WO2021244634A1 - Composé imidazopyridine et son utilisation - Google Patents

Composé imidazopyridine et son utilisation Download PDF

Info

Publication number
WO2021244634A1
WO2021244634A1 PCT/CN2021/098296 CN2021098296W WO2021244634A1 WO 2021244634 A1 WO2021244634 A1 WO 2021244634A1 CN 2021098296 W CN2021098296 W CN 2021098296W WO 2021244634 A1 WO2021244634 A1 WO 2021244634A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
substituted
alkyl
pyridin
difluoro
Prior art date
Application number
PCT/CN2021/098296
Other languages
English (en)
Chinese (zh)
Inventor
张学军
臧杨
李莉娥
杨成兵
Original Assignee
武汉人福创新药物研发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉人福创新药物研发中心有限公司 filed Critical 武汉人福创新药物研发中心有限公司
Publication of WO2021244634A1 publication Critical patent/WO2021244634A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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]

Definitions

  • the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to imidazopyridine compounds, and more specifically, the present invention relates to an imidazopyridine compound, a preparation method thereof, and use thereof in the preparation of medicines.
  • P2X receptor is a non-selective ATP-gated ion channel receptor, namely purinergic receptor, which can bind to extracellular ATP, which mainly comes from damaged or inflamed tissues.
  • This receptor is widely expressed in the nervous, immune, cardiovascular, bone, gastrointestinal, respiratory, endocrine and other systems, and is involved in the regulation of heart rhythm and contractility, the regulation of vascular tension, the regulation of nociception, especially chronic pain, and the contraction of the vas deferens during ejaculation. .
  • P2X receptors include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and three heterologous receptors: P2X2/3, P2X4/6, P2X1/5.
  • P2X3 is a subtype of the P2X receptor family, which is selectively expressed in the dorsal root ganglia, spinal cord and brain neurons of the nerve endings, that is, primary sensory neurons with small and medium diameters.
  • P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in the acute injury, hyperalgesia and hypersensitivity of rodents.
  • Many studies have shown that the up-regulation of P2X3 receptor expression can lead to the formation of hyperalgesia and participate in the signal transmission of pain.
  • P2X3 knockout mice showed reduced pain response.
  • P2X3 receptor antagonists showed the effect of reducing nociception.
  • P2X3 is distributed in the primary afferent nerves around the airway and can regulate coughing. Studies have shown that ATP released from damaged or inflamed tissues in the airways acts on the P2X3 receptors of primary neurons to trigger depolarization and action potentials. These potential transmissions cause the cough impulse and cause coughing. Preclinical and clinical data strongly prove that P2X3 receptors play an important role in cough reflex hypersensitivity, which leads to chronic cough. By antagonizing the binding to the P2X3 receptor, the hypersensitivity reaction of the cough reflex can be inhibited, thereby inhibiting excessive coughing in patients with chronic cough.
  • P2X3 is involved in the afferent pathway that controls the bladder volume reflex.
  • P2X3 knockout mice have a significant decrease in urination frequency and a significant increase in bladder volume. Therefore, inhibiting the binding of P2X3 receptor antagonists to P2X3 receptors has the effect of treating urine storage and urination disorders, such as overactive bladder. Therefore, P2X3 antagonists may be potential drugs for the treatment of related diseases such as overactive bladder.
  • P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension or asthma, so P2X3 antagonists are also expected to become new drugs for the treatment of these diseases.
  • P2X3 antagonists have shown great prospects in many disease fields. Therefore, the development of P2X3 antagonists is of great clinical significance.
  • the present invention aims to provide a P2X3 receptor antagonist, which can be used to prepare medicines for treating cough, pain, respiratory system diseases and urogenital system diseases.
  • the present invention provides a compound, which is a compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
  • R 1 is independently C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl) substituted by 1-5 identical or different halogens;
  • R 2 is independently H, halogen or methyl
  • R 3 is independently methyl or halogen
  • R 4 is independently
  • R 41 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 42 is independently deuterium substituted with 1-5 C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 3 -C 6 cycloalkyl; R 421 is a substituted C 1 -C 6 alkyl substituted with R 421 C 3 -C 6 cycloalkyl, or one of the substituents of R 421 may be one or more of Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring A is independently unsubstituted or R 43 is an unsubstituted 4-8 membered heterocycloalkyl, or R 43 substituted or unsubstituted 6-11 membered heteroalkyl spiro cycloalkyl;
  • R 43 is a substituted 4-8 membered heterocycloalkyl or R 43 substituted 6-11 membered heteroalkyl spiro cycloalkyl group, the R 43 may be substituted with one or more substituents, the R 43 are each independently a group of the following substituents : Halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl or C 3 -C 6 cycloalkyl
  • R 5 is independently H, a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 51,
  • the R 51 substitution may be one or more substitutions, and each of the R 51 is independently the following substituents: 1 to 5 are the same or C 1 -C 6 alkyl, halogen or C 1 -C 6 alkyl substituted by different halogens; when there are multiple substituents, the substituents are the same or different;
  • R 52 is independently unsubstituted or substituted by R 521 5-8 membered heteroaryl, unsubstituted or substituted by R 521 C 1 -C 6 alkyl, unsubstituted or substituted by R 521 -O-(C 1- C 6 alkyl), unsubstituted or substituted by R 521 C 3 -C 6 cycloalkyl, or, unsubstituted or substituted by R 521 -O-(C 3 -C 6 cycloalkyl);
  • R 521 is a 5-8 membered heteroaryl substituted with an aryl group, R 521 is substituted by C 1 -C 6 alkyl, R 521 is substituted with -O- (C 1 -C 6 alkyl), substituted-described R 521 the C 3 -C 6 cycloalkyl (C 3 -C 6 cycloalkyl group), a substituted alkyl group or said R 521 R 521 -O-
  • R 53 is independently -O-(C 1 -C 6 alkyl);
  • the compound represented by formula I does not include the following compounds, their tautomers, stereo Isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are
  • ring B, R 4 and R 5 are as described above.
  • R 1 when R 1 is halogen, the halogen is F, Cl or Br.
  • R 1 when R 1 is halogen, said is F or Cl.
  • R 1 when R 1 is -O-(C 1 -C 6 alkyl), the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl base.
  • R 1 is -O-(C 1 -C 6 alkyl)
  • the C 1 -C 6 alkyl is methyl or ethyl.
  • R 1 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 1 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • R 1 is a C 1 -C 6 alkyl group substituted with 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group. , N-propyl or isopropyl.
  • R 1 is a C 1 -C 6 alkyl group substituted with 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is methyl or ethyl .
  • R 1 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the halogen is substituted with 1, 2, or 3.
  • R 1 is a C 1 -C 6 alkyl substituted with 1 to 5 identical or different halogens
  • the halogen is substituted with 2 or 3 halogens.
  • said R 4 is
  • R 41 when R 41 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl or sec-butyl.
  • R 41 when R 41 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • R 41 is a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 41 when R 41 is C 3 -C 6 cycloalkyl, said C 3 -C 6 cycloalkyl is cyclopropyl or cyclobutyl.
  • said R 4 is
  • R 42 is a C 1 -C 6 alkyl group substituted with 1-5 deuteriums
  • the C 1 -C 6 alkyl group is methyl, ethyl, or n-propyl. Or isopropyl.
  • R 42 is a C 1 -C 6 alkyl group substituted with 1-5 deuteriums
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • R 42 is a C 1 -C 6 alkyl group substituted with 1-5 deuterium
  • the deuterium substitution is 1, 2, or 3.
  • R 42 is a C 1 -C 6 alkyl substituted with 1 to 5 deuteriums
  • the deuterium substitution is 3.
  • R 42 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 421
  • the C 1 -C 6 alkyl group is methyl, ethyl, or n-propyl. , Isopropyl, n-butyl, isobutyl or sec-butyl.
  • R 42 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 421
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • R 42 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 421
  • the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl.
  • Cyclopentyl or cyclohexyl is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 421 .
  • R 42 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 421
  • the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl .
  • R 42 when when when R 42 is R 421 is C 1 -C 6 substituted alkyl or R 421 is a substituted C 3 -C 6 cycloalkyl group, the number of the substituents R 421 1, 2, 3, 4 or 5.
  • R 42 when when R 42 is R 421 is C 1 -C 6 substituted alkyl or R 421 is a substituted C 3 -C 6 cycloalkyl group, the number of the substituents R 421 1, 2, or 3.
  • R 421 is cyano
  • R 421 when R 421 is halogen, the halogen is F, Cl, Br or I.
  • R 421 when R 421 is halogen, the halogen is Cl or F.
  • R 421 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 421 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • said R 4 is
  • ring A is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 43
  • the 4-8 membered heterocycloalkyl group is aziridinyl, nitrogen Heterocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
  • the heterocycloalkyl group is a 4-8 membered azetidinyl.
  • the 6-11 membered heteroalkyl spiro cycloalkyl when the ring A is unsubstituted or substituted by R 43 6-11 membered heteroalkyl spiro cycloalkyl group, the 6-11 membered heteroalkyl spiro cycloalkyl aza-spiro [3.3 ]Heptyl, oxazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl or oxazaspiro[5.3]nonyl.
  • the 6-11 membered hetero cycloalkyl is spiro-oxa-azaspiro [3.3] Heptyl.
  • R 43 is ring A is a substituted 4-8 membered heterocycloalkyl of R 43 or a heteroalkyl substituted 6-11 membered spiro cycloalkyl group, the number of R 43 substituents It is 1, 2, 3, 4, or 5.
  • R 43 is ring A is a substituted 4-8 membered heterocycloalkyl of R 43 or a heteroalkyl substituted 6-11 membered spiro cycloalkyl group, the number of R 43 substituents One, two or three.
  • R 43 when R 43 is halogen, the halogen is F, Cl, Br or I.
  • R 43 when R 43 is halogen, the halogen is Cl or F.
  • R 43 when R 43 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 43 when R 43 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
  • ring B when ring B is a 5-8 membered heterocycloalkyl group, the 5-8 membered heterocycloalkyl group is azacyclopropyl, oxcyclopropyl, or azacycloalkyl.
  • ring B is a 5-8 membered heterocycloalkyl
  • the 5-8 membered heterocycloalkyl is tetrahydro-2H-thiopyranyl, 1,1-dioxyl Tetrahydro-2H-thiopyranyl, morpholinyl or azetidinyl.
  • ring B is C 3 -C 6 cycloalkyl
  • said C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • ring B is C 3 -C 6 cycloalkyl
  • said C 3 -C 6 cycloalkyl is cyclopropyl or cyclobutyl.
  • a 5-8 membered heteroaryl is pyrrolyl, furanyl, thienyl, Imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.
  • a 5-8 membered heteroaryl is thiazolyl, thiadiazolyl, pyrazolyl Azolyl or pyrimidinyl.
  • R 5 is a 5-8 membered heteroaryl substituted by R 51
  • the number of R 51 substitutions is 1, 2, 3, 4, or 5 .
  • R 5 is a 5-8 membered heteroaryl substituted by R 51
  • the number of R 51 substitutions is 1, 2, or 3.
  • R 51 is a C 1 -C 6 alkyl group substituted by 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group. , N-propyl or isopropyl.
  • R 51 is a C 1 -C 6 alkyl group substituted with 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is methyl or ethyl .
  • R 51 is a C 1 -C 6 alkyl substituted with 1 to 5 halogens that are the same or different, the halogen is F, Cl, Br or I.
  • R 51 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the halogen is F or Cl.
  • R 51 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the number of halogens is 1, 2, 3 , 4 or 5.
  • R 51 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the number of the halogens is 1, 2, or 3.
  • R 51 when R 51 is halogen, the halogen is F, Cl, Br or I.
  • R 51 when R 51 is halogen, the halogen is F or Cl.
  • R 51 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 51 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is a methyl group
  • R 5 is
  • R 52 when R 52 is independently a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 521 , the 5-8 membered heteroaryl group is pyrrolyl, furyl, or thienyl , Imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.
  • R 52 is independently a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 521 , the 5-8 membered heteroaryl group is thiazolyl.
  • the C 1 -C 6 alkyl R 52 when the C 1 -C 6 alkyl R 52 is unsubstituted or substituted with R 521, the C 1 -C 6 alkyl is methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl or sec-butyl.
  • R 52 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 521
  • the C 1 -C 6 alkyl group is methyl, ethyl or isopropyl .
  • the C 1 -C 6 alkyl is methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.
  • the C 1 -C 6 alkyl is methyl or ethyl base.
  • R 52 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 521
  • the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl.
  • Cyclopentyl or cyclohexyl is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 521 .
  • R 52 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 521
  • the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl .
  • the C 3 -C 6 cycloalkyl is cyclopropyl Group, cyclobutyl, cyclopentyl or cyclohexyl.
  • the C 3 -C 6 cycloalkyl is cyclopropyl Group or cyclobutyl.
  • R 52 when R 52 is phenyl substituted with R 521 5-8 membered heteroaryl, substituted with R 521 C 1 -C 6 alkyl, R 521 is substituted with -O- (C 1 -C 6 alkyl), R 521 is a substituted C 3 -C 6 cycloalkyl group, when substituted R 521 -O- (C 3 -C 6 cycloalkyl), the number of the substituents R 521 1, 2, 3, 4 or 5.
  • R 52 when R 52 is phenyl substituted with R 521 5-8 membered heteroaryl, substituted with R 521 C 1 -C 6 alkyl, R 521 is substituted with -O- (C 1 -C 6 alkyl), R 521 is a substituted C 3 -C 6 cycloalkyl group, when substituted R 521 -O- (C 3 -C 6 cycloalkyl), the number of the substituents R 521 1, 2, or 3.
  • R 521 is cyano
  • R 521 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 521 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is a methyl group
  • R 521 is a C 1 -C 6 alkyl group substituted with 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is a methyl group or an ethyl group. , N-propyl or isopropyl.
  • R 521 is a C 1 -C 6 alkyl group substituted with 1-5 identical or different halogens
  • the C 1 -C 6 alkyl group is methyl or ethyl .
  • R 521 is a C 1 -C 6 alkyl substituted with 1 to 5 halogens that are the same or different, the halogen is F, Cl, Br or I.
  • R 521 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the halogen is F or Cl.
  • R 521 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the number of the halogens is 1, 2, or 3. , 4 or 5.
  • R 521 is a C 1 -C 6 alkyl substituted with 1-5 identical or different halogens
  • the number of the halogens is 3.
  • R 5 is
  • R 53 when R 53 is -O-(C 1 -C 6 alkyl), the C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl or sec-butyl.
  • R 53 when R 53 is -O-(C 1 -C 6 alkyl), the C 1 -C 6 alkyl group is methyl.
  • said R 1 is methyl, ethyl, -CHF 2 , methoxy or Cl.
  • R 5 is H.
  • R 5 when R 5 is a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 51 , said R 5 is
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently deuterium substituted with 1-5 C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 3 -C 6 cycloalkyl; R 421 is a substituted C 1 -C 6 alkyl substituted with R 421 C 3 -C 6 cycloalkyl, or one of the substituents of R 421 may be one or more of Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring A is independently unsubstituted or R 43 is an unsubstituted 4-8 membered heterocycloalkyl, or R 43 substituted or unsubstituted 6-11 membered heteroalkyl spiro cycloalkyl;
  • R 43 is a substituted 4-8 membered heterocycloalkyl or R 43 substituted 6-11 membered heteroalkyl spiro cycloalkyl group, the R 43 may be substituted with one or more substituents, the R 43 are each independently a group of the following substituents : Halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl or C 3 -C 6 cycloalkyl
  • R 5 is independently H, a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 51, In the 5-8 membered heteroaryl group substituted by R 51 , the R 51 substitution may be one or more substitutions, and the R 43 is each independently the following substituents: 1 to 5 are the same or C 1 -C 6 alkyl, halogen or C 1 -C 6 alkyl substituted by different halogens; when there are multiple substituents, the substituents are the same or different;
  • R 52 is independently unsubstituted or substituted by R 521 5-8 membered heteroaryl, unsubstituted or substituted by R 521 C 1 -C 6 alkyl, unsubstituted or substituted by R 521 -O-(C 1- C 6 alkyl), unsubstituted or substituted by R 521 C 3 -C 6 cycloalkyl, or, unsubstituted or substituted by R 521 -O-(C 3 -C 6 cycloalkyl);
  • the substitution of R 521 may be one or more substitutions, and each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different;
  • R 53 is independently -O-(C 1 -C 6 alkyl).
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently deuterium substituted with 1-5 C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 3 -C 6 cycloalkyl; R 421 is a substituted C 1 -C 6 alkyl substituted with R 421 C 3 -C 6 cycloalkyl, or one of the substituents of R 421 may be one or more of Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl
  • R 5 is independently
  • R 52 is independently unsubstituted or substituted by R 521 5-8 membered heteroaryl, unsubstituted or substituted by R 521 C 1 -C 6 alkyl, unsubstituted or substituted by R 521 -O-(C 1- C 6 alkyl), unsubstituted or substituted by R 521 C 3 -C 6 cycloalkyl, or, unsubstituted or substituted by R 521 -O-(C 3 -C 6 cycloalkyl);
  • the substitution of R 521 may be one or more substitutions, and each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 41 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 42 is independently deuterium substituted with 1-5 C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 1 -C 6 alkyl, unsubstituted or substituted with R 421 is C 3 -C 6 cycloalkyl; R 421 is a substituted C 1 -C 6 alkyl substituted with R 421 C 3 -C 6 cycloalkyl, or one of the substituents of R 421 may be one or more of Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring A is independently unsubstituted or R 43 is an unsubstituted 4-8 membered heterocycloalkyl, or R 43 substituted or unsubstituted 6-11 membered heteroalkyl spiro cycloalkyl;
  • R 43 is a substituted 4-8 membered heterocycloalkyl or R 43 substituted 6-11 membered heteroalkyl spiro cycloalkyl group, the R 43 may be substituted with one or more substituents, the R 43 are each independently a group of the following substituents : Halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl or C 3 -C 6 cycloalkyl
  • R 5 is independently an unsubstituted or substituted 5-8 membered heteroaryl group with R 51, In the 5-8 membered heteroaryl group substituted by R 51 , the R 51 substitution may be one or more substitutions, and the R 43 is each independently the following substituents: 1 to 5 are the same or C 1 -C 6 alkyl, halogen or C 1 -C 6 alkyl substituted by different halogens; when there are multiple substituents, the substituents are the same or different;
  • R 52 is independently unsubstituted or substituted by R 521 5-8 membered heteroaryl, unsubstituted or substituted by R 521 C 1 -C 6 alkyl, unsubstituted or substituted by R 521 -O-(C 1- C 6 alkyl), unsubstituted or substituted by R 521 C 3 -C 6 cycloalkyl, or, unsubstituted or substituted by R 521 -O-(C 3 -C 6 cycloalkyl);
  • the substitution of R 521 may be one or more substitutions, and each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently unsubstituted or substituted with R 421 is C 1 -C 6 alkyl group; R 421 is a substituted C 1 -C 6 alkyl, said R 421 may be substituted with one or more Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl
  • R 5 is independently
  • R 52 is independently unsubstituted or substituted by R 521 -O-(C 1 -C 6 alkyl); in the -O-(C 1 -C 6 alkyl) substituted by R 521, the The R 521 substitution of R 521 may be one or more substitutions.
  • Each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently unsubstituted or substituted with R 421 is C 1 -C 6 alkyl group; R 421 is a substituted C 1 -C 6 alkyl, said R 421 may be substituted with one or more Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl
  • R 5 is independently
  • R 52 is independently unsubstituted or substituted by R 521 -O-(C 1 -C 6 alkyl); in the -O-(C 1 -C 6 alkyl) substituted by R 521, the The R 521 substitution of R 521 may be one or more substitutions.
  • the R 521 is each independently the following substituents: C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently unsubstituted or substituted with R 421 is C 1 -C 6 alkyl group; R 421 is a substituted C 1 -C 6 alkyl, said R 421 may be substituted with one or more Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl
  • R 5 is independently
  • R 52 is independently unsubstituted or substituted by R 521 -O-(C 1 -C 6 alkyl); in the -O-(C 1 -C 6 alkyl) substituted by R 521, the The R 521 substitution of R 521 may be one or more substitutions.
  • Each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 4 is independently
  • R 42 is independently unsubstituted or substituted with R 421 is C 1 -C 6 alkyl group; R 421 is a substituted C 1 -C 6 alkyl, said R 421 may be substituted with one or more Substitution, each of the R 421 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • Ring B is 5-8 membered heterocycloalkyl
  • R 5 is independently
  • R 52 is independently unsubstituted or substituted by R 521 -O-(C 1 -C 6 alkyl); in the -O-(C 1 -C 6 alkyl) substituted by R 521, the The R 521 substitution of R 521 may be one or more substitutions.
  • Each of R 521 is independently the following substituents: C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 Alkyl, halogen or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
  • R 1 is independently C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl, or -O-(C 1 -C 6 alkyl) substituted by 1-5 identical or different halogens.
  • R 1 is selected from methyl or chlorine.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any of the following Compound:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically Acceptable salts or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients.
  • the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts thereof.
  • a prodrug and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient are mixed to prepare a pharmaceutical preparation, which is suitable for oral or parenteral administration.
  • Administration methods include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
  • the preparation can be administered by any route, for example, by infusion or bolus injection, by the route of absorption through epithelial or mucosal skin (for example, oral mucosa or rectum, etc.). Administration can be systemic or local.
  • preparations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like.
  • the formulation can be prepared by a method known in the art, and contains a carrier, diluent or excipient conventionally used in the field of pharmaceutical formulations.
  • the present invention proposes the above-mentioned compounds, and their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions are used in the preparation of Use in medicines for treating diseases related to P2X3.
  • the use of the aforementioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the aforementioned pharmaceutical compositions in the preparation of medicines can be used to treat or prevent pain.
  • pains include, for example, chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain.
  • the use of the aforementioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the aforementioned pharmaceutical compositions in the preparation of medicines can be used to treat or prevent coughs, including chronic coughs, refractory chronic coughs and acute coughs.
  • the use of the aforementioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the aforementioned pharmaceutical compositions in the preparation of medicines can be used to treat or prevent genitourinary system diseases.
  • diseases include, for example, decreased bladder volume, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urgency, overactive bladder Symptoms, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatic pain, cystitis.
  • the use of the aforementioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the aforementioned pharmaceutical compositions in the preparation of medicines can be used to treat or prevent respiratory diseases.
  • diseases include, for example, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, and obstructive apnea.
  • the present invention provides a method for treating P2X3 related diseases.
  • the method includes: administering the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, A pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 13.
  • the above method may further include at least one of the following additional technical features:
  • the P2X3 related disease is pain, cough, respiratory system disease or urogenital system disease.
  • the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain, any Selected as endometriosis pain and neuropathic pain.
  • the genitourinary system diseases are decreased bladder volume, frequent urination, urge incontinence, stress incontinence, hyperresponsiveness of the bladder, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, Frequent urination, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatic pain, cystitis, or idiopathic bladder hypersensitivity, optionally overactive bladder.
  • the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, and obstructive apnea.
  • the cough is refractory chronic cough and acute cough.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.
  • pharmaceutical composition means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • excipients refers to pharmaceutically acceptable inert ingredients.
  • examples of types of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical preparation, that is, make the preparation more suitable for direct compression by increasing fluidity and/or adhesion.
  • prodrug refers to a compound of the invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • Prodrugs include compounds formed by connecting a hydroxyl group or amino group to any group in the compound of the present invention. When the prodrug of the compound of the present invention is administered to a mammal, the prodrug is split to form a free hydroxyl group and a free group. The amino group.
  • stereoisomer refers to the isomers produced by the different arrangements of atoms in the molecule in space, including cis and trans isomers, enantiomers, diastereomers and conformational isomers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form. An attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • 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 in the scope of the present 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, and diastereomers Conformers, D-isomers, L-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures fall within the scope of the present invention within.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a step well known in the art Diastereoisomers are resolved by crystallization or chromatography, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that can effectively treat the target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable .
  • it means that two hydrogen atoms are replaced.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • C u- C v indicates that the following group has from u to v carbon atoms.
  • C 1- C 6 alkyl means that the alkyl group having 1 to 6 carbon atoms.
  • C 1 -C 6 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbuty
  • C 3 -C 6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 4-8 membered heterocycloalkyl refers to a monocyclic ring having a total of 4, 5, 6, 7 or 8 ring atoms and containing one or two identical or different ring heteroatoms or heteroatom-containing groups Saturated heterocyclic ring, the ring heteroatom or heteroatom-containing group is selected from: N, NH, O, S, SO and SO 2 , and the heterocycloalkyl group can pass through any carbon atom or (if present) nitrogen The atom is connected to the rest of the molecule.
  • the heterocycloalkyl group may be a 4-membered ring, such as azetidinyl, oxetanyl, or thietane; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxyl Pentyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiolanyl, 1,2-oxazolidinyl, 1,3-oxa Azolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithiazyl, thiomorpholinyl, Piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazepine.
  • heterospirocycloalkyl refers to a bicyclic saturated heterocyclic ring having a total of 6, 7, 8, 9, 10, or 11 ring atoms, wherein the two rings share a common ring carbon atom.
  • Heterospirocycloalkyl contains one or two identical or different ring heteroatoms or heteroatom-containing groups selected from: N, NH, O, S, SO and SO 2 ; the heterospirocycloalkane The group can be connected to the rest of the molecule through any carbon atom (except the spiro carbon atom) or (if present) a nitrogen atom.
  • the heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[ 3.3]heptyl, oxazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro Heterosspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiaazaspiro[3.3] Heptyl, thiaazaspiro[4.3]octyl, or one of other homologous skeletons, such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[
  • 5-8 membered heteroaryl should be understood as a monovalent group having 5-8 ring atoms, especially 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S Monocyclic, bicyclic or tricyclic aromatic ring group.
  • the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridine Group, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention has at least one of the following technical effects:
  • P2X3 antagonists with novel structure, excellent pharmacokinetic properties, and good pharmacodynamics or druggability are provided, which can be used to effectively treat P2X3 related diseases and disorders;
  • the compound of the present invention compared with the P2X2/3 type, has a more significant selective antagonistic activity against the P2X3 type, and can significantly improve the side effects caused by binding to the P2X2/3 receptor, such as taste Loss; Compared with the positive control compound, the compound of the present invention has better pharmacokinetic properties.
  • the compound of the present invention compared with the positive control compound, the compound of the present invention has better permeability, is more conducive to absorption, and has better druggability.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
  • HATU O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • EGTA ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • IC 50 half maximal inhibitory concentration, refers to a concentration at which half maximal inhibition effect.
  • the reference compound was synthesized with reference to patent application WO2014117274A1.
  • control compound refers to the compound described in Comparative Example 1.
  • Step 1 Synthesis of (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2)
  • reaction solution was extracted with water (1000 mL) and dichloromethane (400 mL*8), and concentrated under reduced pressure to obtain a white solid compound (R)-2-formylmorpholine-4-carboxy Tert-butyl ester (A-2) (43 g, yield 86%).
  • Step 2 Synthesis of (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate A)
  • methyl 2,3,5-trifluoro-4-formylbenzoate (8.5g, 35.6mmol) was added to methanol (85mL), and then triethylamine (10.8g, 107mmol) and 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (521mg, 711 ⁇ mol), pass carbon monoxide, and stir for 10 hours at 70°C and 1.5MPa.
  • TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. Separation and purification by a silica gel column gave a yellow oily compound 2,3,5-trifluoro-4-formylbenzoic acid methyl ester (B) (3.2 g, yield 41%).
  • (2S)-2-((7-methyl-2-(2,3,6-trifluoro-4-(carbomethoxy)phenyl)imidazo[1,2-a]pyridine- 3-yl)methyl)morpholine-4-carboxylate 120mg, 231 ⁇ mol
  • lithium hydroxide monohydrate 20mg, 477 ⁇ mol
  • (2S)-2-((2-(4-(cyclopropylaminocarbonyl)-2,3,6-trifluorophenyl)-7-methylimidazo[1,2-a] Pyridin-3-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (100 mg, 184 ⁇ mol) was added to methanol hydrochloric acid (4.00M, 1.00 mL), and then stirred at room temperature for 10 hours.
  • TLC detects the completion of the reaction, and concentrates under reduced pressure to obtain the yellow oily compound (S)-3,5-difluoro-N-methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazole) And [1,2-a]pyridin-2-yl)benzamide (3E) (3.5g, 8.72mmol, 97% yield), used directly in the next step.
  • the synthetic route of the target compound is as follows:
  • the synthetic route of the target compound is as follows:
  • the synthetic route of the target compound is as follows:
  • the synthetic route of the target compound is as follows:
  • TLC detects that the reaction is complete and p-TLC separates (S)-2-((2-(4-bromo-2,3,6-trifluorophenyl)-7-methylimidazo[1,2-a] Pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (5.3 g, 10.3 nmol, 57.1% yield).
  • TLC detects that the reaction is complete, concentrates to dryness, and p-TLC separates to obtain (S)-2-((7-methyl-2-(2,3,6-trifluoro-4-(methylsulfonamido)phenyl) ) Imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester.
  • the synthetic route of the target compound is as follows:
  • TLC detects that the reaction is complete, concentrates to dryness, and p-TLC separates to obtain (S)-2-((2-(4-(ethylsulfonamido)-2,3,6-trifluorophenyl)-7-methan Methyl imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester.
  • the synthetic route of the target compound is as follows:
  • TLC detects that the reaction is complete, concentrates to dryness, and p-TLC separates to obtain (S)-2-((2-(4-(cyclopropylsulfonamido)-2,3,6-trifluorophenyl)-7- Methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester.
  • TLC detects that the reaction is complete, and is separated by p-TLC to obtain a brown solid compound (S)-2-((7-methyl-2-(2,3,6-trifluoro-4-((1-methylcyclopropyl) )Aminocarbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (100 mg, 179 ⁇ mol, 90% yield).
  • the third step (S)-2-((7-methyl-2-(2,3,6-trifluoro-4-((1-methylcyclopropyl)aminocarbonyl)phenyl)imidazo[ 1,2-a)pyridin-3-yl)methyl)morpholine-4-methyl carboxylate (target compound I-10)
  • TLC detects that the reaction is complete, and p-TLC separates (S)-2-((7-methyl-2-(2,3,6-trifluoro-4-((1-methylcyclopropyl)aminocarbonyl)) Phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester.
  • TLC detects that the reaction is complete, and p-TLC separates (S)-2,3,5-trifluoro-N-methyl-4-(7-methyl-3-((4-propionylmorpholin-2-yl) )Methyl)imidazo[1,2-a]pyridin-2-yl)-benzamide.
  • TLC detects that the reaction is complete, and p-TLC separates (S)-2,3,5-trifluoro-4-(3((4-isobutyrylmorpholin-2-yl)methyl)-7-methylimidazole And [1,2-a]pyridin-2-yl)-N-methylbenzamide.
  • reaction mixture was diluted with dilute hydrochloric acid (4.00M, 100mL), and then extracted with methyl tert-butyl ether (100mL ⁇ 3), and the organic layers were combined to obtain a crude product.
  • the reaction mixture was diluted with water (15.0mL), and then extracted with dichloromethane (15.0mL ⁇ 3). The organic layers were combined and concentrated to obtain the crude product, which was separated and purified by high performance liquid chromatography.
  • the first step 4-(3-((1,1-tetrahydro-2H-thiopyran-4-yl)methyl)-7-methylimidazo[1,2-a]pyridine-2- Yl)-3,5-difluoro-N-methylbenzamide (I-15) synthesis
  • the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily compound 4-(3-((( S)-4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-7-ethylimidazo[1,2-a]pyridin-2-yl)-2,3,5-trifluoro Benzoic acid (17E) (2.90 g, crude product).
  • 6-bromo-2,3-difluoro-4-methoxybenzaldehyde (7.50g, 83.6mmol) was added to dioxane (50mL) and water (25mL), and then phosphoric acid Potassium (19.0g, 89.6mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (11.3g, 89.6mmol) and 1,1-bis (Diphenylphosphorus)ferrocene palladium chloride (1.09g, 1.49mmol) was added to the reaction solution, and stirred at 110°C for 3 hours under nitrogen protection.
  • 2,3-difluoro-4-formyl-5-methylphenyl trifluoromethanesulfonate 5.30g, 17.4mmol was added to methanol (50mL), and triethylamine ( 5.29g, 52.3mmol), 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (255mg, 348 ⁇ mol), pass carbon monoxide (1 atmosphere), stir for 24 hours at 60°C, after the reaction is complete, the reaction solution Concentrate under reduced pressure.
  • the seventh step 4-(3-(((S)-4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine- Synthesis of 2-yl)-2,3-difluoro-5-methylbenzoic acid (18E)
  • TLC detects the completion of the reaction, and concentrates under reduced pressure to obtain the yellow oily compound 2,3-difluoro-N,5-dimethyl-4-(7-methyl-3-((S)-morpholin-2-ylmethyl) Yl)imidazo[1,2-a]pyridin-2-yl)benzamide (18G) (700 mg, 96.6% yield).
  • the first step 4-(3-(((S)-4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine- Synthesis of 2-yl)-2,3,5-trifluorobenzoic acid (19B)
  • the fourth step 4-(3-(((S)-4-(2-cyanoacetyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine Synthesis of -2-yl)-2,3,5-trifluoro-N-methylbenzamide (I-19)
  • the synthetic route of target compound I-20 is as follows:
  • the third step 4-(3-(((1R,3S)-3-aminocyclobutyl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3, Synthesis of 5-difluoro-N-methylbenzamide hydrochloride (20E)
  • the fourth step ((1S,3R)-3-((2-(2,6-difluoro-4-(methylaminocarbonyl)phenyl)-7-methylimidazo[1,2-a] (Pyridin-3-yl)methyl)cyclobutyl)methyl carbamate (target compound I-20)
  • the fifth step 3-((2-(2,6-difluoro-4-(methylaminocarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl Yl) azetidine-1-carboxylic acid methyl ester (target compound I-22)
  • TLC detects that the reaction is complete, add 6M hydrochloric acid dropwise to the reaction solution to adjust the pH to 5-6, add dichloromethane (40mL ⁇ 2) for extraction, and concentrate the organic phase under reduced pressure to obtain a brown solid compound (S)-3,5-difluoro -4-(3-((4-(Methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)benzoic acid (24D ) (1.20 g, 2.69 mmol, 77.4% yield).
  • the first step (S)-2-((2-(4-(3,3-difluoroazetidine-1-carbonyl)-2,6-difluorophenyl)-7-methylimidazo[ 1,2-a)pyridin-3-yl)methyl)morpholine-4-methyl carboxylate (target compound I-25)
  • TLC detects that the reaction is complete, and the reaction solution is concentrated and then separated and purified by high performance liquid chromatography.
  • TLC detects that the reaction is complete, and the reaction solution is concentrated and then separated and purified by high performance liquid chromatography.
  • the first step (S)-2-((2-(4-(cyclobutylaminocarbonyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine- 3-yl)methyl)morpholine-4-methyl carboxylate (target compound I-27)
  • TLC detects that the reaction is complete, and the reaction solution is concentrated and then separated and purified by high performance liquid chromatography.
  • the aqueous phase was collected.
  • the fourth step 4-(7-(Difluoromethyl)-3-((S)-morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)-2, Synthesis of 3,5-trifluoro-N-methylbenzamide hydrochloride (28G)
  • the synthetic route of target compound I-30 is as follows:
  • reaction mixture was diluted with water (20mL), and then extracted with ethyl acetate (20mL ⁇ 3). The organic layers were combined, dried, filtered and concentrated. The residue was separated and purified by high performance liquid chromatography.
  • reaction mixture was diluted with water (15.0 mL), and then extracted with ethyl acetate (10.0 mL ⁇ 3). The organic phases were combined, washed with water (10.0 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily compound (2S)-2-[(2-(2,6-Difluoro-4-[( 2 H)methylaminocarbonyl]phenyl)-7-methylimidazo[1,2-a]pyridine-3 -Yl)methyl]morpholine-4-carboxylic acid tert-butyl ester (31C) (515mg, crude product), directly used in the next reaction.
  • reaction mixture was concentrated under reduced pressure to obtain 3,5-difluoro-N-( 2 H)methyl-4-(7-methyl-3-([(2S)-morpholin-2-yl]methyl) as a yellow solid (Yl)imidazo[1,2-a]pyridin-2-yl)benzamide hydrochloride (31D) (530mg, crude product), used directly in the next reaction.
  • reaction mixture was diluted with water (15.0 mL), and then extracted with ethyl acetate (10.0 mL ⁇ 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • reaction mixture was diluted with water (15.0 mL), and then extracted with ethyl acetate (10.0 mL ⁇ 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • reaction mixture was diluted with water (10.0 mL), and then extracted with ethyl acetate (10.0 mL ⁇ 3). The organic layers were combined, washed with water (10.0 mL ⁇ 3), and dried to obtain a crude product.
  • reaction mixture was diluted with water (10.0 mL), and then extracted with ethyl acetate (10.0 mL ⁇ 3). The organic layers were combined to obtain the crude product, which was separated and purified by high performance liquid chromatography.
  • (2S)-2-((7-ethyl-2-(2,3,6-trifluoro-4-(methylaminocarbonyl)phenyl)imidazo[1,2-a]pyridine-3- (Yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (1.00g, 2.03mmol) was dissolved in methanol (10mL), then lithium hydroxide monohydrate (100mg, 2.38mmol) and water (1.00g, 55.5mmol) were added The solution was then stirred at 25°C for 10 hours.
  • reaction mixture was diluted with water (10mL), then extracted with dichloromethane (10mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified twice by high performance liquid chromatography.
  • reaction mixture was diluted with water (10mL), and then extracted with dichloromethane (10mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by high performance liquid chromatography.
  • the reaction mixture was diluted with water (10mL), then extracted with dichloromethane (10mL ⁇ 3), and the organic layers were combined to obtain the crude product, which was separated and purified by high performance liquid chromatography.
  • reaction mixture was diluted with water (10mL), and then extracted with dichloromethane (10mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by high performance liquid chromatography.
  • Test Example 1 FLIPR method to determine the selectivity of hP2X3 antagonists to hP2X3 and hP2X2/3
  • the selectivity of human P2X3 receptor (hP2X3) antagonists to hP2X3 and hP2X2/3 was evaluated using FLIPR Calcium 4 Assay Kit (Molecular Devices, R8141) and FLIPR TETRA instrument (Molecular Devices, 0296).
  • the 1321N1 cells (adherent cells) stably transfected with hP2X3 and hP2X2/3 receptors were cultured and subcultured in culture flasks, digested and centrifuged about 24 hours before the experiment, resuspended in plating medium (DMEM+10% DFBS) and counted.
  • Table 1 The selectivity of test compounds to hP2X3 and hP2X2/3 antagonistic activity
  • the experimental results show that, compared with the control compound, the compound of the present invention exhibits better antagonistic activity against human P2X3, and I-1, I-2, I-7 ⁇ I-10, I-19, I- 23.
  • the selectivity of I-25, I-28 and I-33 to human P2X3 is significantly better than the control compound.
  • Test example 2 Rat and dog pharmacokinetic test
  • rat pharmacokinetic test 3 male SD rats, 180-240g, fasted overnight, orally administered 10mg/kg by gavage. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. The blood sample was centrifuged at 8000 rpm at 4°C for 6 minutes, and the plasma was collected and stored at -20°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and mix with 3 times the amount of water, and take an appropriate amount of the mixture Perform LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed with WinNonlin 7.0 software non-compartmental model.
  • the experimental results show that, compared with the control compound, the compounds I-1, I-2, I-7, I-8, I-9, I-11, I-23, I-28 and I-33 of the present invention show More excellent pharmacokinetic properties, especially in the canine pharmacokinetic test, compounds I-1, I-2, I-7, I-8, I-9, I-11, I-28 and I -33 showed a significant increase in exposure.
  • Test case 3 MDCK test
  • the cell density of MDCK-MDR1 was adjusted to 2.2 ⁇ 10 5 cells/mL and then seeded in Millicell 24-well cell plate. Add 400 ⁇ L/well of cell suspension to the top side of the filter membrane, add 25mL cell-free medium to the bottom side, replace the culture medium every other day, and then use the HBSS solution containing 0.3% DMSO and 5 ⁇ M fluorescent yellow to verify MDCK. Integrity of cell membrane layer and measurement of transmembrane resistance with Millicell ERS resistance meter.
  • Apparent permeability coefficient (Papp) (receiving side volume/(membrane area ⁇ incubation time)) ⁇ (receiving side drug concentration at the end of incubation)/(dosing side drug concentration at the beginning of incubation ⁇ dilution multiple)
  • Papp is ⁇ 5 ⁇ 10 -6 cm/sec: low permeability
  • Papp is 5-10 ⁇ 10 -6 cm/sec: medium permeability
  • Papp is> 10 ⁇ 10 -6 cm/sec: high permeability
  • test results show that, compared with the control compound, the apparent penetration of the compounds I-1, I-2, I-7, I-8, I-9, I-17, I-23 and I-33 of the examples of the present invention
  • the coefficient is higher, indicating that the permeability of the compound of the present invention is greatly improved compared with the control compound, which is more conducive to absorption and has better drug-making properties.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé imidazopyridine et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule I, un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, son procédé de préparation et son utilisation dans la préparation de médicaments.
PCT/CN2021/098296 2020-06-05 2021-06-04 Composé imidazopyridine et son utilisation WO2021244634A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010507978 2020-06-05
CN202010507978.2 2020-06-05

Publications (1)

Publication Number Publication Date
WO2021244634A1 true WO2021244634A1 (fr) 2021-12-09

Family

ID=78787385

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/098296 WO2021244634A1 (fr) 2020-06-05 2021-06-04 Composé imidazopyridine et son utilisation

Country Status (2)

Country Link
CN (1) CN113754654A (fr)
WO (1) WO2021244634A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805340A (zh) * 2021-01-22 2022-07-29 武汉人福创新药物研发中心有限公司 咪唑并吡啶类化合物的制备方法及其中间体
WO2022161462A1 (fr) * 2021-01-29 2022-08-04 上海海雁医药科技有限公司 Dérivé de morpholine, composition pharmaceutique et leur utilisation
WO2023020156A1 (fr) * 2021-08-20 2023-02-23 苏州璞正医药有限公司 Modulateur sélectif du récepteur p2x3 d'un dérivé d'imidazopyridine et son utilisation pharmaceutique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246888A (zh) * 2013-01-31 2016-01-13 尼奥迈德研究所 咪唑并吡啶化合物及其用途
WO2020174283A1 (fr) * 2019-02-25 2020-09-03 Bellus Health Cough Inc. Traitement avec des modulateurs de p2x3
CN112409331A (zh) * 2019-08-21 2021-02-26 上海翰森生物医药科技有限公司 杂环类衍生物抑制剂、其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246888A (zh) * 2013-01-31 2016-01-13 尼奥迈德研究所 咪唑并吡啶化合物及其用途
WO2020174283A1 (fr) * 2019-02-25 2020-09-03 Bellus Health Cough Inc. Traitement avec des modulateurs de p2x3
CN112409331A (zh) * 2019-08-21 2021-02-26 上海翰森生物医药科技有限公司 杂环类衍生物抑制剂、其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GABRIELLA MARUCCI, DIEGO DAL BEN, MICHELA BUCCIONI, ALEIX MARTí NAVIA, ANDREA SPINACI, ROSARIA VOLPINI, CATIA LAMBERTUCCI: "Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 29, no. 12, 2 December 2019 (2019-12-02), GB , pages 943 - 963, XP055704067, ISSN: 1354-3776, DOI: 10.1080/13543776.2019.1693542 *

Also Published As

Publication number Publication date
CN113754654A (zh) 2021-12-07

Similar Documents

Publication Publication Date Title
WO2019196812A1 (fr) Composé ciblant une dégradation protéique, utilisation antitumorale, intermédiaire de celui-ci et utilisation de l'intermédiaire
CN111471021B (zh) 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
WO2021244634A1 (fr) Composé imidazopyridine et son utilisation
JP2021506966A (ja) Ｎｌｒｐ３インフラマソーム調節剤としてのスルホニル尿素誘導体
WO2021027911A1 (fr) Nouvel inhibiteur de k-ras g12c spirocyclique
WO2022100623A1 (fr) Composés thiophène hétérocycliques substitués par azote et leur utilisation
TW201103909A (en) Quaternary ammonium salt compound
TW201524953A (zh) 治療活性化合物及其使用方法（二）
TW201211053A (en) Spiro compound and drug for activating adiponectin receptor
WO2020182018A1 (fr) Composé hétérocyclique azoté, son procédé de préparation et son utilisation
US20230227445A1 (en) Benzamide compound and use thereof
TW202315863A (zh) 脫磷酸裸蓋菇素之前藥及衍生物及其用途
WO2021249533A1 (fr) Composé modulateur du récepteur des oestrogènes et son utilisation
WO2019137201A1 (fr) Composé tétrahydropyridine hétéroarylo, procédé de préparation, composition pharmaceutique et application de celui-ci
WO2022253101A1 (fr) Composé pyridazinone utilisé comme inhibiteur de parp7
TW202110848A (zh) 取代的稠合雙環類衍生物、其製備方法及其在醫藥上的應用
WO2020244539A1 (fr) Dérivé de pyridone, son procédé de préparation et son application pharmaceutique
WO2022237858A1 (fr) Composé ayant une activité antitumorale et son utilisation
WO2022199599A1 (fr) Composé à substitution acryloyle, composition pharmaceutique le contenant et son utilisation
WO2022002097A1 (fr) Composé de pyrazolo[1,5-a]pyridine, son procédé de préparation et son utilisation
WO2019085996A1 (fr) Composés de pyridopyrimidine agissant en tant qu'inhibiteurs de la double kinase mtorc 1/2
CN107428682B (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
WO2021228216A1 (fr) COMPOSÉ BIARYLE CAPABLE DE SERVIR DE MODULATEUR DE RORγ
WO2021228217A1 (fr) COMPOSÉ ANILINE UTILISÉ COMME RÉGULATEUR DE RORγ
WO2022017442A1 (fr) Composé chimère bifonctionnel ciblant la dégradation protéique, son procédé de préparation et son utilisation médicale

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21818858

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21818858

Country of ref document: EP

Kind code of ref document: A1