WO2023020156A1 - Modulateur sélectif du récepteur p2x3 d'un dérivé d'imidazopyridine et son utilisation pharmaceutique - Google Patents

Modulateur sélectif du récepteur p2x3 d'un dérivé d'imidazopyridine et son utilisation pharmaceutique Download PDF

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WO2023020156A1
WO2023020156A1 PCT/CN2022/104594 CN2022104594W WO2023020156A1 WO 2023020156 A1 WO2023020156 A1 WO 2023020156A1 CN 2022104594 W CN2022104594 W CN 2022104594W WO 2023020156 A1 WO2023020156 A1 WO 2023020156A1
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alkyl
halogen
independently selected
alkoxy
deuterium
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PCT/CN2022/104594
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Chinese (zh)
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朱加望
姚瑶
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苏州璞正医药有限公司
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    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicine, and relates to a P2X3 receptor selective modulator compound of imidazopyridine derivatives, a preparation method, a pharmaceutical composition and an application for disease treatment.
  • P2X purinergic receptors belong to the ligand-gated ion channel family activated by ATP, and multiple members of this family have been cloned so far [Burnstock 2013, Front Cell Neurosci 7:227].
  • the composition of these ion channels can exist in homomeric and heteromeric forms [Saul 2013, Front Cell Neurosci 7:250].
  • Purine (such as ATP) has been considered as an important neurotransmitter, and through the action of different receptors, it shows a variety of different physiological and pathological effects [Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 2011, Prog Neurobiol 95:229-274; Jiang 2012, Cell Health Cytoskeleton 4:83-101].
  • P2X3 receptor is a protein encoded by the P2RX3 gene in the human body (Garcia-Guzman M, Stuhmer W, Soto F (September 1997)—Molecular characterization and pharmacological properties of the human P2X3 purinoceptor” Brain Res Mol Brain Res 47(1-2):59-66) Composition.
  • P2XR P2X receptors
  • COPD chronic obstructive pulmonary disease
  • P2X3 receptors play a key role in mediating the primary sensory effects of ATP (see Ford, Purinergic Signaling (2012) 8(Suppl 1): 3-26), which include cough, pruritus, pain, urinary tract disorders, and Sensation of other related disorders.
  • P2X3 receptors are predominantly located on small and medium diameter C- and A ⁇ fibers of sensory neurons in dorsal root ganglia (DRG) and intracranial sensory ganglia, as well as in the receptive fields of various tissues including skin and joints peripheral nerve endings.
  • P2X3R P2X3 receptor
  • P2X3R P2X3 receptor
  • Clinical trials have shown that P2X3 receptor (P2X3R) modulators can effectively treat patients with recurrent chronic cough (Abdulqawi et al., Supra; US Pat. 9,284,279), but side effects are significant, especially the problem of taste impact.
  • P2X3R highly active and highly selective P2X3 receptor
  • the present invention provides a heterocyclic compound as shown in formula I, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates , solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • Ring A is selected from C3-C12 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl;
  • n 1, 2, 3 or 4;
  • R 1 is independently selected from H, deuterium, halogen, -OH, -CN, -NH 2 , -NO 2 , unsubstituted or optionally substituted by one, two or more R 1 a from the following groups: C1 -C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C14 aryl, 5-14 membered hetero Aryl; or, when there are two adjacent R 1s , the adjacent two R 1s together with the directly connected ring carbon atoms form a C3 ⁇ C12 cycloalkyl, a C3 ⁇ C12 cycloalkenyl, a C3 ⁇ C12 C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl;
  • n 1, 2, 3 or 4;
  • Each R 2 is the same or different, independently selected from H, deuterium, halogen, -OH, -CN, -NH 2 , -NO 2 , unsubstituted or optionally replaced by one, two or more R 2 a
  • the following groups are substituted: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 alkoxy;
  • R 3 is independently selected from the following groups that are unsubstituted or optionally substituted by one, two or more R 3a : 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and the ring Alkyl and heterocycloalkyl can be further fused with 5-14 membered heteroaryl.
  • R 4 and adjacent R 2 together with the ring carbon atom to which it is directly attached form an unsubstituted or optionally substituted by one, two or more R 4a
  • the following groups C3-C12 cycloalkyl, C3-C12 cycloalkenyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl.
  • the heteroatom in the C3-C10 heterocycloalkyl, is one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1-3;
  • the C3-C10 heterocycloalkyl In the cycloalkenyl group the heteroatom is one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1 to 3; in the 5- to 14-membered heteroaryl group, the heteroatom is one of oxygen, sulfur and nitrogen One or more of them, the number of heteroatoms is 1-3.
  • Ring A is selected from C6 aryl or 5-6 membered heteroaryl
  • n 1, 2, 3 or 4;
  • R 1 is independently selected from H, deuterium, halogen, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R 1 a from the following groups: C1-C5 alkyl, C2- C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6 aryl, 5-6 membered heteroaryl; or, when there are adjacent When there are two R 1 , the adjacent two R 1 together with the directly connected ring carbon atoms form C3 ⁇ C6 cycloalkyl, C3 ⁇ C6 cycloalkenyl, C3 ⁇ C6 heterocycloalkyl, C3 ⁇ C6 Heterocycloalkenyl;
  • n 1, 2, 3 or 4;
  • Each R 2 is the same or different, independently selected from H, deuterium, halogen, -OH, -CN, -NH 2 , -NO 2 , unsubstituted or optionally replaced by one, two or more R 2 a
  • the following groups are substituted: C1-C5 alkyl, C1-C5 alkoxy;
  • R 3 is independently selected from the following groups that are unsubstituted or optionally substituted by one, two or more R 3a : 3-10 membered cyclic groups, 3-10 membered heterocyclic groups, and the cycloalkyl group ,
  • the heterocycloalkyl group can be further fused with a 5-6 membered heteroaryl group.
  • R 4 and adjacent R 2 together with the ring carbon atom to which it is directly attached form an unsubstituted or optionally substituted by one, two or more R 4a
  • the following groups C3-C12 cycloalkyl, C3-C6 cycloalkenyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl.
  • the heteroatom in the heterocycloalkyl group, is one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is 1 to 3, and the heteroatom is one of oxygen, sulfur and nitrogen.
  • the number of heteroatoms is 1 to 3; in the 5- to 14-membered heteroaryl group, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1 to 3 .
  • each R 1 is the same or different and is independently selected from methyl, ethyl, propyl, -F, -Cl, -CN;
  • each R 2 is the same or different and is independently selected from methyl, ethyl, propyl, -F, -Cl, -CN, methoxy;
  • R 3 is selected from the following structures:
  • the R3 is selected from the following structures:
  • the ring A choose from the following structures:
  • the heteroaryl group is a 5-membered heteroaryl group, and in the 5-membered heteroaryl group, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1-3, preferably selected from thienyl (the key on the left side of the structural formula and connected)
  • the heteroaryl group is a 6-membered heteroaryl group, and in the 6-membered heteroaryl group, the heteroatom is one or more of N, S and O, and the number of heteroatoms is 1-3; preferably selected from pyridyl pyrimidinyl (the key on the left side of the structural formula and connected).
  • ring A is preferably selected from phenyl (the key on the left side of the structural formula and connected )
  • ring A (including ring substitution forms) can be further selected from the following structures:
  • R 2 , n, and R 4 are as defined above.
  • M 1, M 2 are independently selected from CR 7 or N, S or a chemical bond; preferably CR 7 , S or a chemical bond; R 7 are independently selected from H, deuterium, halogen, hydroxy, cyano, nitro and optionally The following groups substituted by one, two or more Rm: amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 haloalkane C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cyano substituted C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 heterocyclyl, C6- C14 aryl, 5-14 membered heteroaryl, Rm is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6 alkyl, C2-C
  • R 4 is preferably selected from the following structures:
  • the compound of formula I is further selected from the following formula II:
  • R 1 is independently selected from the following groups: H, deuterium, halogen, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R 1 a: C1- C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6 aryl, 5-6 membered heteroaryl; Or, when there are two adjacent R 1s , the two adjacent R 1s together with the directly connected ring carbon atoms form a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 heterocyclic ring Alkyl, C3 ⁇ C6 heterocycloalkenyl;
  • n 1, 2, 3 or 4;
  • Each R 2 is the same or different, independently selected from H, deuterium, halogen, -OH, -CN, -NH 2 , -NO 2 , unsubstituted or optionally replaced by one, two or more R 2 a
  • the following groups are substituted: C1-C5 alkyl, C1-C5 alkoxy;
  • R 4 and adjacent R 2 together with the ring carbon atom to which it is directly attached form an unsubstituted or optionally substituted by one, two or more R 4a
  • the following groups C3-C12 cycloalkyl, C3-C6 cycloalkenyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl.
  • Ring B is selected from C3-C12 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl;
  • M 1, M 2 are independently selected from CR 7 or N, S or a chemical bond; preferably CR 7 , S or a chemical bond; R 7 are independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro and are optionally selected from one , The following groups substituted by two or more Rm: amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cyano substituted C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 heterocyclyl, C6-C14 Aryl, 5-14 membered heteroaryl, Rm independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6 alky
  • a 1 and A 2 are selected from C, N, O, S; preferably, A 1 is selected from O, and A 2 is selected from N;
  • x is an integer of 0 to 8; for example, 0, 1, 2, 3, 4, 5, 6, 7, 8.
  • R is selected from H, deuterium, halogen, C1-C6 alkyl, C3-12 cycloalkyl or C3-10 heterocycloalkyl;
  • y is an integer of 0-7; for example, 0, 1, 2, 3, 4, 5, 6, 7.
  • R6 is selected from H, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6 alkylsulfonyl, C1-C6 alkanoyl, C1-C6 alkyl, C1-C6 alkanoyl, C2-C6 Alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cyano substituted C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl.
  • the compound of formula I is further selected from the following formula III:
  • R 1 is independently selected from H, deuterium, halogen, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R 1 a from the following groups: C1- C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6 aryl, 5-6 membered heteroaryl; Or, when there are two adjacent R 1s , the two adjacent R 1s together with the directly connected ring carbon atoms form a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 heterocyclic ring Alkyl, C3 ⁇ C6 heterocycloalkenyl;
  • n 1, 2, 3 or 4;
  • Each R 2 is the same or different, independently selected from H, deuterium, halogen, -OH, -CN, -NH 2 , -NO 2 , unsubstituted or optionally replaced by one, two or more R 2 a
  • the following groups are substituted: C1-C5 alkyl, C1-C5 alkoxy;
  • R 4 and adjacent R 2 together with the ring carbon atom to which it is directly attached form an unsubstituted or optionally substituted by one, two or more R 4a
  • the following groups C3-C12 cycloalkyl, C3-C6 cycloalkenyl, C3-C10 heterocycloalkyl, C3-C10 heterocycloalkenyl, C6-C14 aryl or 5-14 membered heteroaryl.
  • x is an integer of 0-7; for example, 0, 1, 2, 3, 4, 5, 6, 7.
  • R is selected from H, deuterium, halogen, C1-C6 alkyl, C3-12 cycloalkyl or C3-10 heterocycloalkyl;
  • y is an integer of 0 to 5; for example, 0, 1, 2, 3, 4, 5.
  • R6 is selected from H, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6 alkylsulfonyl, C1-C6 alkanoyl, C1-C6 alkyl, C1-C6 alkanoyl, C2-C6 Alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cyano substituted C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl.
  • the A1 is selected from C, N, O, S; preferably, A1 is selected from C, O;
  • M 3 , M 4 , M 5 , M 6 are independently selected from CR 8 , S, N, NR 9 or chemical bonds;
  • R 8 , R 9 are each independently selected from H, deuterium, halogen, amino, hydroxyl, cyano, nitric acid C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted by cyano, C3-C12 cycloalkyl, 3-12 heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl, the amino , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1
  • the compounds represented by the formula I (including formula II-III) and their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, Among esters, prodrugs or pharmaceutically acceptable salts thereof, illustrative, non-limiting specific examples of compounds of formula I are shown below:
  • the nitrogen oxides of the heterocyclic compounds represented by the formula I are exemplified as follows:
  • heterocyclic compounds shown in formula I their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, Metabolites, esters, pharmaceutically acceptable salts or prodrugs and their substituents are selected to provide stable heterocyclic compounds as shown in formula I, their stereoisomers, geometric isomers isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, including but not limited to the compounds described in the embodiments of the present invention.
  • the present invention also includes isotope-labeled heterocyclic compounds of the present invention as shown in formula I, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, Metabolites, esters, pharmaceutically acceptable salts or prodrugs wherein one or more atoms are replaced by one or more atoms having a specified atomic mass or mass number.
  • isotopes that may be incorporated into compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S and 36Cl).
  • Isotopically-labeled compounds of the invention are useful in assays of tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include3H and14C. Furthermore, in certain instances, substitution with heavier isotopes such as deuterium (2H or D) can afford increased metabolic stability, which affords therapeutic advantages such as increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of the invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the heterocyclic compounds represented by formula I their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically Acceptable salts or prodrugs can be synthesized by methods including methods similar to well-known methods in the chemical field, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, especially according to the description herein.
  • Starting materials are generally from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (available through SciFinder, Reaxys online database).
  • the heterocyclic compound shown in formula I can also be obtained by modifying the periphery of the prepared heterocyclic compound shown in formula I using conventional methods in the art Other said heterocyclic compounds as shown in formula I.
  • the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in Formula I.
  • the following reaction schemes and examples serve to further illustrate the present invention.
  • the present invention also provides the heterocyclic compounds represented by the formula I and their racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites,
  • the preparation method of ester, prodrug or its pharmaceutically acceptable salt comprises the steps:
  • the imidazopyridine ring-containing structure and the benzene ring-containing structure are reacted in a suitable reagent, and the corresponding substitution structures are sequentially introduced through a suitable reaction; optionally, under suitable conditions, the above Protecting group, deprotecting group step.
  • the present invention further provides a pharmaceutical composition, which comprises the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide Compounds, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
  • the carrier in the pharmaceutical composition is "acceptable” in that it is compatible with (and preferably, capable of stabilizing) the active ingredients of the composition and is not deleterious to the subject being treated.
  • One or more solubilizing agents can be used as pharmaceutical excipients for the delivery of the active compounds.
  • the present invention further provides the compound of formula I and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or Use of its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or conditions mediated by P2X3 receptors (P2X3R).
  • P2X3 receptors P2X3 receptors
  • the present invention further provides the compound of formula I and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or Use of its pharmaceutically acceptable salt or the pharmaceutical composition in preparing a P2X3 modulator.
  • the present invention also provides a method for treating a disease or condition comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention alone, or optionally, in combination with another compound of the present invention.
  • a therapeutically effective amount of at least one compound of the present invention alone, or optionally, in combination with another compound of the present invention.
  • a combination of a compound and/or at least one other type of therapeutic agent is
  • the diseases or conditions include but are not limited to cough, pain, urinary incontinence, dysuria, endometriosis, skin itching.
  • the antipruritic includes skin pruritus, pruritus of psoriasis, atopic dermatitis, seborrheic dermatitis or stasis dermatitis.
  • said pain comprises migraine, endometriosis pain.
  • said cough comprises chronic recurrent cough.
  • the compounds of the invention may be used in combination with additional therapeutic agents.
  • the present invention further provides a method for preventing and/or a disease or condition mediated by P2X3 receptors (P2X3R), said method comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound of the invention.
  • P2X3R P2X3 receptors
  • the present invention provides combined formulations of a compound described herein and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Enantiomer refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • Diastereoisomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist.
  • each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototro pictautomers
  • Valen cetautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • substituted means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
  • a substituent may substitute at each substitutable position of the substituent. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.
  • C1 ⁇ C6 alkyl or “C1-6 alkyl” may be in the form of a straight chain or a branched chain, especially referring to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl; "C1-4 alkyl” specifically refers to independently disclosed methyl, ethyl, C3 alkyl (ie propyl, including n-propyl and isopropyl), C4 alkyl (ie butyl, including n-propyl butyl, isobutyl, sec-butyl and tert-butyl).
  • linking substituents are described.
  • the Markush variables recited for that group are to be understood as linking groups.
  • the Markush group definition for that variable recites “alkyl” or “aryl,” it is understood that “alkyl” or “aryl” respectively represents the linking group.
  • alkyl used in the present invention means containing 1 to 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms), saturated A linear or branched monovalent hydrocarbyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl Base, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2- Methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,
  • alkyl group when an alkyl group is clearly indicated as a linking group, the alkyl group represents a linked alkylene group, for example, the group "halo-C1 ⁇ C6 alkyl"
  • alkylene means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene (-CH2-), ethylene (including -CH2CH2- or -CH(CH3)-), isopropylidene (including -CH(CH3)CH2- or -C (CH3)2-) and so on, similarly, the terms “alkenylene” and “alkynylene” are unsaturated divalent groups.
  • alkenyl denotes a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms), There is at least one unsaturated site, that is, a carbon-carbon sp2 double bond, which includes the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • alkynyl includes both straight and branched chain alkynyl groups.
  • C2-12 alkynyl has 2 to 12 carbon atoms (for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms) and one or two triple bonds, which It may be, but is not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl, and hexynyl.
  • alkoxy or "alkyl-O-" means that an alkyl group is attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has a meaning as described herein.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, and the like.
  • haloalkyl denotes an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoro Methyl, trifluoromethoxy, etc.
  • C 3-12 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as decahydronaphthalene rings.
  • cycloalkenyl denotes a monocyclic, unsaturated carbocycloalkenyl group containing 3-12 ring carbon atoms (eg "C3-C12 cycloalkenyl” or preferably “C3-C6 cycloalkenyl”) .
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cyclohexadienyl, and the like.
  • heterocycloalkyl refers to a saturated monocyclic or bicyclic ring system containing 3-10 ring carbon atoms (eg 3, 4, 5, 6, 7, 8, 9, 10 ring carbon atoms), It may include fused, bridged, or spiro ring systems (e.g. bicyclic ring systems ("bicyclic heterocycloalkyl”); which contain 3-10 ring carbon atoms and at least one compound selected from the group consisting of nitrogen, sulfur and oxygen (“C3-C10 heterocycloalkyl”).
  • a heterocycloalkylbicyclic ring system may include one or more heteroatoms in one or both rings.) and is saturated.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • Ring nitrogen atoms can optionally be oxidized to N-oxides.
  • the heterocycloalkyl is a C3-C5 heterocycloalkyl, which means that the heterocycloalkyl contains 3-5 ring carbon atoms and at least one ring heteroatom selected from O, S and N.
  • heterocycloalkyl groups include, but are not limited to: oxiranyl, thietanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl , tetrahydrofuryl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, oxazinyl, thiomorpholinyl and piperazinyl, etc.
  • exemplary C3-C9 heterocycloalkyl groups include, but are not limited to, the above-mentioned C3-C5 heterocycloalkyl groups together with azepanyl, oxepanyl, thiepanyl Heptyl, Diazacycloheptyl, Azacyclohexyl, Oxacyclocantetraalkyl, Thiecanetetraalkyl, Quinuclidinyl, Octahydroindolyl, Octahydroisoindoyl Indolyl, decahydroquinolinyl, decahydroisoquinolinyl, or isomers and stereoisomers thereof.
  • heterocycloalkenyl refers to a monocyclic or bicyclic ring system containing a partially unsaturated alkenyl group, which contains 3-10 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10 ring carbon atoms) and at least one ring atom selected from nitrogen, sulfur, and oxygen atoms (“C3-C9 heterocycloalkenyl”); wherein the heterocycloalkenyl is non-aromatic and does not contain any aromatic ring.
  • the sulfur atom of the ring can be optionally oxidized to S -Oxide.
  • the nitrogen atom of the ring can optionally be oxidized to N-oxide.
  • the heterocycloalkenyl is preferably C3 ⁇ C5 heterocycloalkenyl; Examples include, but are not limited to, dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazole Dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, thiazolyl Fyranyl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxaziny
  • exemplary C3 ⁇ C9 heterocycloalkenyl groups include, but are not limited to, the above-mentioned C3 ⁇ C5 heterocycloalkenyl groups together with octahydroisoquinolyl, 3H-indolyl, dihydroisoquinolyl, dihydroquinolyl Or 4H-quinazinyl, or its isomers and stereoisomers.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl means a monocyclic or bicyclic ring containing 6-14 ring atoms (e.g. 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms), or 6-10 ring atoms and tricyclic carbon ring systems.
  • aryl groups may include phenyl, naphthyl and anthracenyl. .
  • heteroaryl denotes monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms (eg, for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms) , wherein at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, sulfur. Unless otherwise stated, said heteroaryl groups may be attached to the rest of the molecule (eg, the main structure in the general formula) through any reasonable point (could be C in CH, or N in NH).
  • Examples include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, etc.
  • Benzimidazolyl also include, but are by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl, oxoindolyl, imidazopyridyl, pyrazolopyridyl, Pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl and the like.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, etc., when administered to a human.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • prodrug used in the present invention means that a compound is transformed into a compound represented by formula I in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs with phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, Carbamates and amino acid esters.
  • a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound.
  • Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups.
  • prodrugs can be found in the following literature: T. Higuchiand V. Stella, Pro-drugsas Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carrie rsin Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Designa nd Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal, 15, 230 Medicine -2345.
  • metabolite used in the present invention refers to the product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid-formed salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as ethyl Salt, oxalate, maleate, tartrate, citrate, succinate, malonate; or obtain these salts by other methods such as ion exchange method described in books and literature.
  • salts include, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactate, Laurate, Lauryl Sulfate , malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropane salt, picrate, pi
  • Salts obtained by reaction with an appropriate base include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts.
  • the present invention also contemplates quaternary ammonium salts of any compound containing an N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metals which can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1- 8 sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • esters in the present invention refers to in vivo hydrolyzable esters formed from compounds containing hydroxyl or carboxyl groups. Such esters are, for example, pharmaceutically acceptable esters which hydrolyze in the human or animal body to yield the parent alcohol or acid.
  • the compounds of formula I of the present invention contain a carboxyl group, which can form in vivo hydrolyzable esters with suitable groups, such groups include, but are not limited to, alkyl, arylalkyl and the like.
  • N-oxide in the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with m-chloroperoxybenz
  • any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, “treating” refers to preventing or delaying the onset, development or worsening of a disease or condition.
  • the biological activity of the compounds of the invention can be assessed by using any conventionally known method. Suitable detection methods are well known in the art. For example, the P2X3 inhibitory activity, pharmacokinetic activity and/or hepatic microsomal stability of the compounds of the present invention can be tested by appropriate conventional methods.
  • the detection method provided in the present invention is presented as an example only and does not limit the present invention.
  • Compounds of the invention are active in at least one assay provided herein.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the compound of formula I provided by the invention has high biological activity and high selectivity of P2X3 receptor (P2X3R) modulator, and better physical properties and other druggability.
  • P2X3R P2X3 receptor
  • the compound of formula I provided by the present invention provides an effective, safe and low-side effect drug for the prevention and treatment of cough, pain, itching and urinary tract diseases.
  • Example 1 compound under nitrogen atmosphere, compound 1-5 (500mg, 1.03mmol, 1.0eq), 1,2-diaminoethane (124mg, 2.06mmol, 2.0eq) was dissolved in toluene (10mL), AlMe 3 (2M in toluene, 1.03mL, 2.06mmol, 2.0eq) was slowly added dropwise in an ice bath and then refluxed for 16 hours. Concentration under reduced pressure and separation and purification by HPLC (0.1% TFA/H 2 O/ACN) gave a white solid, namely the compound of Example 1 (6.77 mg, yield 1.3%).
  • Example 4 HATU (60mg, 0.16mmol, 1.5eq) and DIPEA (42mg, 0.05 mL, 0.32mmol, 3.0eq), stirred at room temperature for 2 hours. Diluted with water, extracted with EtOAc (10mL*2), combined the organic phases, dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure, separated by HPLC and lyophilized to obtain a white solid, namely Example 4 compound (20mg, yield 37 %).
  • Synthesis of Compound 5-2 Add MeNH 2 (414mg, 4.00mmol, 1.0eq, 30% in EtOH) to a solution of Compound 5-1 (585mg, 4.00mmol, 1.0eq) in ethanol (10mL) at room temperature . Then the mixture was heated to 120°C for 16 hours. After cooling to room temperature, the precipitated solid by filtration was the target compound 5-2 (217 mg, yield 42.0%, purity>95%).
  • Example 6 Compound: Compound 6-7 (78mg, 0.19mmol, 1.00eq.) was dissolved in DMF (3mL), then TEA (92 mg, 0.94mmol, 5.0eq.), methyl chloroformate (27mg , 0.28mmol, 1.5eq.), stirred at room temperature for 3 hours. Concentrated under reduced pressure, the residual crude product was purified by reverse phase (methanol/water, 0%-100% 35min, 49%), and freeze-dried to obtain compound Example 6 as a white solid (15.0mg, 0.03mmol, yield 18%, purity 95.3%) .
  • Example 9 Compound: At room temperature, compound 5-2A (50 mg, 0.125 mmol, 1.0 eq) was added to a solution of compound 9-2 (37.0 mg, 0.280 mmol, 2.0 eq) in ethanol (1.0 mL), and then The mixture was heated to 120°C and reacted for 16 hours. After the reaction solution returned to room temperature, it was concentrated under reduced pressure. The crude product was separated and prepared by Pre-HPLC and freeze-dried to obtain a white solid, namely the compound of Example 9 (3.58mg, yield 5.7%, purity 96.26%) ).
  • Example 10 Compound 10-5 (26mg, 0.069mmol, 1.0eq), 1,1-bis(methylthio)-2-nitrosoethylene (34mg, 0.207mmol, 3.0eq) under microwave conditions for 120 °C for 1 hour. Add MeNH 2 (0.07mmol, 1.0eq, 30% in EtOH), microwave reaction at 100°C for 1 hour, return to room temperature, filter, and spin dry under reduced pressure. The crude product was separated by Pre-HPLC to obtain a white solid, namely the compound of Example 10 ( 1.53mg, yield 4.65%).
  • reaction solution was quenched with water (50 mL), extracted with DCM (50 mL*2), and washed with saturated brine (40 mL).
  • reaction solution was diluted with aqueous solution (100 mL), extracted with DCM (100 mL*3), and washed with saturated brine (100 mL).
  • the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 12-2 (4.95 g, 23.00 mmol, yield 100.00%) as a yellow oil, which was directly used in the next step.
  • Synthesis of compound 12-7 Dissolve compound 12-6 (7.65g, 16.57mmol) and compound 12-3 (3.5g, 16.57mmol) in toluene (100mL), add compound 12-6A, nitrogen atmosphere, room temperature Add CuCl (492.05mg, 4.97mmol) and Cu(OTf) 2 (1.80g, 4.97mmol), replace with nitrogen and keep under nitrogen atmosphere, stir at 85°C for 10min, then add DMAC (721.68mg, 8.28mmol, 770.21 ⁇ L ) into the above reaction solution, and stirred at 85° C.
  • reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL*2), and washed with saturated brine (50 mL).
  • Example 12 Compound 12-9 (120mg, 0.16mmol) was dissolved in trifluoroacetic acid (4.50g, 39.48mmol, 2.92mL), the reaction solution was stirred at 50°C for 12h, and the reaction solution was concentrated under reduced pressure to obtain the crude product Pre-HPLC separation prepared a white solid, namely the compound of Example 12 (12.2 mg, 0.02 mmol, yield 22.50%, purity 100%).
  • Example 13 Compound 13-9 (1.59g, 2.15mmol, 1eq) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 12h, and the reaction solution was concentrated under reduced pressure to obtain a crude product that was separated by pre-HPLC A white solid was prepared, namely the compound of Example 13 (52.44 mg, 0.1 mmol, 4.6% yield, 99.136% purity).
  • Example 14 Compound 14-2 (230mg, 0.31mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 12 (59.42mg, 0.11mmol, yield 37.49%, purity 97.98%).
  • Example 15 Compound 15-2 (220mg, 0.3mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 15 (48.84mg, 0.09mmol, yield 31.75%, purity 96.558%).
  • Example 16 Compound 16-2 (240mg, 0.32mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 12h, the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC to obtain a white The solid is the compound of Example 16 (40.65mg, 0.08mmol, yield 25.07%, purity 100%).
  • Example 17 Compound 17-2 (0.119g, 0.16mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC.
  • White solid namely the compound of Example 17 (48.27mg, 0.09mmol, yield 57.40%, purity 95.609%).
  • Example 18 Compound 18-2 (230mg, 0.31mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 18 (79.52 mg, 0.15 mmol, yield 49.21%).
  • Example 19 Compound 19-2 (0.11g, 0.15mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC. White solid, namely the compound of Example 19 (37.88 mg, 0.07 mmol, yield 49.38%).
  • Example 20 Compound 20-4 (280mg, 0.34mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 20 (52.59 mg, 0.09 mmol, yield 26.36%).
  • Example 21 Compound 21-3 (0.07g, 0.09mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC.
  • White solid namely the compound of Example 21 (8.35mg, 0.02mmol, chanlü116.82%).
  • Example 22 Compound 22-3 (155mg, 0.20mmol) was dissolved in trifluoroacetic acid (2mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 22 (67.77 mg, 0.12 mmol, yield 62.12%).
  • Example 23 Compound 23-2 (30mg, 0.04mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 23 (10.14mg, 0.02mmol, yield 49.34%, purity 99.69%).
  • Example 24 Compound 24-2 (0.25g, 0.31mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC. White solid, namely the compound of Example 24 (82.43mg, 0.14mmol, yield 46.46%, purity 99.5%).
  • Example 25 Compound 25-2 (180mg, 0.22mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 1h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 25 (65.4 mg, 0.11 mmol, yield 51.42%, purity 99.94%).
  • Example 27 Dissolve compound 27-4 (45mg, 0.06mmol) in trifluoroacetic acid (1mL), stir the reaction solution at 50°C for 1h, adjust the pH of the reaction solution to 7, add saturated NaHCO 3 aqueous solution to dilute, and use Dichloromethane extraction (4mL*3), the organic phase was dried with Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product that was separated by pre-HPLC to obtain a white solid, that is, compound of Example 27 (4.29mg, 0.007mmol, yield 13.07%, purity 96.82%).
  • Example 28 Compound 28-2 (0.168g, 0.22mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC. White solid, namely the compound of Example 28 (50.83mg, 0.09mmol, yield 42.49%, purity 95.9%).
  • Example 30 Compound 30-2 (97mg, 0.12mmol) was dissolved in trifluoroacetic acid (1mL), the reaction solution was stirred at 50°C for 2h, and the reaction solution was concentrated under reduced pressure to obtain a crude product which was separated by pre-HPLC to obtain a white The solid is the compound of Example 30 (22.5mg, 0.04mmol, yield 32.86%, purity 98.13%).
  • Synthesis of Compound 52-2 Synthesis of Compound 52-2: Compound 12-3 (38.90g, 184.12mmol, 1eq), Compound 52-1b (40.41g, 184.12mmol, 1eq), Compound 52-1a (23.67g , 184.12mmol, 1eq) was dissolved in DMSO (400mL), under nitrogen atmosphere, CuCl (1.82g, 18.41mmol, 440.28uL, 0.1eq) and Cu(CF 3 SO 3 ) 2 (6.66g, 18.41mmol, 0.1eq), replaced with nitrogen and maintained under nitrogen atmosphere, stirred at 85°C for 12h, diluted the reaction solution with saturated ammonium chloride (800mL), extracted with ethyl acetate (800mL*2), and washed with saturated brine (500mL*2 )washing.
  • DMSO 400mL
  • Example 52 NH 3 .H 2 O (10.0 mL) was directly added to the reaction solution in the previous step at 0°C, the mixture was stirred at 0°C for 2 h, and the reaction solution was concentrated under reduced pressure to obtain a crude product that was separated by pre-HPLC to prepare the compound Example 52 (10.24g).
  • Example 53 Dissolve Example 52 (200mg, 400.3umol, 1eq) in dichloromethane (5mL) solution, add m-CPBA (85.35mg, 420.4umol, 85% purity, 1.05eq) at 0°C , the reaction solution was stirred, and gradually warmed to room temperature and stirred for 2 h, and the reaction solution was concentrated under reduced pressure to obtain a crude product separated by pre-HPLC to prepare Compound Example 53 (130 mg).
  • m-CPBA 85.35mg, 420.4umol, 85% purity, 1.05eq
  • the P2X3 receptor antagonist properties of the compounds of the present invention are determined, and the compounds can inhibit the increase of intracellular calcium induced by the activation of hP2X3 expressed in HEK293 cells.
  • HEK293/hP2X3 cells were cultured in a cell culture incubator (5% CO 2 , 37°C) supplemented with 10% fetal bovine serum (Giboco, 10099-141C), 1% penicillin/streptomycin (invitrogen) and genetic mold Cultured in G-418 (invitrogen, 10131027). Twenty-four hours before the experiment, the cells were seeded into 384-well culture plates at a density suitable to achieve the desired final confluency.
  • Example 9 0.032 Example 10 greater than 10 Example 11 0.042 Example 12 0.0038 Example 13 0.18 Example 14 0.0015 Example 15 4.12 Example 16 0.021 Example 17 1.45 Example 18 0.0032 Example 19 0.014 Example 20 greater than 10 Example 21 0.034 Example 22 8.23 Example 23 0.0053 Example 24 0.0048 Example 25 0.014 Example 27 greater than 10 Example 28 0.0084 Example 30 0.0089 Example 52 0.019 Example 53 0.21
  • AF-219 has a good effect on refractory cough, but the problem of taste disturbance is seriously affected).
  • the P2X2/3 receptor selectivity of the compound of the present invention is determined, and the compound can inhibit the increase of intracellular calcium induced by the activation of hP2X2/3 expressed in HEK293 cells.
  • HEK293/hP2X2/3 cells were cultured in supplemented with 10% fetal bovine serum (Giboco, 10099-141C), 1% penicillin/streptomycin (invitrogen) and Cultured in geneticin G-418 (invitrogen, 10131027). Twenty-four hours before the experiment, the cells were seeded in 384-well culture plates at a density suitable to achieve the desired final confluency.
  • Cough suppression rate (average cough frequency of test substance group-average cough frequency of vehicle group)/average cough frequency of vehicle group*100%
  • SPF grade male SD rats (6-8 weeks) received adaptive drinking water training for 3 days immediately after entering the warehouse.
  • Water deprivation treatment (removal of drinking water bottles) was carried out overnight every day, and drinking water was given again from 8:30am to 5:30pm. This cycle was repeated for 3 days, and the left and right places of two bottles of water were changed every day. Animals could eat freely during the entire adaptive training period. All animal drinking bottles were removed 20 hours before the official experiment, and water was forbidden until the experiment was started.
  • all animals were randomly divided into groups, and the test compound or vehicle was administered before re-supplying water, and the administration was administered by a single intraperitoneal injection, and the administration time was determined according to the Tmax of the test compound.
  • Compound intravenous injection group vehicle: 5% DMSO+10% Solutol+85% Saline; number of animals: 3 ICR male mice, administered after fasting for 12 hours, and continued fasting for 4 hours after administration.
  • Oral administration of compounds Vehicle: 5% DMSO+10% Solutol+85% Saline; Number of animals: ICR male mice 3 Only, fast for 12 hours after administration, continue to fast for 4 hours after administration.
  • the blood was centrifuged to obtain plasma, the level of the administered compound in the plasma was determined by LC-MS, and the pharmacokinetic parameters were calculated.
  • mice 72 ICR mice (36 males/36 females) were used in the experiment, and were randomly divided into 4 groups according to the animal body weight measured before administration (D-1). /9 females), while the fourth group (300mg/kg) was subjected to toxicological studies.
  • Group 1 was given 0.5% (w/v) methylcellulose aqueous solution as vehicle control, and groups 2, 3 and 4 were given 100 mg/kg, 200 mg/kg and 300 mg/kg of the compound of the present invention, respectively.
  • Animals in groups 1-4 were administered once a day for 2 consecutive weeks, a total of 14 administrations. Intragastric administration, the administration volume is 10ml/kg.
  • clinical observation body weight, food intake, water intake, blood routine, blood biochemistry, coagulation factors, toxicokinetics, and general anatomical observation were tested.
  • Table 7 The toxicokinetic parameters of the compound of the present invention 300mg/kg dose group after the last medicine

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Abstract

La présente invention concerne un modulateur sélectif du récepteur P2X3 d'un dérivé d'imidazopyridine, et plus précisément un composé représenté par la formule I et un racémate, un stéréoisomère, un tautomère, un marqueur isotopique, un solvate, une forme polymorphe, un ester, un promédicament ou un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'une composition pharmaceutique le comprenant, son procédé de préparation et une utilisation pharmaceutique de celui-ci. La structure de formule I est la suivante :
PCT/CN2022/104594 2021-08-20 2022-07-08 Modulateur sélectif du récepteur p2x3 d'un dérivé d'imidazopyridine et son utilisation pharmaceutique WO2023020156A1 (fr)

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CN111601601A (zh) * 2017-09-18 2020-08-28 贝卢斯医疗咳嗽病公司 选择性p2x3调节剂
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CN113912601A (zh) * 2020-07-10 2022-01-11 上海拓界生物医药科技有限公司 一类新的咪唑并[1,2-a]吡啶类衍生物、其制备方法及医药用途

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EP3863640A4 (fr) * 2018-10-10 2022-07-06 Bellus Health Cough Inc. Traitement du prurit avec des antagonistes des récepteurs p2x3
WO2020135771A1 (fr) * 2018-12-29 2020-07-02 武汉朗来科技发展有限公司 Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation
AU2020228760A1 (en) * 2019-02-25 2021-09-23 Glaxosmithkline Intellectual Property (No. 3) Limited Treatment with P2X3 modulators
CN113549068B (zh) * 2020-04-24 2022-12-02 上海拓界生物医药科技有限公司 一类新型咪唑并吡啶化合物、其制备方法及其在医药上的应用
CN114085220B (zh) * 2020-06-22 2023-06-16 上海海雁医药科技有限公司 取代的吗啉-4-羧酸酯衍生物、其组合物及医药上的用途
EP4169921A4 (fr) * 2020-06-29 2024-06-19 Wuhan Ll Science And Tech Development Co Ltd Forme cristalline d'un composé hétérocyclique, son procédé de préparation et son utilisation

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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
CN111601601A (zh) * 2017-09-18 2020-08-28 贝卢斯医疗咳嗽病公司 选择性p2x3调节剂
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
WO2021161105A1 (fr) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Modulateurs de p2x3
CN113754654A (zh) * 2020-06-05 2021-12-07 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及其用途
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