WO2024255859A1 - Composé hétérocyclique utilisé en tant qu'antagoniste d'at2r et son utilisation - Google Patents

Composé hétérocyclique utilisé en tant qu'antagoniste d'at2r et son utilisation Download PDF

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WO2024255859A1
WO2024255859A1 PCT/CN2024/099297 CN2024099297W WO2024255859A1 WO 2024255859 A1 WO2024255859 A1 WO 2024255859A1 CN 2024099297 W CN2024099297 W CN 2024099297W WO 2024255859 A1 WO2024255859 A1 WO 2024255859A1
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alkyl
cycloalkyl
compound
ring
alkoxy
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张学军
臧杨
付浩亮
孙小川
安可
孙红娜
李莉娥
杨俊�
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • patent application number 202410669486.1 entitled “Heterocyclic compounds as AT2R antagonists and their uses”, filed with the State Intellectual Property Office of China on May 27, 2024;
  • the present invention belongs to the field of medicine, and in particular, relates to a heterocyclic compound as an angiotensin II (Ang II) type 2 receptor (AT2R) antagonist and its use.
  • Ang II angiotensin II
  • A2R angiotensin II type 2 receptor
  • Neuropathic pain is a chronic pain disease caused by primary damage or dysfunction of the nervous system. It can be divided into peripheral neuropathic pain and central neuropathic pain according to the location of the lesion. Trauma, inflammation, infection or compression can cause neuropathic pain, such as diabetic neuropathy (DNP), postherpetic neuralgia (PHN), primary neuropathy, secondary neuropathy, peripheral neuropathy, and neuropathy caused by mechanical nerve damage or biochemical nerve damage.
  • DNP diabetic neuropathy
  • PPN postherpetic neuralgia
  • primary neuropathy secondary neuropathy
  • peripheral neuropathy and neuropathy caused by mechanical nerve damage or biochemical nerve damage.
  • the drugs used in clinical treatment of neuropathic pain mainly include antiepileptic drugs, antidepressants and narcotic analgesics, such as gabapentin, pregabalin, tricyclic antidepressants, etc.
  • Ang II angiotensin II receptors
  • AT1R Ang II type 1 receptor
  • AT2R Ang II type 2 receptor
  • Ang II has been shown to regulate blood pressure, body fluid and electrolyte homeostasis in many organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract and reproductive organs.
  • GPCRs G protein-coupled receptors
  • AT1R is expressed throughout the life cycle and is mainly responsible for regulating blood pressure. Its blockers are widely used as antihypertensive drugs in clinical practice. AT1R controls most of the physiological effects of Ang II.
  • AT2R is mainly expressed in embryonic tissues and is related to blood pressure regulation, nerve growth, pain control and myocardial regeneration. Drugs targeting AT2R can improve cardiovascular function and relieve neuropathic pain.
  • AT2R is related to pain mechanisms in the nervous system and is mainly expressed in dorsal root ganglia and trigeminal ganglia. Compared with normal nerves, damaged nerves and painful neuromas have higher AT2R expression.
  • the second messenger pathway activated by G protein-coupled receptors can sensitize ion channels in neurons. Sensitization leads to ion channel activation, which in turn excites neurons.
  • AT2R antagonists have been proven to be useful for pain relief through animal and clinical trials.
  • the object of the present invention is to provide a compound as an AT2R antagonist and its use.
  • the compound has a structure as shown in the first aspect of the present invention, and the compound can be used to prepare a drug, a pharmaceutical composition or a preparation for treating and/or preventing a disease or condition associated with AT2R; or to treat and/or prevent a disease or condition associated with AT2R.
  • Ring A is selected from a 5-6 membered heteroaromatic ring
  • n is selected from 0, 1, 2, 3 or 4; when there are multiple substituents R 1 , the R 1 are the same or different;
  • R 2 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring; the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring is optionally substituted by 1, 2, 3, 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl; and R 2 is not methyl, ethyl, isopropyl, -CF 3 ;
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; when there are multiple substituents R 2 , the R 2 are the same or different;
  • Ring E is selected from a benzene ring or a 6-membered heteroaromatic ring
  • R3 is selected from halogen, hydroxyl, cyano, dimethylamino, C1- C6 alkyl, C1 - C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy , C3 - C7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, cyano, C1 - C6 alkyl, C1 - C6 alkoxy , C3 - C7 cycloalkyl;
  • p is selected from 0, 1, 2, 3 or 4; when there are multiple substituents R 3 , the R 3 are the same or different;
  • M is selected from carboxylic acid, -CONHSO 2 R 5 , -SO 2 NHCOR 5 , tetrazole or tetrazole bioisostere; the bioisostere includes but is not limited to phosphoric acid,
  • R 5 is selected from H, OH, NH 2 , ONa, OK (potassium ion), C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, 5-6 membered heterocycle; the C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, 5-6 membered heterocycle are optionally substituted with 1-4 substituents selected from the following groups: halogen, amino, C 3 -C 7 heterocycloalkyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy.
  • the ring A is a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring contains 1, 2, or 3 heteroatoms;
  • the heteroatom is selected from N, O, and S; more preferably, the heteroatom is N.
  • the ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine;
  • the ring A is selected from: pyridine, pyrimidine, pyridazine, pyrazine.
  • the ring A is selected from
  • the ring E is a benzene ring or a 6-membered heteroaromatic ring
  • the 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms
  • the heteroatom is selected from N, O and S.
  • the ring E is selected from benzene ring, pyridine, pyrimidine and pyridazine.
  • the ring E is selected from a benzene ring.
  • n is selected from 0, 1, 2, 3 or 4.
  • R 1 is selected from halogen, methyl, halomethyl, methoxy; and m is selected from 0.
  • the compound is selected from the following structures:
  • Ring A, M, L, R 1 , R 3 , m and p are as defined in the first aspect of the present invention.
  • the compound is selected from the following structures:
  • Ring A, M, L, R 1 , R 3 , m and p are as defined in the first aspect of the present invention.
  • the compound is selected from the following structures:
  • M and R2 are as defined in the first aspect of the present invention.
  • the compound of formula IV has structure IVa, IVb:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • it has structure IV-2a, IV-2b, IV-3a or IV-3b:
  • R 2 is selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocycle, 5-6 membered heteroaromatic ring, benzene ring; the C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocycle, benzene ring are optionally substituted by 1, 2, 3, 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl; and R 2 is not methyl, ethyl, isopropyl, -CF 3 .
  • n is selected from 1, 2, and 3.
  • n 1
  • said R 2 is selected from CH 2 F, CHF 2 , C 1 -C 3 alkyl-C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 1 -C 3 alkyl-C 3 -C 7 cycloalkyl;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8.
  • said R 2 is selected from CH 2 F, CHF 2 , methyl-methoxy, cyclopropyl.
  • R 2 is selected from CH 2 F and CHF 2 .
  • said R 2 is selected from CHF 2 .
  • the R 3 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl;
  • p is selected from 0, 1, 2, 3 or 4.
  • R 3 is selected from F, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, methyl-cyclopropyl; p is selected from 1, 2, 3.
  • R 3 is selected from F, methyl, trifluoromethyl, isobutyl, isobutyl substituted with F, methyl-cyclopropyl; p is selected from 2.
  • p is selected from 2
  • R 3 is selected from F and isobutyl.
  • the M is selected from carboxylic acid, -CONHSO 2 R 5 , -SO 2 NHCOR 5 , tetrazole; and the R 5 is selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl.
  • the M is selected from carboxylic acid, tetrazole, and -CONHSO 2 CH 2 CH 3 .
  • the M is selected from carboxylic acid and tetrazole.
  • the M is selected from tetrazole.
  • the R 2 is selected from CHF 2
  • the M is selected from tetrazole and carboxylic acid.
  • the R 2 is selected from CH 2 F
  • the M is selected from carboxylic acid, tetrazole, and -CONHSO 2 CH 2 CH 3 .
  • the R 2 is selected from CH 2 F
  • the M is selected from carboxylic acid and tetrazole.
  • the R 2 is selected from CH 2 F
  • the M is selected from tetrazole.
  • the R 2 is selected from CH 2 F
  • the M is selected from carboxylic acid
  • the R 2 is selected from CH 2 F
  • the M is selected from -CONHSO 2 CH 2 CH 3 .
  • the R 2 is selected from cyclopropyl
  • the M is selected from tetrazole.
  • said R 2 is selected from The M is selected from tetrazole.
  • L is absent or is selected from carbonyl, methylene, -CH2CH2- , -CH( CH3 )- , -CH2CH2CH2- , -CH2CH ( CH3 )-, -O - CH2- .
  • the L is selected from methylene, -CH 2 CH 2 -, -CH(CH 3 )-, and -O-CH 2 -.
  • said L is selected from methylene.
  • the compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, A pharmaceutically acceptable salt or prodrug, characterized in that the compound comprises:
  • the compound of formula I is characterized in that the compound comprises:
  • the present invention provides a pharmaceutical composition, comprising the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier
  • the compound shown in formula I as described in the first aspect is used to prevent and/or treat AT2R-mediated diseases, and/or prevent and/or treat diseases that expect or require reduced AngII effects.
  • the use described in the third aspect and the fourth aspect may further include at least one of the following technical features:
  • a compound of formula I as described in the first aspect its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, which is expected to be used for treating neuropathy or neuropathic pain.
  • Neuropathies that should be mentioned include primary neuropathies, secondary neuropathies, peripheral neuropathies, neuropathies caused by mechanical or biochemical nerve damage or diabetic-related neuropathies.
  • Neuropathic pain that should be mentioned includes postherpetic neuralgia or diabetic neuropathy.
  • the compound of formula I described in the first aspect of the present invention is suitable for the treatment and/or preventive treatment of the above-mentioned diseases.
  • the fifth aspect of the present invention provides a method for treating a disease, wherein the disease is an AT2R-mediated disease, and/or a disease in which it is desired or necessary to reduce the effect of AngII, and/or a disease in which AT2R is expressed and inhibition is desired or necessary, the method comprising administering a therapeutically effective amount of the compound of formula I described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect to a person suffering from or susceptible to the disease.
  • the disease comprises an AT2R-mediated disease, a disease in which a reduction in the action of Ang II is desired or required.
  • the disease comprises primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, or diabetic-related neuropathy.
  • the disease comprises postherpetic neuralgia or diabetic neuropathy.
  • the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • the term "one or more” refers to one substitution to the maximum possible number of substitutions, i.e., replacing one hydrogen to all hydrogens are replaced by substituents.
  • the term "1-4" refers to 1, 2, 3 or 4 substitutions, i.e., 1, 2, 3 or 4 hydrogens are replaced by substituents.
  • saturated, partially saturated or unsaturated includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.
  • AT2 receptor and “AT2R” have the same definition.
  • bioisostere has the usual meaning in the art when used alone or as part of other substituents, and refers to a group or substituent with similar physical or chemical properties, and has similar biological activity as the group or substituent. Bioisosteres are usually obtained by replacing one atom or group with another roughly similar atom or group, and may have one or more enhanced properties compared to the original compound, group or substituent (such as reduced toxicity, increased bioavailability, altered or increased activity, or improved metabolism).
  • tetrazole and its bioisostere refers to tetrazole, and a group or substituent with similar physical and chemical properties in a biological sense to tetrazole, and a substance with roughly similar or related biological activity.
  • heterocycloalkyl has the definition of the term “heterocycloalkyl” below.
  • heterocycloalkyl includes but is not limited to carboxylic acid, phosphoric acid,
  • halogen by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.
  • amino by itself or as part of another substituent means -NH2 .
  • alkyl when alone or as part of other substituents, the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.
  • Alkyl can be unsubstituted or substituted with one or more suitable substituents.
  • Alkyl can also be an isotope isomer of a natural abundance alkyl rich in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl radical 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, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylmethylbutyl, 2,
  • alkylene is understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, etc.
  • C 1 -C 6 alkoxy is understood to mean a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or is represented by C 1 -C 6 alkyl-OC 1 -C 6 alkyl.
  • alkyl is as described in the present specification, and the oxygen atom can be connected to any carbon atom of the straight or branched chain of C 1 -C 6 alkyl. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-).
  • haloalkoxy alone or as part of another substituent refers to an alkoxy group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkoxy group are replaced by fluorine, chlorine, bromine or iodine.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • aryl or "aromatic ring” when used alone or as part of another substituent refers to a monocyclic or polycyclic carbon ring having 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is non-aromatic, the group may be attached via the aromatic ring or via the non-aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl.
  • heteromatic ring refers to a monocyclic or polycyclic carbocyclic ring, wherein at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring.
  • the group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible).
  • the group may be connected by an aromatic ring or by a non-aromatic ring.
  • heteroaryl examples include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline.
  • heteromatic ring can be used interchangeably with the term “heteroaromatic ring”, “heteroaryl” or “heteroaromatic ring group”.
  • heteroaryl when alone or as part of other substituents, the term “5-10 membered heteroaromatic ring” can be used interchangeably with “5-10 membered heteroaryl”, and should be understood as an aromatic ring group having 5-10 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S.
  • the term “5-6 membered heteroaromatic ring” should be understood as an aromatic ring group having 5 or 6 ring atoms - and it contains 1-3 - heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl.
  • cycloalkyl refers to a cyclic alkyl group.
  • mn-membered cycloalkyl or “C m -C n cycloalkyl” should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
  • 3-15-membered cycloalkyl or “C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings.
  • 5-8-membered cycloalkyl contains 5-8 carbon atoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. Cycloalkyl can be substituted by one or more substituents. In some embodiments, the cycloalkyl can be a cycloalkyl fused to an aryl or heteroaryl group.
  • halocycloalkyl by itself or as part of another substituent refers to a cycloalkyl as described above, wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl are replaced by fluorine, chlorine, bromine or iodine.
  • heterocycloalkyl refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P.
  • heterocycloalkyl can be saturated or unsaturated, but not aromatic.
  • Heterocycloalkyl can also contain 1, 2 or 3 rings, including bridged rings and spirocyclic structures.
  • heterocycloalkyl should be understood to mean a monocyclic, bicyclic or tricyclic ring with 3 to 8 atoms, wherein the heteroatoms are preferably selected from N, O and S, and it should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other.
  • heterocycloalkyl include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.
  • the term "monocyclic" when alone or as part of other substituents means a group having only one ring, which may be saturated, unsaturated or partially saturated, and may be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).
  • heterocycle includes “heterocycloalkyl” and “heteroaryl” when used alone or as part of other substituents, and refers to a cycloalkyl or aromatic ring group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S and P.
  • inert solvent includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as but not limited to carboxyl, hydroxyl and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups).
  • Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.
  • Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • the term “optional” or “optionally” means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.
  • “optionally substituted aryl” means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.
  • the term "optionally substituted by” or “optionally substituted by” means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents.
  • aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 alkyl” means that aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 alkyl, and the description includes both substituted aryl and unsubstituted aryl.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or organic base that retains the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary amine, a secondary amine or a tertiary amine with an acid.
  • the acid includes the inorganic acid or the organic acid described in the present application.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule.
  • the prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to a functional group isomer 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 may exist in two or more interconvertible species.
  • Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer generally produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form is predominant; whereas in phenols, the enol form is predominant.
  • the present invention encompasses all tautomeric forms of the compounds.
  • the term "pharmaceutical composition” refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • the term "pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
  • solvate means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • prodrug refers to a compound of the present 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.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of the type of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • treatment and other similar synonyms include the following meanings:
  • the inventors unexpectedly developed a compound as an AT2R antagonist, the compound having the structure shown in the present invention.
  • the compound of the present invention can prevent or treat diseases or conditions related to AT2 receptors, exhibits excellent pharmacokinetic properties, and has high safety and drug properties.
  • IC 50 Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56 mL, 29.1 mmol, 2.5 M n-hexane solution
  • n-butyllithium n-hexane solution means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
  • DIPEA N,N-diisopropylethylamine
  • PE Petroleum ether
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the synthetic route of the target compound I-3 is as follows:
  • Triethylamine (1.4 g, 13.8 mmol) and acetyl chloride (542 mg, 6.9 mmol) were added to a solution of (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 4.6 mmol) in dichloromethane (10 mL), and then stirred at room temperature for 2 h.
  • the reaction solution was poured into water (50 mL) and extracted three times with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.
  • Step 2 Synthesis of tert-butyl (R)-4-acetyl-3-(methoxymethyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (R)-3-(methoxymethyl)piperazine-1-carboxylate
  • Step 4 Synthesis of tert-butyl (R)-3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate
  • Triethylamine (182 mg, 1.8 mmol) and (R)-3-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.6 mmol) were added to a solution of 3-(chloromethyl)pyridazine (116 mg, 0.9 mmol) in N,N-dimethylformamide (1.3 mL), and then stirred at 50 ° C for 18 h.
  • the reaction solution was poured into water (50 mL) and washed three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Step 6 Synthesis of (R)-2-fluoro-4-isobutyl-6-(3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzonitrile
  • Step 7 Synthesis of (R)-3-((4-(3-fluoro-5-isobutyl-2-(2H-tetrazolyl-5-yl)phenyl)-2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine
  • the synthetic route of the target compound I-5 is as follows:
  • Step 1 Synthesis of tert-butyl (R)-3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate
  • Step 3 Synthesis of (R)-methyl 4-bromo-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzoate
  • Step 4 Synthesis of (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid methyl ester
  • Step 5 Synthesis of (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid
  • the synthetic route of the target compound I-6 is as follows:
  • Step 1 Synthesis of (R)-N-(ethylsulfonyl)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzamide
  • reaction solution was stirred at room temperature for 10 min, and then ethylsulfonamide (324 mg, 2.98 mmol) was added, and the reaction solution was reacted at 50 ° C for 3 h.
  • the synthetic route of the target compound I-1 is as follows:
  • (2R)-2-(difluoromethyl)piperazine dihydrochloride (1.00 g, 4.81 mmol) and triethylamine (1.46 g, 14.43 mmol) were dissolved in DMF (20 mL), 2,6-difluoro-4-isobutylbenzonitrile (Intermediate A1, 940 mg, 4.81 mmol) was added thereto, and stirred at 80°C for 16 h.
  • Step 2 Synthesis of 6-((3R)-4-(pyridazine-3-ylcarbonyl)-3-(difluoromethyl)piperazine-1-yl)-2-fluoro-4-isobutylbenzonitrile
  • Step 3 Synthesis of ((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazolyl-5-yl)-5-isobutylphenyl)piperazin-1-yl)(pyridazine-3-yl)methanone
  • Step 4 Synthesis of 3-(((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazolyl-5-yl)-5-isobutylphenyl)piperazin-1-yl)methyl)pyridazine
  • the synthetic route of the target compound I-7 is as follows:
  • Step 1 Synthesis of tert-butyl (3R)-3-(difluoromethyl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl (3R)-3-(difluoromethyl)-4-(pyridazine-3-carbonyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazine-1-carboxylate
  • Step 4 Synthesis of 3-(((2R)-2-(difluoromethyl)piperazin-1-yl)methyl)pyridazine
  • Step 5 Synthesis of methyl 4-bromo-2-((3R)-3-(difluoromethyl)-4-(((pyridazine-3-yl)methyl)piperazine-1-yl)-6-fluorobenzoate
  • Step 6 Synthesis of methyl 2-((3R)-3-(difluoromethyl)-4-((pyridazine-3-yl)methyl)piperazine-1-yl)-6-fluoro-4-(2-methylpropyl)benzoate
  • Step 7 Synthesis of 2-((3R)-3-(difluoromethyl)-4-((pyridazine-3-yl)methyl)piperazine-1-yl)-6-fluoro-4-(2-methylpropanoic acid)benzoic acid
  • Example 6 The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.
  • the compounds prepared in the examples can be tested using the following test methods.
  • Test Example 1 Compound binding to AT2R
  • the experiment was performed according to the instruction manual of the Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio).
  • the 10mM compound stock solution was serially diluted according to the dilution factor of 5 ⁇ (including 10 concentrations, each concentration was repeated twice), and 160nL of the compound of different concentrations was added to a 384-well plate.
  • 40 ⁇ L 1 ⁇ TLB was added to each well and shaken at room temperature for 15 minutes.
  • a 15mL centrifuge tube with 5mL 1 ⁇ TLB was prepared in advance for use.
  • the frozen labeled cells were thawed in a 37°C water bath (1-2 minutes), and the thawed cells were quickly transferred to the above 15mL centrifuge tube, mixed and centrifuged at 1000g for 5 minutes at room temperature. The supernatant was removed and 2.7mL 1 ⁇ TLB was added to resuspend the cells. Take a new 384-well plate and add 10 ⁇ L of the mixed cells to the corresponding wells according to the experimental design. Add 5 ⁇ L of 4 ⁇ compound solution and 5 ⁇ L of 4 ⁇ Tag-lite red fluorescent labeled ligand to each well. After incubation at room temperature for 1 hour, read the results using the HTRF mode of EnVision. Data.
  • the IC 50 value was calculated using GraphPad Prism8 software, where X: logarithmic value of compound concentration; Y: ratio of A665nM/B615nM.
  • the present invention exemplifies the results of some compounds, see Table 1 for details.
  • test compound has a strong binding effect with AT2R.
  • mice Male SD rats were used, 3 rats in each group, 180-240g, fasted overnight, and each group was orally gavaged with 10 mg/kg. Blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood sample was centrifuged at 8000 rpm and 4°C for 6 minutes, and the plasma was collected and stored at -20°C.
  • the plasma at each time point was taken, 3-5 times the amount of acetonitrile solution containing the internal standard was added and mixed, vortexed for 1 minute, centrifuged at 13000 rpm and 4°C for 10 minutes, the supernatant was taken and added with 3 times the amount of water to mix, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software. The results of some compounds are exemplified in the present invention, see Table 2 for details.
  • Mouse pharmacokinetic test using male ICR mice, 3 mice per group, 20-30g, fasted overnight, each group was given 10mg/kg by oral gavage. Blood was collected before administration and at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours after administration. The blood sample was centrifuged at 6000g/min at 2-8°C for 3 minutes, and the plasma was collected and stored at -20°C.
  • the plasma at each time point was taken, 10 times the amount of 50% methanol acetonitrile solution containing internal standard was added and mixed, vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, the supernatant was taken and 1 times the amount of water was added to mix, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • the present invention exemplifies some compounds For details of the results, see Table 3.
  • Test Example 4 Manual patch clamp technique to detect the effect of compounds on hERG channel current
  • hERG potassium channel cells were purchased from Creacell (Cat. No. A-0320). The final concentrations of the test compounds were prepared on the same day and dissolved in the extracellular solution.
  • the extracellular solution (mM) was: 40mM NaCl, 3.5mM KCl, 1mM MgCl 2 ⁇ 6H 2 O, 2mM CaCl 2 ⁇ 2H 2 O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH 2 PO 4 ⁇ 2H 2 O; pH 7.4 (NaOH titration).
  • the intracellular solution was: 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl 2 ⁇ 6H 2 O, 5 mM EGTA, 10 mM HEPES, 2 mM Na 2 -ATP; pH 7.4 (KOH titration).
  • Electrophysiological test After whole-cell sealing, the cell membrane voltage was clamped at -80mV. The clamping voltage was depolarized from -80mV to -50mV for 0.5s (as leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data were collected repeatedly every 10s to observe the effect of the drug on the hERG tail current (Peak tail current compound ). A 0.5s stimulation of -50mV was used as a leakage current detection. Drug administration began after the hERG current recorded by the whole cell was stable. After each drug concentration acted for 5min (or the current was stable), the next concentration was detected.
  • One or more concentrations were detected for each test compound.
  • the current detected in the external solution without the compound (Peak tail current Control ) of each cell was used as its own control group. At least two cells were used for each concentration and the detection was repeated twice independently. All electrophysiological tests were performed at room temperature. The experimental data were collected by the IPA amplifier (Sutter Instrument) and stored in the Sutter Patch software.
  • the experimental results show that compared with the control compound I, the compound of the present invention has a lower risk of hERG inhibition in an in vitro system and a lower risk of cardiac safety.
  • the tightness of the ligature was based on the visible slight twitching of the calf muscle or toes when the knot was tied; the muscles, subcutaneous tissues and skin were sutured in turn, the wound was cleaned and disinfected with iodine. The skin was sutured and disinfected.
  • the animals were randomly divided into groups, with 8 animals in each group, and the vehicle or the corresponding compound solution was orally gavaged. The mechanical pain threshold of the animals was tested with Von-Frey fibers before and after drug administration.
  • Mechanical pain threshold detection method The test animal is continuously stimulated with Von-Frey fiber to make the fiber bend, and the animal's foot retraction reaction is observed. The test animals are stimulated one by one in the order of the fiber weight from small to large, and each fiber weight is stimulated 5 times in a row. If the positive reaction is less than 3 times, the larger fiber is used to repeat the above operation. When the positive reaction occurs 3 or more times for the first time, the fiber is the pain threshold of the animal (each animal is tested 3 times and the average value is taken). Fiber weight: 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0; the cut-off value is 15.0g.
  • GraphPad Prism 8.0 was used for data statistics of each group, and the statistical method was one-way ANOVA. The statistical differences between the groups were compared, and P ⁇ 0.05 was considered statistically significant.
  • the experimental results show that the compounds of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by the rat sciatic nerve modeling in the rat chronic constriction injury model, and have excellent analgesic effect.

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Abstract

La présente invention concerne un composé représenté par la formule I, et un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé peut être utilisé en tant qu'antagoniste d'AT2R.
PCT/CN2024/099297 2023-06-16 2024-06-14 Composé hétérocyclique utilisé en tant qu'antagoniste d'at2r et son utilisation Ceased WO2024255859A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2014105664A1 (fr) * 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Composés [1,2,4]triazolo[1,5-c]quinazolin-5-amines à substitution par pipérazine ayant des propriétés d'antagonistes du récepteur a2a
CN106715413A (zh) * 2014-08-07 2017-05-24 生命医药公司 作为肝x受体调节剂的哌嗪衍生物
WO2023006893A1 (fr) * 2021-07-30 2023-02-02 Confo Therapeutics N.V. Composés pour le traitement de la douleur, en particulier de la douleur neuropathique, et/ou d'autres maladies ou troubles associés à at2r et/ou à la signalisation médiée par at2r

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014105664A1 (fr) * 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Composés [1,2,4]triazolo[1,5-c]quinazolin-5-amines à substitution par pipérazine ayant des propriétés d'antagonistes du récepteur a2a
CN106715413A (zh) * 2014-08-07 2017-05-24 生命医药公司 作为肝x受体调节剂的哌嗪衍生物
WO2023006893A1 (fr) * 2021-07-30 2023-02-02 Confo Therapeutics N.V. Composés pour le traitement de la douleur, en particulier de la douleur neuropathique, et/ou d'autres maladies ou troubles associés à at2r et/ou à la signalisation médiée par at2r

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