基和烷氧基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    R 5为H、D、烷基、碳环基、杂环基、芳基或杂芳基，其中所述的烷基、碳环基、杂环基、芳基和杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代；
    R 6为H、D、烷基或烷氧基烷基，其中所述烷基和烷氧基烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    R 7为OH、烷基、环烷基、杂环基、芳基、杂芳基。
  2. 根据权利要求1所述的化合物，其中，
    T是一个键、C 1-6亚烷基、C 1-6亚烷基-O-或C 1-6亚烷基-NH-，且T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 3-7环烷基、3-7元杂环基、C 1-6烷氧基、C 6-10芳基、5-12元杂芳基或C 1-6烷基氨基的取代基所取代。
  3. 根据权利要求1-2任意一项所述的化合物，其中，
    T是一个键、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-(CH 2) 4-、-(CH 2) 5-、-(CH 2) 6-、-(CH 2) 2-O-或-(CH 2) 2-NH-，且所述T任选地被1、2、3或4个选自D、OH、F、Cl、Br、I、CN、CF 3、甲基、乙基、丙基、2-羟基乙基、1-羟基乙基、环丙基、环丁基、环戊基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、氧杂环丁烷基、甲氧基、乙氧基、丙氧基、丁氧基、苯基、甲氨基和二甲氨基的取代基所取代。
  4. 根据权利要求1-3任意一项所述的化合物，其中，
    G为6-12元螺碳环基或6-12元螺杂环基；
    R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NR 5R 6、OR 7、-NR 6C(＝O)R 7、-S(＝O) 2R 7、-S(＝O)R 7、-C(＝O)R 7、-C(＝O)OR 7、氧代、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、C 1-6烷氧基C 1-6烷基、C 1-6羟基烷基；
    R 5为H、D、C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基或5-10元杂芳基，其中所述的C 1-6烷基、3-12元碳环基、3-12元杂环基、C 6-10芳基和5-10元杂芳基各独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、C 1-6烷基氨基、烷基、烷基磺酰基、烷氧基、芳基和杂芳基的取代基所取代；
    R 6为H、D、C 1-6烷基或C 1-6烷氧基C 1-6烷基，其中所述C 1-6烷基和C 1-6烷氧基C 1-6烷基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    R 7为OH、C 1-6烷基、C 3-6环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基。
  5. 根据权利要求1-4任意一项所述的化合物，其中，
    G为以下子结构式：
    Figure PCTCN2020113240-appb-100002
    其中，各环T1独立地为4-7元的碳单环或杂单环；
    Z 1和Z 2独立为-CH 2-、-O-、-S-、-NH-；
    Z 3为-O-、-S-、-NH-；
    n1为0、1或2；
    n2为1、2或3；
    n3为0或1。
  6. 根据权利要求1-5任意一项所述的化合物，其中，
    G为以下子结构式：
    Figure PCTCN2020113240-appb-100003
    R a为D、OH、NH 2、F、CF 3、Cl、Br、I、CN、NH 2、NHCH 3、-NHC(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)CH 3、-C(＝O)CH 3、-C(＝O)OH、氧代、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基、环戊基、甲氧基甲基、乙氧基甲基、羟基甲基、2-羟基乙基、1-羟基乙基、2-羟基丙基、2-羟基-2-甲基丙基；
    R 5为H、D、甲基、乙基、正丙基、异丙基、正丁基、环丙基、环戊基、吡咯烷基、苯基或吡唑基；其中所述的甲基、乙基、正丙基、环丙基、环戊基、吡咯烷基、苯基和吡唑基各自独立任选地被1、2、3或4个选自F、Cl、Br、OH、NH 2、甲基、-S(＝O) 2CH 3、甲氧基、乙氧基和苯基的取代基所取代；
    R 6为H、D、甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基或甲氧基乙基，其中所述甲基、乙基、正丙基、正丁基、甲氧基甲基、乙氧基甲基和甲氧基乙基各独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    R 7为OH、甲基、乙基、NH 2、N(CH 3) 2、正丙基、异丙基、叔丁基、环丙基或苯基。
  7. 根据权利要求1-6任意一项所述的化合物，其中，
    A为5-12元亚桥环基、5-12元亚并环基或5-12元亚螺环基，且A任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-6烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
  8. 根据权利要求1-7任意一项所述的化合物，其中，
    A为以下子结构式：
    Figure PCTCN2020113240-appb-100004
    其中，Z 1a和Z 2a各独立地为-CH 2-或-NH-；
    Z 3a为-CH-或-N-；
    Z 4a为-O-、-S-或-NH-；
    各Z 5a、Z 6a独立地为-CH 2-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或-NH-；
    m和t各独立地为0、1或2；
    n和t1各独立地为0或1；
    其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
  9. 根据权利要求1-8任意一项所述的化合物，其中，
    A为以下子结构式：
    Figure PCTCN2020113240-appb-100005
    其中A的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
  10. 根据权利要求1-9任意一项所述的化合物，其中，
    M为H、D、5-10元杂芳基、C 6-10芳基、C 3-7环烷基或3-12元杂环基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NR 5R 6、OR 7、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6卤代烷氧基、C 6-10芳基、C 1-6烷氧基C 1-6烷基、氧代、C 1-6烷基酰基、3-7元杂环基、C 3-7环烷基的取代基所 取代。
  11. 根据权利要1-10任意一项所述的化合物，其中，
    M为H、D、吡啶基、嘧啶基、吡唑基、咪唑基、恶唑基、异恶唑基、吡嗪基、苯基、环戊基、环丙基、环己基、环丁基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、吗啉基、四氢噻喃基、氧杂环丁烷基、1,2-二氢吡啶基、7-氮杂双环[2.2.1]庚烷基、六氢呋喃[3,4-c]并吡咯基、3-氮杂双环[3.1.0]己烷基、八氢吡咯并[1,2-a]吡嗪基或5-氮杂螺[2.4]庚烷基；且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF 3、NH 2、NHCH 3、N(CH 3) 2、三氟甲氧基、2,2,2-三氟乙氧基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲基、乙基、正丙基、异丙基、苯基、甲氧基甲基、甲氧基乙基、氧代、甲酰基、乙酰基、吗啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、环丙基和环己基的取代基所取代；
  12. 根据权利要求1-11任意一项所述的化合物，其中，
    R 1为H、D、CN、F、Cl、Br、甲基、乙基或环丙基，其中所述的甲基、乙基和环丙基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代；
    R 4为H、D、F、Cl、Br、甲基、乙基、正丙基、甲氧基或乙氧基，其中所述的甲基、乙基、正丙基、甲氧基和乙氧基可独立任选地被1、2、3或4个选自F、Cl、Br、CN、NH 2、OH和NO 2的取代基所取代。
  13. 根据权利要求1-12任意一项所述的化合物，其中，
    各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、C 1-6羟基烷基、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-7环烷基、C 3-7环烷基C 1-6烷基、C 6-10芳基或5-10元杂芳基；
    或，R 2、R 3和与之相连的同一个C原子成3-7元碳环或3-7元杂环。
  14. 根据权利要求1-13任意一项所述的化合物，其中，
    各R 2、R 3独立地为OH、F、CF 3、H、D、CN、Cl、Br、NH 2、羟基甲基、2-羟基乙基、1-羟基乙基、甲基、乙基、N(CH 3) 2、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲氧基、环丙基、环戊基、环丙基甲基、环戊基乙基、环戊基甲基、苯基、吡啶基、吡嗪基；
    或，R 2、R 3和与之相连的同一个C原子成环戊烷、环丙烷、环丁烷、四氢吡喃、四氢呋喃、哌啶或吡咯烷。
  15. 根据权利要求1-14任意一项所述的化合物，其中，
    Q为一个键、-O-、-(CH 2) 2O-、-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-CH 2CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2NHCH 2-、-(C＝O)OC(CH 3) 2CH 2-、-(C＝O)(CH 2) 2(S＝O) 2CH 2-、-(C＝O)CH(OH)CH 2-、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH 2-、-(C＝O)-、-(S＝O) 2-、-(C＝O)CH 2CH(OH)-、-(C＝O)CH 2-、-(C＝O)CH(CH 2OH)-、-(C＝O)C(CH 3) 2-、-(C＝O)CH 2NHC(CH 3) 2CH 2-、-(C＝O)CH 2CH(N(CH 3) 2)-、-(C＝O)(CH 2) 2N(CH 3)CH 2-、-(C＝O)C(CH 3) 2CH 2-、-(C＝O)C(OH)(CH 3)CH 2-、-(C＝O)CH 2OCH 2-、-(C＝O)(CH 2) 3-、-(C＝O)CH(NH 2)-、-(C＝O)(CH 2) 3N(CH 3)CH 2-、-(C＝O)(CH 2) 2-、-(C＝O)CH 2CH(OH)CH 2-、-(C＝O)CF 2CH 2-、-(C＝O)CH(OH)C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3) 2CH 2-、-(C＝O)CH 2C(CH 3)(OH)CH 2-、-(S＝O) 2CH 2-、-(S＝O) 2CH 2C(CH 3) 2CH 2-、-(C＝O)CH(OCH 3)-、-(C＝O)NHCH(CH 2OH)(CH 2) 2-、-(C＝O)NH-、-(C＝O)N(CH 3)-、-(C＝O)N(CH 2CH 2CH 2CH 3)-、-(C＝O)N(CH 2CH 3)(CH 2) 2-、-(C＝O)NHC(CH 3) 2CH 2-、-(C＝O)N(CH 3)(CH 2) 2-、 -(C＝O)NHCH 2CH(CH 3)CH 2-、-(C＝O)NHCH 2-、-(C＝O)NH(CH 2) 2OCH 2-、-(C＝O)N(CH 3)(CH 2) 2OCH 2-、-(S＝O) 2NHC(CH 3) 2CH 2-、-CH 2CH(OH)C(CH 3) 2CH 2-、-CH(CH 3)CH(OH)-、-CH 2(C＝O)NHCH(CH 3)CH 2-、-CH 2(C＝O)-、-(CH 2) 2(C＝O)N(CH 3)CH 2-、-CH 2CH(OH)-、-CH 2CH(OH)CH 2-、-CH 2CH(OH)CH(CH 3)CH 2-、-(C＝O)CH(N(CH 3) 2)-、-(C＝O)C(CH 3) 2CH 2OCH 2-、-(C＝O)C(OCH 3)(CF 3)-、-(C＝O)N(CH 2CH 2OCH 3)CH 2CH(OCH 3)-、-CH 2CH(OCF 3)-、-CH 2CH(OCH(CH 3) 2)-、-CH 2CH(OC(CH 3) 3)-、-CH 2CF 2-、-CH(CH 3)-、-CH 2CH(OCH 3)C(CH 3) 2-、-CH 2CH(N(CH 3) 2)-、-NH-、-(C＝O)NHOCH 2-、-(C＝O)NHOCH 2(CHOH)-、-(S＝O) 2(CH 2CH 3)-、-(S＝O) 2O-、-(S＝O) 2-NHC(CH 3) 2-、-(CH 2) 2(S＝O) 2-、
    Figure PCTCN2020113240-appb-100006
    Figure PCTCN2020113240-appb-100007
  16. 权利要求1-15任意一项所述的化合物具有式(I-1)的结构，或式(I-1)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2020113240-appb-100008
    其中，
    环A1为以下子结构式：
    Figure PCTCN2020113240-appb-100009
    其中Z 1a和Z 2a各独立地为CH 2或NH；
    且A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
  17. 根据权利要求16所述的化合物，其中，
    A1为子结构式：
    Figure PCTCN2020113240-appb-100010
    Figure PCTCN2020113240-appb-100011
    其中A1的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
  18. 权利要求1-15任意一项所述的化合物具有式(I-2)或(I-3)的结构，或式(I-2)或(I-3)结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2020113240-appb-100012
    其中，Z 1、Z 2和Z 3a各独立地为CH或N；
    m和t各独立地为0、1或2；
    n和t1各独立地为0或1；
    其中
    Figure PCTCN2020113240-appb-100013
    独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR 5R 6、R 5(C＝O)NR 6-、氨基C 1-4烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6亚环烷基和3-6元亚单杂环基的取代基所取代。
  19. 根据权利要求18所述的化合物，其中，
    Figure PCTCN2020113240-appb-100014
    为以下子结构式：
    Figure PCTCN2020113240-appb-100015
    Figure PCTCN2020113240-appb-100016
    为以下子结构式：
    Figure PCTCN2020113240-appb-100017
    其中
    Figure PCTCN2020113240-appb-100018
    的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH 2、NHCH 3、CH 3(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF 3、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。
  20. 权利要求1-19任意一项所述的化合物具有以下结构之一，或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2020113240-appb-100019
    Figure PCTCN2020113240-appb-100020
    Figure PCTCN2020113240-appb-100021
    Figure PCTCN2020113240-appb-100022
    Figure PCTCN2020113240-appb-100023
    Figure PCTCN2020113240-appb-100024
    Figure PCTCN2020113240-appb-100025
    Figure PCTCN2020113240-appb-100026
    Figure PCTCN2020113240-appb-100027
    Figure PCTCN2020113240-appb-100028
    Figure PCTCN2020113240-appb-100029
    Figure PCTCN2020113240-appb-100030
    Figure PCTCN2020113240-appb-100031
    Figure PCTCN2020113240-appb-100032
    Figure PCTCN2020113240-appb-100033
    Figure PCTCN2020113240-appb-100034
    Figure PCTCN2020113240-appb-100035
    Figure PCTCN2020113240-appb-100036
    Figure PCTCN2020113240-appb-100037
    Figure PCTCN2020113240-appb-100038
    Figure PCTCN2020113240-appb-100039
    Figure PCTCN2020113240-appb-100040
    Figure PCTCN2020113240-appb-100041
    Figure PCTCN2020113240-appb-100042
    Figure PCTCN2020113240-appb-100043
  21. 一种药物组合物，包含权利要求1-20任意一项所述的化合物，和药学上可接受的辅剂。
  22. 权利要求1-20任意一项所述的化合物或权利要求21所述的药物组合物在制备用于预防或治疗RET相关疾病的药物中的用途。
  23. 根据权利要求22所述的用途，其中，RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
  24. 权利要求1-20任意一项所述的化合物或权利要求21所述的药物组合物用于预防或治疗RET相关疾病。
  25. 根据权利要求24所述的化合物或药物组合物，其中，RET相关疾病为癌症、肠易激综合征或与肠易激综合征相关的疼痛。
  26. 一种用于预防或治疗RET相关疾病的方法，包括给予患者如权利要求1-20任意一项所述的化合物或权利要求21所述的药物组合物的有效治疗量。
  27. 根据权利要求26所述的方法，其中，RET相关疾病为癌症、肠易激综合征或与肠易激综合征相关的疼痛。
PCT/CN2020/113240 2019-09-04 2020-09-03 一种ret抑制剂、其药物组合物及其用途 WO2021043209A1 (zh)

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