WO2024051700A1 - Nouveau composé hétérocyclique substitué par un éther benzylique deutéré d'aryle utilisé en tant qu'agoniste de glp1r - Google Patents

Nouveau composé hétérocyclique substitué par un éther benzylique deutéré d'aryle utilisé en tant qu'agoniste de glp1r Download PDF

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WO2024051700A1
WO2024051700A1 PCT/CN2023/117078 CN2023117078W WO2024051700A1 WO 2024051700 A1 WO2024051700 A1 WO 2024051700A1 CN 2023117078 W CN2023117078 W CN 2023117078W WO 2024051700 A1 WO2024051700 A1 WO 2024051700A1
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saturated
alkyl
cycloalkyl
group
substituted
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PCT/CN2023/117078
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Chinese (zh)
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张龙
牛张明
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德睿智药(苏州)新药研发有限公司
杭州德睿智药科技有限公司
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Publication of WO2024051700A1 publication Critical patent/WO2024051700A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically includes novel aryl ether-substituted heterocyclic compounds with GLP1R agonistic activity, compositions containing such compounds, and the application of such compounds in the preparation of drugs for the treatment or prevention of diseases related to GLP1/GLP1R. Medication method.
  • Glucagon-like peptide-1 (GLP-1) is a long peptide hormone containing 30 or 31 amino acids. It is produced and secreted by enteroendocrine L cells and certain neurons in the nucleus of the solitary tract in the brainstem during feeding. GLP-1 stimulates insulin secretion, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates ⁇ -cell proliferation in a physiological and glucose-dependent manner. In non-clinical experiments, GLP-1 promotes ⁇ -cell persistence by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting ⁇ -cell regeneration (Meier, et al. Biodrugs. 2003; 17(2):93 -102).
  • the GLP1 receptor has been proven to be an ideal target for the treatment of metabolic diseases such as obesity, diabetes, and fatty liver.
  • metabolic diseases such as obesity, diabetes, and fatty liver.
  • GLP1R agonist peptide drugs such as dulaglutide and semaglutide have been approved for marketing abroad. For the treatment of diabetes and weight loss.
  • these peptides need to be injected, and patient follow-up is poor; they are also costly, have poor accessibility, and have a heavy medical burden; they need to be refrigerated, and are inconvenient to carry and store; they are also suitable for diseases with complex causes that require the combination of multiple drugs for treatment, such as non-alcoholic fatty liver disease, etc. It is difficult to form a compound with existing oral small molecule drugs. Therefore, there is an urgent need to develop small molecule oral GLP1R agonists.
  • PF-06882961 can achieve similar or better efficacy than GLP1 peptides (https://doi.org/10.1101/2020.09.29.319483). Although the efficacy and safety have been initially verified, PF-06882961 has major pharmaceutical deficiencies such as poor oral absorption, extremely low bioavailability, high clinical dosage, heavy burden on cost and gastrointestinal tract of patients, and cannot be passed Further increase the dosage to achieve better hypoglycemic and weight-lowering effects. Therefore, there is a need to develop new small molecule GLP1 agonists with better druggability to meet the needs of a wider range of patients.
  • the inventor unexpectedly discovered that some of the novel aryl deuterated benzyl ether-substituted heterocyclic compounds of the formula (I) of the present invention not only have significant GLP1R agonistic activity, but also have better GLP1R agonistic activity than reference compounds PF-06882961 and non-deuterated compounds with known structures.
  • the modern compounds also have better pharmacokinetic properties (including more stable metabolism of liver microsomes and liver cells, longer T1/2, higher exposure) and bioavailability. It is expected that there will be better Human PK properties, and are more suitable for development as drug candidates for the prevention or treatment of diseases related to GLP1/GLP1R targets or signaling pathways.
  • the object of the present invention is to provide compounds represented by formula (I) or pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions thereof,
  • Rings A, B, C and D are independently selected from monocyclic or polycyclic structures with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, etc. Ring, heterocyclic, paracyclic, spirocyclic or bridged ring structure;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IA),
  • Rings B and C are arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring. , parallel ring, spiro ring or bridge ring structure;
  • X 0 , X 8 and X 9 are independently selected from –CR 5 - or -N-;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl group, 5-8-membered heteroaryl group, 3-8-membered saturated or partially saturated cycloalkyl group and 3-8-membered saturated or partially saturated heterocyclic group, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, halo
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IB),
  • X 0 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 and X 9 are independently selected from –CR 5 - or -N-;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 alkylsulfonyl base, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group, C 3-10 cycloalkylamino group, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, al
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily chosen from an integer among 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IC),
  • X 0 , X 8 and X 9 are independently selected from –CR 5 - or -N-;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene group, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, optimally optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 Heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, Aryl
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cycloalkyl group, C 3-10 heterocyclic hydrocarbon group, consisting of C 3-10 cycloalkyl group or C 3-10 hetero group C 1-10 alkyl substituted by cycloalkyl, and C 1-10 heteroalkyl substituted by C 3-10 cycloalkyl and C 3-10 heterocycloalkyl; wherein, the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl or
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily chosen from an integer among 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (ID),
  • X 0 , X 1 , X 4 , X 8 are independently selected from –CR 5 - or -N-;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily chosen from an integer among 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IE),
  • X 1 and X 8 are independently selected from –CR 5 - or -N-;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl base or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl base-substituted carboxyl or carboxyl substitute.
  • the carboxyl substitute is:
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cycloalkyl group, C 3-10 heterocyclic hydrocarbon group, consisting of C 3-10 cycloalkyl group or C 3-10 hetero group C 1-10 alkyl substituted by cycloalkyl, and C 1-10 heteroalkyl substituted by C 3-10 cycloalkyl and C 3-10 heterocycloalkyl; wherein, the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl or
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily chosen from an integer among 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IF),
  • X 1 , X 2 , X 3 , X 4 and X 8 are independently selected from –CR 5 - or -N-;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl base or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl base-substituted carboxyl or carboxyl substitute.
  • the carboxyl substitute is:
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated Cyclo
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily chosen from an integer among 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IG),
  • X 1 is independently selected from –CR 5 - or -N-;
  • Z is independently selected from -C(R d1 )(R d2 )-, single bond, double bond or triple bond; and the hydrogen on Z is preferably optionally substituted by the following substituents, the substituents are deuterium, halogen , -CN, -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl base or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl base-substituted carboxyl or carboxyl substitute.
  • the carboxyl substitute is:
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • R 1 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl Or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 ring Alkyl or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 Alkyl-substituted carboxyl or carboxyl substitute, most preferably, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl , C 3-10 saturated or partially saturated Cycloalkyl, C 3-10 saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily chosen from an integer among 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (IH),
  • X 1 , X 2 , X 3 , X 4 and X 8 are independently selected from –CR 5 - or -N-;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, -NR d8 R d9 , 6-10-membered aryl, 5-8-membered heteroaryl, 3-8-membered saturated or partially saturated cycloalkyl, and 3-8-membered saturated or partially saturated heterocyclyl, in which R 0 represents C 1-10 alkyl Base, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group And the 3-8 membered saturated or partially saturated heterocyclyl group is optionally preferably substituted by 1 to more substituent groups, and the substituent groups are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalky
  • Each R 1 may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute, most optionally, the carboxyl substitute is: The C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated
  • R 2 , R 2' and R d1 , R d2 may be the same or different, and are independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1 -10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 ring Alkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aromatic
  • Each R 4 may be the same or different, and may be independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclic hydrocarbyl, composed of C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl groups substituted by cycloalkyl groups, and C 1-10 heteroalkyl groups substituted by C 3-10 cycloalkyl groups and C 3-10 heterocycloalkyl groups; wherein, the C 1-10 alkyl groups, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally saturated with 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 or Partially saturated cycloalkyl
  • Each R 5 and R 6 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C 3- A C 1-10 alkyl group substituted by a 10- ring hydrocarbon group or a C 3-10 heterocyclyl group substituted by a C 3-10 cycloalkyl group or a C 3-10 heterocycloalkyl group; wherein, the C 1-10 alkyl group , C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, via C C 1-10 alkyl substituted
  • R a and R b may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or halogen; and at least one of R a and R b is Deuterium or halogen;
  • any one of R a and R b can also form a 5 to 30-membered cyclic structure together with R 5 , and the cyclic structure optionally contains 1 to more heteroatoms, and the heteroatoms are independently selected from O, N, Heteroatoms of S and P and their isotopes;
  • R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 may be the same or different, and may be independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2 -10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl , C 3-10 Heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl; wherein, The C 1-10 alkyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 1-10 alkyl acyl group, C 1-10 alkylsulfonyl group, C 2
  • the heterorepresentatives represent any heteroatoms independently selected from O, N, S, P and their isotopes;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • q is arbitrarily selected from an integer among 0, 1, 2, 3, 4, and 5;
  • t is arbitrarily chosen from an integer among 0, 1, 2, and 3.
  • R0 may be selected from the structures shown below:
  • R 1 can be selected from COOH, F,
  • R 2 and R 2 ' are both H;
  • R 4 is H, F, methyl; X 8 is selected from CH or N.
  • the above-mentioned compound or its pharmaceutically acceptable salt, or its isomer or isotope substitution is selected from compounds with structures as listed in the examples of the present invention.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution. kind.
  • the pharmaceutical composition is formulated for administration by a route selected from: oral, injectable, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, Intramuscular, intravenous, intradermal, intrathecal and epidural.
  • the pharmaceutical composition is preferably administered orally.
  • the oral dosage form is not particularly limited, and any oral dosage form well known in the art can be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.
  • the dosage standard used is, for example, 500-1500 mg/day, and the preferred dosage is 700-1200 mg/day, preferably 800-1000 mg/day, and the most preferred dosage is 1000 mg/day.
  • the medication time of the pharmaceutical composition according to the present invention may depend on the degree of the disease, preferably at least 1 month, for example, 1, 2, 3, 4, 5 or 6 months, and may require lifelong medication at the longest due to the condition. .
  • the pharmaceutical composition may further include pharmaceutically acceptable auxiliary materials, which are selected from at least one of the following auxiliary materials including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, and osmotic pressure regulators.
  • auxiliary materials including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, and osmotic pressure regulators.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the use of the above compounds in the preparation of drugs for preventing and/or treating diseases related to the GLP1/GLP1R signaling pathway.
  • the diseases related to the GLP1/GLP1R signaling pathway include but are not limited to overweight, obesity, diabetes (T1D and/or T2DM, including prediabetes), idiopathic T1D (type 1B), and latent autoimmune diabetes in adults (LADA).
  • EOD early-onset T2DM
  • YOAD atypical diabetes of the young
  • MODY mature-onset diabetes of the young
  • malnutrition-related diabetes gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance , diabetic neuropathy, diabetic nephropathy, renal disease (e.g., acute kidney disease, tubular dysfunction, proinflammatory changes in the proximal tubule), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, Obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (such as osteoarthritis and urinary incontinence), eating disorders (including binge drinking syndrome, bulimia nervosa, and syndromic obesity such as Prader- Willi and Bardet-Biedl syndrome), weight gain due to other drug use (e.g., use of steroids and antipsychotics), excessive glucophilia, dyslipidemia (including hyper
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, as well as the pharmaceutical composition for preventing and/or treating GLP1 /Use in diseases related to GLP1R signaling pathway.
  • the diseases related to the GLP1/GLP1R signaling pathway have the definitions described above.
  • the invention also provides a method for preventing and/or treating diseases related to the GLP1/GLP1R signaling pathway, which includes administering to the patient a preventive or therapeutically effective amount of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. At least one of the compounds, enantiomers and isotope substitutions, or administering to the patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition.
  • the diseases related to the GLP1/GLP1R signaling pathway have the definitions described above.
  • the patient is a mammal, preferably a human.
  • C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10
  • C 2-10 is selected from C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10
  • C 3-10 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • alkyl refers to a straight or branched chain monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl.
  • alkylene refers to a straight or branched divalent hydrocarbon group of the formula -( CH2 ) n- .
  • Non-limiting examples include ethylene and propylene.
  • carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • the carbocyclic ring may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g. 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • the carbocycle may be monocyclic or polycyclic, it may be a saturated cycloalkyl group or it may optionally contain one, two or more double and/or triple bonds on its ring, thereby forming a so-called Cycloalkenyl or cycloalkynyl.
  • a carbocyclic ring When a carbocyclic ring has multiple rings, these rings can form spiro, fused, and bridged ring structures.
  • monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl, cyclooctyl, cyclooctatetraenyl, etc.
  • non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which are selected from N, O, NH, Heteroatoms or atomic groups of S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (eg 1, 2, 3 and 4); more preferably it contains 3 to 6 ring atoms (eg 3, 4, 5, 6).
  • the heterocyclyl group may be attached to the remainder of the molecule through any one of the carbon atoms or nitrogen atom, if present, or oxygen or sulfur atom (particularly in the case of an onium salt).
  • the heterocyclyl group may include fused or bridged rings and/or spirocyclic rings.
  • Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl , dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiophenyl Alkyl group, trithialkyl group, homopiperazinyl group, diazepanyl group, etc., preferably piperidinyl group and pyrrolidinyl group.
  • Polycyclic heterocyclyl groups include spirocyclic, fused-ring and bridged-ring heterocyclyl groups, and may also be benzo-fused heterocyclyl groups such as dihydroisoquinolinyl groups.
  • the heterocyclyl group may be bicyclic, and non-limiting examples thereof include hexahydrocyclopenta[c]pyrrole-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazine-2(1H) )-base.
  • Heterocyclyl may also be partially unsaturated, i.e.
  • it may contain one or more double bonds, non-limiting examples of which include dihydrofuryl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl , 4H-[1,3,4]thiadiazinyl, 4,5-dihydroxazolyl or 4H-[1,4]thiazinyl.
  • Heterocyclyl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • heteroaryl/heteroaryl ring refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus.
  • the heteroaryl group is preferably 5 to 10 yuan (for example, 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tris Azolyl, thiadiazolyl, thi-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolinyl, purinyl, etc.
  • the heteroaryl/heteroaryl ring may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one, two or more independently of each other.
  • aliphatic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • the carbocyclic ring may contain 3 to 20 carbon atoms, preferably 3 to 20 carbon atoms. 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle may be monocyclic or polycyclic, it may be a saturated cycloalkyl group or it may optionally contain one, two or more double and/or triple bonds on its ring, thereby forming a so-called Cycloalkenyl or cycloalkynyl.
  • a carbocyclic ring When a carbocyclic ring has multiple rings, these rings can form spiro, fused, and bridged ring structures.
  • monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl, cyclooctyl, cyclooctatetraenyl, etc.
  • non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • aryl or "aromatic ring” refers to: It should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic or bicyclic ring (such as a fused ring, a bridged ring, a spiro ring) with 6 to 20 carbon atoms. ) or a tricyclic hydrocarbon ring, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl".
  • C 6-14 aryl is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings (“C 6-14 aryl”), especially rings with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or with 9 carbon atoms a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution
  • aryl, aromatic ring, heterocyclyl, heteroaryl or heteroaromatic ring includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 may be included Forms in which -, if present, are substituted at one, two or more positions or bonded to other groups, including pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3 - base; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , as well as salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutic
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • “Pharmaceutically acceptable salts” as used herein belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with an acid or salt with a base.
  • examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts such as Na salt, potassium salt, amine salt, quaternary ammonium salt of the parent compound, etc.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic bases and organic bases, the inorganic acid or organic acid being selected from 2-acetoxybenzoic acid, 2-hydroxyethyl sulfonate Acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid Amino acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonate Acid, nitric acid, oxa
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.
  • solvate refers to an association of one or more solvent molecules with a compound of the invention.
  • Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Therefore, the term “hydrate” refers to an association of solvent molecules that is water.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by step-by-step procedures well known in the art. Diastereomers are resolved by crystallization or chromatography, and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • the invention is now further described by way of examples.
  • the examples given below are for illustrative purposes only and do not limit the scope of the invention.
  • the compounds of the present invention can be prepared by many methods known in the art of organic synthesis.
  • Embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based on them.
  • Preferred methods include, but are not limited to, the methods described below.
  • aq is aqueous solution
  • TLC thin layer chromatography
  • RT room temperature
  • MeOH is methanol
  • EtOH is ethanol
  • EtOAc is ethyl acetate
  • THF is tetrahydrofuran
  • equivalent is eq
  • CDI carbonyldiimidazole
  • DCM Dichloromethane
  • PE is petroleum ether
  • DIAD is diisopropyl azodicarboxylate
  • DMF is N, N-dimethylformamide
  • DMSO is dimethyl sulfoxide
  • CBz is benzyloxycarbonyl
  • BOC is tert-butyl Carbonyl
  • HOAc is acetic acid
  • Ms is methanesulfonyl: NMP is N-methylpyrrolidone;
  • Triethylamine (4.00 g, 39.25 mmol) was added to a solution of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (2.00 g, 18.00 mmol) in dry dichloromethane (20 mL). The resulting mixture was cooled to 0°C, MsCl (3.12g, 27.23mmol) was added dropwise, and the reaction was continued to stir at 0°C for 1 h. The reaction mixture was then stirred at room temperature for a further 2 h, then diluted with dichloromethane (50 mL) and washed with brine (25 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (1-(cyanomethyl)cyclopropyl)methanesulfonate (3.26g, 17.23mmol).
  • n-butyllithium (1.26 mL, 3.15 mmol) was added to a solution of dry tetrahydrofuran (10 mL) dissolved in 5-bromo-1,2-dimethyl-1H-imidazole (500 mg, 2.86 mmol). 2.5M hexane), and the mixture was stirred at -78°C for 30 min, then N,N-dimethylformamide (626 mg, 8.58 mmol) was slowly added at 0°C. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, the reaction was quenched with water (50 mL) at 0°C and extracted with ethyl acetate (2 ⁇ 30 mL).
  • Triethylamine (510 mg, 5.05 mmol) was added to dissolved (1,2-dimethyl-1H-imidazol-5-yl)methanamine hydrochloride (200 mg, 1.01 mmol), 3-fluoro-4-nitrate into a stirred solution of methyl benzoate (201 mg, 1.01 mmol) in tetrahydrofuran (3 mL) and methanol (2 mL), and the mixture was stirred at 60°C for 3 hours. The resulting mixture was poured into brine (50 mL) and extracted with ethyl acetate (2 x 20 mL).
  • potassium acetate 470 mg, 4.80 mmol
  • 1,1'-bisdiphenylphosphine ferrocene palladium dichloride 117 mg, 0.16 mmol
  • 5-bromo-N1-( (1-ethyl-1H-imidazol-5-yl)methyl)-3-fluorobenzene-1,2-diamine 500 mg, 1.60 mmol
  • methanol/N,N-dimethylformamide 5 mL/ 5 mL
  • Example 1-18 methyl 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (Intermediate A -18) synthesis;
  • Example 1-20 synthesis of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (intermediate A-20);
  • triphenylphosphine (205 mg) was added to the dissolved compound 4-(6-(hydroxymethyl-d 2 )pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester. (155 mg, 0.5 mmol) and 3-fluoro-4-hydroxybenzonitrile (68.5 mg, 0.5 mmol) in tetrahydrofuran (10 mL), then diisopropyl azodicarboxylate (198 mg) was added dropwise at 0°C ). The reaction was then stirred at room temperature for 16 hours.
  • the organic phase was concentrated under reduced pressure and purified by reverse-phase flash chromatography under the following conditions: (column: spherical C18, 20-40 ⁇ m, 120 g; mobile phase A: water (0.1% ammonia); mobile phase B: acetonitrile; flow rate: 80 mL /min; gradient: 0% B-95% B in 30 minutes; detector: 254nm.) Collect the mobile phase containing the desired product at 72% B, and concentrate under reduced pressure to obtain 4-(2-(4-( (6-((4-cyano-2-fluorophenoxy)methyl-d 2 )pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl) Methyl-1H-imidazol-5-yl)methyl)amino)benzoate (161 mg, yield: 25%). LC-MS m/z:644[M+H] + .
  • the temperature of the resulting mixed reaction liquid is raised to 60°C and stirred for 3 hours.
  • the mixed reaction was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • reaction solution was diluted with water (10 mL), then adjusted to pH 5-6 with formic acid (purity: 98%), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • reaction solution is diluted with water, the pH is adjusted to 5-6 with FA (purity: 98%), and then extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Test Example 1 Detection of agonist activity of test substance on GLP-1R
  • %Activity (cAMP level of testing sample-average cAMP level of LC)/(average cAMP level of HC-average cAMP level of LC) ⁇ 100%
  • Test Example 2 Study on the metabolic stability of human liver cells of the test substance:
  • the final concentration of the test substance is 1 ⁇ M
  • the final concentration of the control substance is 3 ⁇ M
  • the final concentration of liver cells is 0.5 ⁇ 106 cells/mL
  • the final concentration of the total organic solvents is 1.0%
  • the final concentration of DMSO is 0.1 %.
  • the concentrations of test substances and reference substances were semi-quantitatively determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS), excluding standard curves and quality control samples.
  • the concentration in the sample is expressed as the ratio of the analyte peak area to the internal standard peak area.
  • the retention time of analytes and internal standards, chromatogram acquisition, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).

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Abstract

La présente invention concerne un nouveau composé hétérocyclique substitué par un éther arylique ayant une activité agoniste de GLP1R. L'invention concerne en particulier un composé ayant une structure telle que représentée par la formule (I) utilisé en tant qu'agoniste de GLP1R, ou un sel, un solvate, un hydrate, un substitut isotopique ou un isomère pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/117078 2022-09-05 2023-09-05 Nouveau composé hétérocyclique substitué par un éther benzylique deutéré d'aryle utilisé en tant qu'agoniste de glp1r WO2024051700A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325530A (zh) * 2016-12-16 2019-10-11 辉瑞大药厂 Glp-1受体激动剂及其用途
WO2022165076A1 (fr) * 2021-01-28 2022-08-04 Carmot Therapeutics, Inc. Agonistes du récepteur gpcr, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2022235717A1 (fr) * 2021-05-03 2022-11-10 Carmot Therapeutics, Inc. Agonistes du récepteur benzimidazoyl glp-1, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2023029380A1 (fr) * 2021-08-30 2023-03-09 杭州德睿智药科技有限公司 Nouveau composé hétérocyclique substitué par un éther arylique utilisés en tant qu'agoniste du glp1r
WO2023049518A1 (fr) * 2021-09-27 2023-03-30 Terns Pharmaceuticals, Inc. Acides benzimidazole carboxyliques utilisés en tant qu'agonistes de glp-1r
CN116102555A (zh) * 2022-12-23 2023-05-12 华中药业股份有限公司 咪唑并芳杂基类衍生物及其应用
CN116675680A (zh) * 2023-08-02 2023-09-01 药康众拓(北京)医药科技有限公司 一种氘代化合物及其制备方法、药物和应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325530A (zh) * 2016-12-16 2019-10-11 辉瑞大药厂 Glp-1受体激动剂及其用途
WO2022165076A1 (fr) * 2021-01-28 2022-08-04 Carmot Therapeutics, Inc. Agonistes du récepteur gpcr, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2022235717A1 (fr) * 2021-05-03 2022-11-10 Carmot Therapeutics, Inc. Agonistes du récepteur benzimidazoyl glp-1, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2023029380A1 (fr) * 2021-08-30 2023-03-09 杭州德睿智药科技有限公司 Nouveau composé hétérocyclique substitué par un éther arylique utilisés en tant qu'agoniste du glp1r
WO2023049518A1 (fr) * 2021-09-27 2023-03-30 Terns Pharmaceuticals, Inc. Acides benzimidazole carboxyliques utilisés en tant qu'agonistes de glp-1r
CN116102555A (zh) * 2022-12-23 2023-05-12 华中药业股份有限公司 咪唑并芳杂基类衍生物及其应用
CN116675680A (zh) * 2023-08-02 2023-09-01 药康众拓(北京)医药科技有限公司 一种氘代化合物及其制备方法、药物和应用

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