WO2021057963A1 - Inhibiteur de ret, composition pharmaceutique comprenant celui-ci et utilisation associée - Google Patents

Inhibiteur de ret, composition pharmaceutique comprenant celui-ci et utilisation associée Download PDF

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WO2021057963A1
WO2021057963A1 PCT/CN2020/118065 CN2020118065W WO2021057963A1 WO 2021057963 A1 WO2021057963 A1 WO 2021057963A1 CN 2020118065 W CN2020118065 W CN 2020118065W WO 2021057963 A1 WO2021057963 A1 WO 2021057963A1
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alkyl
group
membered
ring
independently
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Chinese (zh)
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谢洪明
罗明
张英俊
杨桂珍
王凯
贾媛媛
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广东东阳光药业有限公司
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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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or 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
    • A61K31/435—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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), Jun 2013, 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-, alkylene-O-alkylene or alkylene-NH-, and the T is optionally selected from 1, 2, 3, or 4 From D, OH, F, Cl, Br, I, CN, NH 2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino Is substituted by the substituent;
  • Ring G is a bridged carbocyclic group or a bridged heterocyclic 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, OH, NR 5 R 6 , OR 7 , substituted by substituents of alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and 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 and R 3 is independently OH, F, H, D, CN, Cl, Br, NH 2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl Group, cycloalkylalkyl, aryl or 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, heterocyclyl, aryl or heteroaryl.
  • T is a bond, C 1-6 alkylene, C 1-6 alkylene-O-, C 1-6 alkylene-OC 1-6 alkylene, 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, NH 2 , C 1-6 alkyl, C 1- 6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 1-6 alkoxy, C 6-10 aryl, 5-12 membered heteroaryl And C 1-6 alkylamino substituents.
  • 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-, -(CH 2 ) 2 -O-CH 2 -or -(CH 2 ) 2 -NH-, and the T is optionally divided by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH 2 , CF 3 , CHF 2 , CHCl 2 , methyl, ethyl, propyl, 2-hydroxyethyl, 1- Hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, o
  • Ring G is a 6-12-membered bridged carbocyclic group or a 6-12-membered bridged 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 Selected from F, Cl, Br, OH, NH 2 , C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, C 6-10 aryl And 5-10 membered heteroaryl substituents;
  • 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 or 5-10 membered heteroaryl.
  • ring G has the following sub-structure:
  • Each Z 1 is independently CH or N;
  • ring G has 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 , methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
  • ring A has the following sub-structure:
  • each of Z 1a and Z 2a is independently CH 2 or NH;
  • Each of Z 3a and Z 7a is independently CH or N;
  • Z 4a is O, S or NH
  • Each of m and t is independently 0, 1 or 2;
  • n and t1 are independently 0 or 1;
  • ring A has 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, NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 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 and 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, hexahydrofuro[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, 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 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 2 , R 3 and the same carbon atom to which they are connected form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
  • each R 2 and R 3 is independently OH, F, CF 3 , CHCl 2 , CHF 2 , 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, cyclopentan Group, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;
  • R 2 , R 3 and the same carbon atom to which they are connected 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:
  • each of Z 1a and Z 2a is independently CH 2 or NH;
  • ring A1 is a sub-structure:
  • the compound of the present invention has the structure of formula (I-3) or (I-4), or the stereoisomers of the structure of formula (I-3) or (I-4), and the geometrical difference Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each of Z 1 , Z 2 , Z 3a and Z 7a is independently CH or N;
  • Each of m and t is independently 0, 1 or 2;
  • n and t1 are 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 medicine 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 means C 1-6 hydroxyalkyl, that is, C 1-6 alkyl substituted by one or more hydroxy groups.
  • C 1-6 hydroxyalkyl means C 1-6 hydroxyalkyl is substituted by one hydroxy group. Substituted C 1-6 alkyl.
  • 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 -, 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.
  • alkoxyalkyl examples include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxy Propyl, 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 carbocyclic and heterocyclic rings 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.
  • heterocycloalkylene refers to a divalent saturated monocyclic heterocyclic ring system.
  • the heterocycloalkylene group contains 3-7 ring atoms, that is, the heterocycloalkylene group is a 3-7 membered heterocycloalkylene group; in other embodiments, the heterocycloalkylene group contains 3 -6 ring atoms, that is, heterocycloalkylene is a 3-6 membered heterocycloalkylene.
  • Examples of heterocycloalkylene groups include, but are not limited to: piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and the like.
  • 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, a C 1-6 alkoxy group 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 so on.
  • 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.
  • 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 anthracene.
  • aryl means 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.
  • 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.
  • 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, tetrahydrofuranyl, dihydro Furanyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl Pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholiny
  • 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 means 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.
  • the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged.
  • the sub-structure a1 of ring A represents that any two possible connected positions on the ring can be used as connection points (ie, attachment points), and the two ends of the connection points can be interchanged.
  • the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two attachment points are attached to the ring On two different ring atoms.
  • a ring is formed by two sub-rings or spiro ring, and the two attachment points on the ring are located on the two sub-rings, then the two attachment points are on the two sub-rings respectively. Any connectable position on the upper part is connected to the rest of the molecule, and the two ends of the connection can be interchanged.
  • the sub-structure a2 of ring A preferably means that the two attachment points on the ring are connected to the rest of the molecule on the H1 ring and the H2 ring respectively, and the two ends of the connection can be interchanged;
  • the sub-structure a3 of ring A is preferably It means that the two attachment points on the ring are connected to the rest of the molecule on the H1' ring and the H2' ring respectively, and the two ends of the connection can be interchanged.
  • 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 tissue.
  • 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, which 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 please 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 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).
  • RET gene expression 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).
  • 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, Y, G, 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-, alkylene-O-alkylene or alkylene-NH-, and the T is optionally substituted by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH 2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, hetero Substituents of aryl or alkylamino are substituted.
  • ring G is bridged carbocyclyl or bridged heterocyclyl.
  • 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 , OH, NR 5 R 6 , OR 7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclic and cycloalkyl substitution Substituted by the group.
  • 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 and R 3 is independently OH, F, H, D, CN, Cl, Br, NH 2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy , Cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;
  • R 2 , R 3 and the same carbon 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, or heteroaryl.
  • T is a bond, C 1-6 alkylene, C 1-6 alkylene-O-, C 1-6 alkylene-OC 1-6 alkylene, 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, C 1-6 alkyl, C 1-6 hydroxy alkane Group, C 1-6 haloalkyl group, C 3-7 cycloalkyl group, 3-7 membered heterocyclic group, C 1-6 alkoxy group, C 6-10 aryl group, 5-12 membered heteroaryl group and C 1 -6 substituted by the substituent of the alkylamino group.
  • 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-, -(CH 2 ) 2 -O-CH 2 -or -(CH 2 ) 2 -NH-, and the T is optionally divided by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH 2 , CF 3 , CHF 2 , CHCl 2 , methyl, ethyl, propyl, 2-hydroxyethyl, 1- Hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, o
  • Ring G is 6-12 membered bridged carbocyclyl or 6-12 membered bridged heterocyclyl.
  • 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, 2, 3 or 4 selected from F, Cl, Br, OH, NH 2 , C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy , C 6-10 aryl and 5-10 membered heteroaryl substituents.
  • 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 heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl.
  • ring G has the following sub-structure:
  • Each Z 1 is independently CH or N;
  • ring G has 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 , methyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.
  • ring A has the following sub-structure:
  • each of Z 1a and Z 2a is independently CH 2 or NH;
  • Each of Z 3a and Z 7a is independently CH or N;
  • Z 4a is O, S or NH
  • Each of m and t is independently 0, 1 or 2;
  • n and t1 are independently 0 or 1;
  • ring A has 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, NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 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 and 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, hexahydrofuro[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, 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 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 2 , R 3 and the same carbon atom to which they are connected form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
  • each R 2 and R 3 is independently OH, F, CF 3 , CHCl 2 , CHF 2 , 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 Group, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;
  • R 2 , R 3 and the same carbon atom to which they are connected 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,
  • R 1, X 1, X 2, X 3, X 4, X 5, E, A, Q, M, T, G, R a, q have the definitions as described in the present invention.
  • 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,
  • R 1, X 1, X 2, X 3, X 4, X 5, E, Q, M, T, G, R a, q have the definitions as described in the present invention
  • Ring A1 is the following sub-structure:
  • each of Z 1a and Z 2a is independently CH 2 or NH;
  • ring A1 is a sub-structure:
  • the compounds of the present invention have the structure of formula (IA1), or the 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, A, T, G, R a, q have the definitions as described in the present invention
  • M 1 is a heteroaryl group or an aryl group.
  • M 1 is 5-10 membered heteroaryl or C 6-10 aryl; and M is optionally 1, 2, 3, or 4 selected from D, F, Cl, CN, OH, NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkane
  • the oxy C 1-6 alkyl group, oxo group, C 1-6 alkyl acyl group, 3-7 membered heterocyclic group and C 3-7 cycloalkyl group are substituted.
  • M 1 is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl; pyridyl, pyrimidinyl, pyrazolyl, imidazole Group, oxazolyl, isoxazolyl, pyrazinyl, phenyl.
  • M 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of the present invention has a structure of formula (I-1aa), or a stereoisomer, geometric isomer, tautomer, or nitrogen oxide of the structure of formula (I-1aa) , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • R 1, X 1, X 2, X 3, X 4, X 5, T, G, R a, q, A1, M 1 have the definitions as described in the present invention.
  • 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,
  • R 1, X 1, X 2, X 3, X 4, X 5, E, Q, M, T, G, R a, q have the definitions as described in the present invention
  • Each of Z 1 , Z 2 , Z 3a and Z 7a is independently CH or N;
  • Each of m and t is independently 0, 1 or 2;
  • n and t1 are 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 the preparation of intermediate compounds represented by the structure of formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3) body.
  • the present invention relates to the preparation of compounds represented by formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3), Methods of separation and purification.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the adjuvant of the present invention includes, but is not limited to, a carrier, excipient, diluent, solvent, or a combination 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 salts of the compounds of the present invention also include those used in the preparation or purification of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) Shows the compound's intermediates or the enantiomers of the compounds represented by formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3)
  • the salt of the structure 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 so on.
  • 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 a compound represented by formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3), the present invention
  • 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, methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter, etc.
  • the composition can be a tablet, pill, powder, lozenge, sachet, cachet, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in 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 formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I- 3)
  • the compounds and their pharmaceutically acceptable salts can be administered as raw chemicals, and can also be provided as active ingredients of pharmaceutical compositions. 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), (IA1), (I-1aa), (I-1) , (I-2) or (I-3) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, adjuvants include but are not limited to carriers, diluents or excipients, Wait.
  • 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), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable compounds thereof
  • the salt is 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 comprising combining the compound of the present invention, especially formula (I), (IA), (IA1), (I-1aa), (I -1), (I-2) or (I-3) compound or a pharmaceutically acceptable salt thereof 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 amount of the compound of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) mixed with a carrier material to prepare a single dosage form of active ingredient It will vary according to the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the treatment time and the age, sex, weight and condition of the patient.
  • 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 pharmaceutical field, 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 ), (IA1), (I-1aa), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate or a pharmaceutical composition thereof.
  • RET-related cancer e.g., comprising having one or more
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., another RET inhibitor, such as a RET inhibitor that is not a compound of the invention).
  • another anticancer 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), (IA1), (I-1aa), (I-1), (I-2), or (I-3) or Treatment with RET inhibitors of pharmaceutically acceptable salts or solvates, or previously (e.g., after tumor resection or radiation therapy) with other anticancer agents.
  • the formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapies or treatments (e.g. Chemotherapy) reagents.
  • 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 general formula (I) or a pharmaceutically acceptable salt or solvate thereof is combined
  • the amount of the substance and the amount of other therapeutic agents are both effective in treating 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 can 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 general formula (I) or a pharmaceutically acceptable salt or solvate thereof, Administer via the same or different administration route, and according to the same or different administration schedule.
  • 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.
  • compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable compounds thereof can be used to treat RET inhibitor resistance mutations (which lead to non-formula (I), (IA), (IA1), (I-1aa), (I-1), (I- 2) or (I-3) compound or pharmaceutically acceptable salt or solvate increased resistance, such as substitution at amino acid position 804, such as V804M, V804L or V804E) cancer patients, the treatment By co-administration or as an existing drug therapy (e.g., not of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) The compound or its pharmaceutically acceptable salt or solvate of other RET kinase inhibitors).
  • RET kinase inhibitors e.g., not of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3) are described herein Other RET kinase inhibitors of the compound or a pharmaceutically acceptable salt or solvate thereof).
  • 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, and 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), (IA1), (I-1aa), ( I-1), (I-2) or (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 of 2.1 ⁇ 30mm, 4 ⁇ m, 10 minutes, flow rate of 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 (IA-3) can be prepared by the above-mentioned synthesis scheme, wherein Hal and Hal 2 are F, Cl, Br, I, preferably Cl, Br.
  • the compound of formula (IA-1a-6) and the compound of formula (IA-2) are in a suitable solvent (such as N,N-dimethylformamide or DMSO) under basic conditions (such as the base is K 2 CO 3)
  • a suitable solvent such as N,N-dimethylformamide or DMSO
  • basic conditions such as the base is K 2 CO 3
  • the reaction takes place to obtain the compound of formula (IA-3).
  • the compound of formula (IA) can be obtained by referring to the synthetic steps of Synthesis 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) under suitable conditions (such as basic conditions, the base is K 2 CO 3 ) in a suitable solvent (such as N,N-dimethylacetamide or N , N-dimethylformamide) in the reaction to obtain the compound of formula (IA).
  • the compound of formula (IAa) can be obtained by referring to the synthetic steps of Synthesis Scheme 2.
  • 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 (0.06g, 2mmol)
  • lithium tetrahydroaluminum (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-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-fluoropyridine- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 3 4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo [1,5-a]pyridine-3-carbonitrile
  • Step 4 4-(6-Fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Add 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a] to azolo[1,5-a]pyridine-3-carbonitrile 250mL single-neck flask under nitrogen protection.
  • Step 5 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 1 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-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-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-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 1 5-(4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • Step 3 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile
  • Step 1 5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • Step 3 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (2,3-Dimethylbenzoyl)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-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6- (4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile
  • Example 5 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5 -(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-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-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile
  • Example 6 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6 -(3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-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 4 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6- (3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile
  • Example 7 4-(6-(6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 6-(2,3-Dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 4-(6-(6-(2,3-Dimethylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 8 4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl) -6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)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 3 4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
  • Step 2 5-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)- 2,5-Diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 5-(2-((3-cyano-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane Tert-Butyl-2-carboxylate
  • Step 4 6-(2-(2,5-diazabicyclo[2.2.1]heptan-2-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
  • Example 10 4-(6-(5-(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 11 4-(6-(5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • LC-MS: m/z 632.30[M+H] + ;
  • Example 12 4-(6-(6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6- (2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 13 4-(6-(5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octane-2-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(4-Methoxybenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 4-(6-(5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octan-2-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 14 4-(6-(5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridine-3- Yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-methyl Nitrile
  • Step 1 5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 4-(6-(5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 15 4-(6-(5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 5-(2,3-Dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 4-(6-(5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -6-(2-(3-oxo-8-azabicyclo[3.2.1]octane-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • the target compound (196)-(201) of Example 196-201, the target compound (207) of Example 207, the target compound (211)-(214) of Example 211-214, the target compound (221) of Example 221 It is prepared by referring to the synthesis route of Example 1 or Synthesis Scheme 1.
  • the specific structure and characterization data are as shown in Table 2 below:
  • the target compound (217) of Example 219, the target compound (219) of Example 222, and the target compound (222) of Example 222 were prepared by referring to the synthetic route of Example 2 or Synthesis Scheme 2.
  • the specific structure and characterization data are described in Table 3 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.
  • the compound of the present invention has a good inhibitory effect on Ret wt.
  • the compound of the present invention also has a good inhibitory effect on Ret V804M.
  • CTG test compound by the method of cell proliferation by 50% inhibitory concentration (IC 50) in a series of tumor cells.
  • BAF3-KIF5B-RET-WT stable transgenic cell line, constructed by the Pharmacology Department of Guangdong Dongyang Sunshine Pharmaceutical Co., Ltd.
  • a Working solution configuration Dissolve each test compound in DMSO to a final concentration of 10 mM stock solution. Prepare 3X serial dilutions with stock solution and complete RPMI medium (89% RPMI + 10% FBS + 1% double antibody), a total of 10 concentrations of working solution, the final concentration of DMSO in each solution is 0.1%.
  • b Cell dosing After the cells are incubated overnight, add 10ul of working solution corresponding to 10 gradient concentrations and incubate in a 37°C, 5% CO2 incubator for 72 hours; at the same time, set up a negative control of no compound plus cells.
  • the cell survival rate is calculated by the formula: Vsample/Vvehicle control x100%.
  • Vsample is the reading of the drug treatment group
  • Vvehicle control is the average value of the solvent control group.
  • GraphPad Prism 5.0 software was used to draw an S-type dose-survival rate curve using a non-linear regression model and calculate the IC 50 value. The experimental results are shown in Table B.

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Abstract

L'invention concerne un inhibiteur de RET, une composition pharmaceutique comprenant celui-ci et une utilisation associée. Plus particulièrement, la présente invention concerne un composé tel que représenté par la formule (I), ou un stéréoisomère, un isomère géométrique, un tautomère, un oxyde d'azote, un solvate, un métabolite, un sel ou un promédicament pharmaceutiquement acceptables du composé tel que représenté par la formule (I), et concerne en outre une composition pharmaceutique comprenant le composé, et une utilisation du composé et de la composition pharmaceutique comprenant celui-ci dans la préparation d'un médicament, lequel médicament est particulièrement utile pour traiter et prévenir des maladies et des affections associées à RET, y compris les cancers, le syndrome du côlon irritable et/ou la douleur associée au syndrome du côlon irritable.
PCT/CN2020/118065 2019-09-29 2020-09-27 Inhibiteur de ret, composition pharmaceutique comprenant celui-ci et utilisation associée WO2021057963A1 (fr)

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Cited By (2)

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EP3891149A4 (fr) * 2018-12-07 2022-09-07 Sunshine Lake Pharma Co., Ltd. Inhibiteurs de ret, compositions pharmaceutiques et utilisations associées

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TW202144348A (zh) * 2020-04-22 2021-12-01 大陸商深圳晶泰科技有限公司 一種吡唑并[1,5-a]吡啶類衍生物及其製備方法，組合物以及用途

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WO2018071447A1 (fr) * 2016-10-10 2018-04-19 Andrews Steven W Composés substitués de pyrazolo[1,5-a]pyridine en tant qu'inhibiteurs de la kinase ret
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* Cited by examiner, † Cited by third party
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EP3891148A4 (fr) * 2018-12-07 2022-09-07 Sunshine Lake Pharma Co., Ltd. Inhibiteurs de ret, compositions pharmaceutiques et utilisations associées
EP3891149A4 (fr) * 2018-12-07 2022-09-07 Sunshine Lake Pharma Co., Ltd. Inhibiteurs de ret, compositions pharmaceutiques et utilisations associées

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