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CN119143734A - Heterocyclic compounds as AT2R antagonists and uses thereof - Google Patents

Heterocyclic compounds as AT2R antagonists and uses thereof Download PDF

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Publication number
CN119143734A
CN119143734A CN202410774534.3A CN202410774534A CN119143734A CN 119143734 A CN119143734 A CN 119143734A CN 202410774534 A CN202410774534 A CN 202410774534A CN 119143734 A CN119143734 A CN 119143734A
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alkyl
cycloalkyl
compound
alkoxy
ring
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Inventor
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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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
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
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    • 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

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  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；该化合物可用作AT2R的拮抗剂， The present invention provides a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound can be used as an antagonist of AT2R.

Description

Heterocyclic compounds as AT2R antagonists and uses thereof
The invention requires enjoying:
Priority of prior application filed 16 AT 6/2023 to the national intellectual property office of China with patent application number 202310724422.2 entitled "heterocyclic Compounds as AT2R antagonists and uses thereof";
priority of prior application filed by the national intellectual property office AT 10/13/2023 under the patent application number 202311331793.0 entitled "heterocyclic compound as AT2R antagonist and use thereof";
Priority of the prior application filed on 1/3/2024 to the national intellectual property office under the patent application No. 202410010872.X entitled "heterocyclic compound as AT2R antagonist and use thereof";
priority of prior application filed in 2024, 5 and 27 to the national intellectual property office under patent application number 202410669486.1 entitled "heterocyclic compound as AT2R antagonist and use thereof";
The entire contents of said prior application are incorporated by reference into the present invention.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a heterocyclic compound serving as an angiotensin II (AngII) 2 type receptor (AT 2R) antagonist and application thereof.
Background
Neuropathic pain is a chronic pain disease caused by the occurrence of primary injury or dysfunction of the nervous system, and can be classified into peripheral neuropathic pain and central neuropathic pain according to the lesion site. Neuropathic pain may be caused by trauma, inflammation, infection, or compression, such as Diabetic Neuralgia (DNP), postherpetic neuralgia (PHN), primary neuropathy, secondary neuropathy, peripheral neuropathy, and neuropathy caused by mechanical or biochemical nerve injury. The current clinical medicines for treating neuropathic pain mainly comprise antiepileptic medicines, antidepressants and narcotic analgesics, such as gabapentin, pregabalin, tricyclic antidepressants and the like. However, these drugs are not targeted, have very limited therapeutic effects, and have serious side effects including cognitive changes, sedation, nausea, and tolerance and dependence, far from meeting clinical medication requirements. Therefore, research on pathogenesis of neuropathic pain and finding out a target spot with definite drug action are needed, and novel drugs which can effectively treat neuropathic pain and have few adverse reactions are developed.
In humans, two major classes of angiotensin II (AngiotensinII, angII) receptors have been identified, designated as AngII type 1 receptor (AT 1R) and AngII type 2 receptor (AT 2R), respectively. AngII has been shown to regulate the physiological effects of blood pressure, body fluids, and electrolyte homeostasis in many organs, including kidney, adrenal gland, heart, blood vessels, brain, gastrointestinal tract, and reproductive organs. The effect of AngII is regulated by the balance of AT1R and AT2R expression of two G Protein Coupled Receptors (GPCRs). AT1R is expressed in the whole life cycle and is mainly responsible for regulating blood pressure, and a blocker thereof is widely used as a antihypertensive drug clinically, and the AT1R controls most of AngII physiological effects. AT2R is mainly expressed in embryonic tissues, and is related to blood pressure regulation, nerve growth, pain control and myocardial regeneration, and drugs targeting AT2R can improve cardiovascular functions, relieve neuropathic pain and the like. AT2R is associated with pain mechanisms in the nervous system, predominantly expressed in the dorsal root ganglion and the trigeminal ganglion. Damaged and painful neuromas have higher AT2R expression compared to normal nerves. The ion channel in neurons can be sensitized by a second messenger pathway activated by G-protein coupled receptors after AT2R activation. Sensitization causes activation of ion channels to excite neurons. AT2R antagonists have been shown to be useful in pain relief by animal and clinical trials.
Although research and use of AT2R antagonists has advanced to some extent, there is still a great room for improvement and there is still a need to continue to research and develop new AT2R antagonists.
Disclosure of Invention
The object of the present invention is to provide a compound as an AT2R antagonist, which has a structure as shown in the first aspect of the present invention, which is useful for preparing a medicament, a pharmaceutical composition or a formulation for treating and/or preventing a disease or a condition associated with AT2R, or for treating and/or preventing a disease or a condition associated with AT2R, and the use thereof.
In a first aspect of the invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
wherein ring A is selected from 5-6 membered heteroaromatic rings;
R 1 is selected from halogen, hydroxy, amino, cyano, oxo (=O), C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl, said C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl optionally substituted with 1-4 substituents selected from halogen, hydroxy, amino, cyano, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl, oxo;
m is selected from 0, 1, 2, 3 or 4, when the substituents R 1 are plural, the R 1 are the same or different;
L is absent or selected from C 0-C6 alkylene-O-C 0-C6 alkylene, C 1-C6 alkylene, said C 1-C6 alkylene-O-C 1-C6 alkylene or C 1-C6 alkylene being optionally substituted with 1 to 4 substituents selected from deuterium, oxo (=O), methyl, ethyl, halomethyl, haloethyl;
r 2 is selected from C 1-C6 alkyl, C 3-C7 cycloalkyl, 5-10 membered heterocycle, 6-10 membered aromatic ring, said C 1-C6 alkyl, C 3-C6 cycloalkyl, 5-10 membered heterocycle, 6-10 membered aromatic ring optionally substituted with 1,2,3, 4 substituents selected from halogen, hydroxy, cyano, amino, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 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 the substituents R 2 are plural, the R 2 are the same or different;
ring E is selected from benzene ring or 6 membered heteroaryl ring;
R 3 is selected from halogen, hydroxy, cyano, dimethylamino, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl, said C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl optionally substituted with 1-4 substituents selected from halogen, hydroxy, cyano, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl;
p is selected from 0,1, 2, 3 or 4, when the substituents R 3 are plural, the R 3 are the same or different;
M is selected from carboxylic acid, -CONHSO 2R5、-SO2NHCOR5, tetrazole, or tetrazole bioisosteres including but not limited to phosphoric acid,
R 5 is selected from H, OH, NH 2, ONa, OK (potassium ion), C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle, said C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle optionally substituted with 1-4 substituents selected from halogen, amino, C 3-C7 heterocycloalkyl, C 1-C3 alkyl, C 3-C6 cycloalkyl, C 1-C3 alkoxy.
In a preferred embodiment of the invention, the ring A is a 5-6 membered heteroaromatic ring, the 5-6 membered heteroaromatic ring containing 1, 2, 3 heteroatoms;
The heteroatom is selected from N, O, S, more preferably the heteroatom is N.
In a preferred embodiment of the invention, the ring A is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine;
In a preferred embodiment of the invention, the ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine.
In a preferred embodiment of the invention, the ring A is selected from
In a preferred embodiment of the invention, the ring E is a benzene ring or a6 membered heteroaromatic ring;
The 6 membered heteroaromatic ring contains 1, 2,3 heteroatoms;
the heteroatom is selected from N, O, S.
In a preferred embodiment of the invention, the ring E is selected from benzene rings, pyridine, pyrimidine, pyridazine.
In a preferred embodiment of the invention, the ring E is selected from benzene rings.
In a preferred embodiment of the invention, R 1 is selected from halogen, hydroxy, amino, cyano, oxo (=o), C 1-C3 alkyl, C 1-C3 haloalkyl, C 1-C3 alkoxy, C 1-C3 haloalkoxy, C 3-C7 cycloalkyl, C 1-C3 alkyl-C 1-C3 alkoxy, C 1-C3 alkyl-C 3-C7 cycloalkyl;
m is selected from 0, 1, 2, 3 or 4.
In a preferred embodiment of the invention, R 1 is selected from halogen, methyl, halomethyl, methoxy and m is selected from 0.
In a preferred embodiment of the invention, the compound is selected from the following structures:
The definition of rings A, M, L, R 1、R3, m and p is as described in the first aspect of the invention.
In a preferred embodiment of the invention, the compound is selected from the following structures:
The definition of rings A, M, L, R 1、R3, m and p is as described in the first aspect of the invention. In a preferred embodiment of the invention, the compound is selected from the following structures:
M, R 2 is as defined in the first aspect of the invention;
Preferably, the compound of formula IV has structures IVa, IVb:
in a preferred embodiment of the invention, the compound is selected from the following structures:
preferably, it has structure IIa or IIb:
in a preferred embodiment of the invention, the compound is selected from the following structures:
Preferably, it has the structure IV-2a, IV-2b, IV-3a or IV-3b:
In a preferred embodiment of the invention, R 2 is selected from the group consisting of C 1-C3 alkyl, C 3-C6 cycloalkyl, 5-6 membered heterocycle, 5-6 membered heteroaryl, benzene ring, said C 1-C3 alkyl, C 3-C6 cycloalkyl, 5-6 membered heterocycle, benzene ring optionally substituted with 1,2, 3, 4 substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-C3 alkyl, C 1-C3 alkoxy, C 3-C6 cycloalkyl, and R 2 is not methyl, ethyl, isopropyl, -CF 3.
In a preferred embodiment of the invention n is selected from 1,2, 3.
In a preferred embodiment of the invention, n is 1.
In a preferred embodiment of the invention, said R 2 is selected from CH 2F、CHF2、C1-C3 alkyl-C 1-C6 alkoxy, C 3-C7 cycloalkyl, C 1-C3 alkyl-C 3-C7 cycloalkyl;
n is selected from 1, 2,3, 4, 5, 6, 7 or 8.
In a preferred embodiment of the invention, R 2 is selected from CH 2F、CHF2、C1-C3 alkyl-C 1-C6 alkoxy, C 3-C7 cycloalkyl, C 1-C3 alkyl-C 3-C7 cycloalkyl.
In a preferred embodiment of the invention, R 2 is selected from CH 2F、CHF2、C1-C3 alkyl-C 1-C3 alkoxy, C 3-C4 cycloalkyl, C 1-C3 alkyl-C 3-C4 cycloalkyl, and n is selected from 1,2, 3.
In a preferred embodiment of the invention, R 2 is selected from CH 2F、CHF2, methyl-methoxy, ethyl-methoxy, cyclopropyl, methyl-cyclopropyl, n is selected from 1.
In a preferred embodiment of the invention, said R 2 is selected from CH 2F、CHF2, methyl-methoxy, cyclopropyl.
In a preferred embodiment of the invention, R 2 is selected from CH 2F、CHF2,
In a preferred embodiment of the invention, said R 2 is selected from CH 2F、CHF2.
In a preferred embodiment of the invention, the R 2 is selected from CHF 2.
In a preferred embodiment of the invention, R 3 is selected from halogen, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl, wherein said C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, hydroxy, cyano, C 1-C6 alkyl, C 1-C6 alkoxy, C 3-C7 cycloalkyl;
p is selected from 0, 1, 2, 3 or 4.
In a preferred embodiment of the invention, R 3 is selected from F, C 1-C5 alkyl, C 1-C5 haloalkyl, methyl-cyclopropyl, and p is selected from 1,2, 3.
In a preferred embodiment of the invention, R 3 is selected from F, methyl, trifluoromethyl, isobutyl, F-substituted isobutyl, methyl-cyclopropyl, and p is selected from 2.
In a preferred embodiment of the invention, p is selected from 2 and said R 3 is selected from F and isobutyl.
In a preferred embodiment of the invention, M is selected from carboxylic acid, -CONHSO 2R5、-SO2NHCOR5, tetrazole, or tetrazole bioisostere.
In a preferred embodiment of the invention, the tetrazole bioisostere is selected from 4-8 membered heterocycloalkyl substituted with -C(＝O)-R5、-C(＝O)NH-R5、-N(R5)C(＝O)-R5、-O-N(Re1)C(＝O)-R5、-S(＝O)-R5、-S(＝O)2-R5、-NH-S(＝O)2-R5、-C(＝O)-NH-S(＝O)2-R5、-NH-C(＝O)-NH-S(＝O)2-R5、-NH-C(＝O)-NH-C(＝O)-R5、-P(＝O)(-R5)2、 by 1,2, 3,4 oxo (=o), wherein said R 5 is selected from H, OH, NH 2, ONa, OK (potassium ion), C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle, said C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle being optionally substituted with 1-4 substituents selected from halogen, amino, C 3-C7 heterocycloalkyl, C 1-C3 alkyl, C 3-C6 cycloalkyl, C 1-C3 alkoxy.
In a preferred embodiment of the invention, M is selected from carboxylic acid, -CONHSO 2R5、-SO2NHCOR5, tetrazole, and R 5 is selected from C 1-C3 alkyl, C 3-C5 cycloalkyl.
In a preferred embodiment of the invention, M is selected from carboxylic acid, tetrazole, -CONHSO 2CH2CH3.
In a preferred embodiment of the invention, said M is selected from carboxylic acids, tetrazoles.
In a preferred embodiment of the invention, said M is selected from tetrazoles.
In a preferred embodiment of the invention, R 2 is selected from CHF 2 and M is selected from tetrazole and carboxylic acid.
In a preferred embodiment of the invention, R 2 is selected from CH 2 F and M is selected from carboxylic acid, tetrazole, -CONHSO 2CH2CH3.
In a preferred embodiment of the present invention, R 2 is selected from CH 2 F, and M is selected from carboxylic acid and tetrazole.
In a preferred embodiment of the invention, R 2 is selected from CH 2 F and M is selected from tetrazole.
In a preferred embodiment of the invention, R 2 is selected from CH 2 F and M is selected from carboxylic acids.
In a preferred embodiment of the invention, R 2 is selected from CH 2 F and M is selected from-CONHSO 2CH2CH3.
In a preferred embodiment of the invention, R 2 is selected from cyclopropyl and M is selected from tetrazole.
In a preferred embodiment of the present invention, R 2 is selected fromThe M is selected from tetrazoles.
In a preferred embodiment of the invention, said L is absent or selected from carbonyl, methylene 、-CH2CH2-、-CH(CH3)-、-CH2CH2CH2-、-CH2CH(CH3)-、-O-CH2-.
In a preferred embodiment of the invention, said L is selected from methylene, -CH 2CH2-、-CH(CH3)-、-O-CH2 -.
In a preferred embodiment of the invention, said L is selected from methylene.
In a preferred embodiment of the present invention, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound comprises:
In a preferred embodiment of the present invention, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound comprises:
In a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first aspect, and optionally a pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first aspect, and a pharmaceutically acceptable carrier
In a third aspect of the present invention, the use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect, as described in the first aspect, comprises:
As AT2R antagonists;
and/or preventing and/or treating AT 2R-mediated diseases;
And/or, preventing and/or treating a disease in which reduced AngII action is desired or required;
and/or preparing a medicament, pharmaceutical composition or formulation as an AT2R antagonist;
and/or preparing a medicament, pharmaceutical composition or formulation for preventing and/or treating a disease in which AT2R is expressed and inhibition thereof is desired or necessary.
There is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as described in the first aspect, or a pharmaceutical composition according to the second aspect is intended for use in the treatment of a neurological disorder or neuropathic pain.
The neuropathy to be mentioned includes primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, or diabetes-related neurological diseases.
Neuropathic pain that should be mentioned includes postherpetic neuralgia or diabetic neuralgia.
The compounds of formula I according to the first aspect of the invention, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical compositions according to the second aspect, are suitable for the therapeutic and/or prophylactic treatment of the diseases mentioned above.
In a fourth aspect the present invention provides a method of treating a disease which is an AT2R mediated disease, and/or in which a reduction in the effect of AngII is desired or necessary, and/or in which AT2R expression and inhibition is desired or necessary, which method comprises administering to a person suffering from or susceptible to such a disease a therapeutically effective amount of a compound of formula I according to the first aspect of the invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect.
In a preferred embodiment of the invention, the disease comprises an AT2R mediated disease, a disease in which reduced ang ii effects are desired or required.
In a preferred embodiment of the invention, the disease comprises primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical or biochemical nerve damage, or diabetes-related neurological disease.
In a preferred embodiment of the invention, the disease comprises postherpetic neuralgia or diabetic neuralgia.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Terminology and definitions
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
The definition of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED," vols. A (2000) and B (2001), plenum Press, new York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH 2 O is equivalent to OCH 2. As used herein,Representing the attachment site of the group. As used herein, "R 1," "R1," and "R 1" are synonymous and interchangeable. For other symbols such as R 2, the meaning of like definition is the same.
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both ends of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1,2, 3, 4, 5, and 6.
In the present application, when the number of substituents is indicated, the term "one or more" means one substitution to the maximum number of substitutions possible, i.e., substitution of one hydrogen to all hydrogens substituted with substituents. When the number of substituents is indicated, the term "1-4" means 1, 2, 3 or 4 substitutions, i.e. 1, 2, 3 or 4 hydrogens are substituted with a substituent.
In the present application, "saturated, partially saturated or unsaturated" includes a substituent saturated with hydrogen, a substituent fully unsaturated with hydrogen, and a substituent partially saturated with hydrogen.
In the present application, "AT2 receptor" and "AT2R" have the same definition.
In the present application, the term "bioisostere" has the usual meaning in the art, alone or as part of another substituent, and refers to a group or substituent having similar physical or chemical properties, having similar biological activity to the group or substituent. Bioisosteres are typically obtained by replacing one atom or group with another substantially similar atom or group, possibly with one or more enhanced properties (e.g., reduced toxicity, increased bioavailability, altered or increased activity, or improved metabolic profile) as compared to the original compound, group or substituent. The term "tetrazole and bioisosteres thereof" refers to tetrazoles, as well as groups or substituents having similar physical and chemical properties in a biological sense as tetrazole, resulting in a substance that is substantially similar or related to biological activity. in some embodiments, the term "tetrazoles and bioisosteres thereof" includes, but is not limited to, 4-8 membered heterocycloalkyl substituted with 1, 2,3, 4 oxo (=o) -C(＝O)-R5、-C(＝O)NH-R5、-N(R5)C(＝O)-R5、-O-N(Re1)C(＝O)-R5、-S(＝O)-R5、-S(＝O)2-R5、-NH-S(＝O)2-R5、-C(＝O)-NH-S(＝O)2-R5、-NH-C(＝O)-NH-S(＝O)2-R5、-NH-C(＝O)-NH-C(＝O)-R5、-P(＝O)(-R5)2、, wherein said R 5 is selected from H, OH, NH 2, ONa, OK (potassium ion), C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle, said C 1-C8 alkyl, C 3-C8 cycloalkyl, C 1-C8 alkoxy, 5-6 membered heterocycle optionally substituted with 1-4 substituents selected from halogen, amino, C 3-C7 heterocycloalkyl, C 1-C3 alkyl, C 3-C6 cycloalkyl, C 1-C3 alkoxy. The 4-8 membered heterocycloalkyl has the definition of the term "heterocycloalkyl" below. For example, the term "tetrazoles and bioisosteres thereof" includes, but is not limited to, carboxylic acids, phosphoric acids,
In the present application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents.
In the present application, the term "amino" means-NH 2, alone or as part of another substituent.
In the present application, the term "hydroxy" means-OH, alone or as part of another substituent.
In the present application, the term "cyano" means-CN, alone or as part of another substituent.
In the present application, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, free of unsaturation, having, for example, 1 to 6 carbon atoms, and linked to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group can also be an isotopic isomer of a naturally abundant alkyl group that is enriched in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
In the present application, the term "C 1-C6 alkyl" alone or as part of another substituent is understood to mean a straight or branched chain saturated hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the groups have 1,2 or 3 carbon atoms ("C 1-C3 alkyl"), such as methyl, methylene, ethyl, n-propyl or isopropyl.
In the present application, the term "alkylene" is understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, and the like.
In the present application, the term "C 1-C6 alkoxy", alone or as part of another substituent, is understood to mean a straight or branched chain saturated hydrocarbon group having 1,2,3, 4,5 or 6 carbon atoms and an oxygen atom, or a definition of C 1-C6 alkyl-O-C 1-C6 alkyl as set forth in the present specification, the oxygen atom may be attached to any one of the straight or branched chain carbon atoms of the C 1-C6 alkyl. Including but not limited to methoxy (CH 3 -O-), ethoxy (C 2H5 -O-), propoxy (C 3H7 -O-), butoxy (C 4H9 -O-).
In the present application, "haloalkoxy" 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 with fluorine, chlorine, bromine or iodine, alone or as part of other substituents.
In the present application, the term "oxo" when used alone or as part of another substituent means that two hydrogens on the methylene group are replaced with oxygen, i.e. the methylene group is replaced with a carbonyl group, meaning =o.
In the present application, "haloalkyl" is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v=1 to 3,w =1 to (2v+1)), alone or as part of another substituent. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
In the present application, the term "aryl" or "aromatic ring" when used alone or as part of another substituent means a monocyclic or polycyclic carbocycle having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthracenyl, and acenaphthylenyl.
In the present application, the term "heteroaryl ring", alone or as part of another substituent, refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, the remaining ring atoms being C, in which 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-linked or N-linked, as long as it is possible). When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrroliyl, and tetrahydroquinolinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaryl" or "heteroaryl ring radical". In the present application, the term "5-10 membered heteroaryl ring" when used alone or as part of another substituent is interchangeable with a 5-10 membered heteroaryl group "and is understood to be 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" is understood to mean an aromatic ring radical having 5 or 6 ring atoms, and which contains 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
In the present application, the term "cycloalkyl" or "carbocyclyl" when used alone or as part of another substituent means a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C m-Cn cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C 3-C15 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, spiro, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups.
In the present application, "halocycloalkyl" refers to cycloalkyl groups as described above, wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced with fluorine, chlorine, bromine or iodine, alone or as part of other substituents.
In the present application, the term "heterocycloalkyl" when used alone or as part of another substituent means a cycloalkyl group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced with heteroatoms such as, but not limited to N, O, S and P. "heterocycloalkyl" may be saturated or unsaturated, but is not aromatic. "heterocycloalkyl" may also be a ring containing 1, 2 or 3 rings, including bridged and spiro structures. The term "3-8 membered heterocycloalkyl" is understood to mean a monocyclic, bicyclic or tricyclic ring having 3 to 8 atoms, wherein the heteroatoms are preferably N, O and S, it being understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.
In the present application, the term "monocyclic" means a group of only one ring, which may be saturated, unsaturated or partially saturated, either carbocyclic (all ring atoms being carbon atoms) or heterocyclic (ring atoms other than carbon atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S), alone or as part of another substituent.
In the present application, the term "heterocycle" includes "heterocycloalkyl" and "heteroaryl" when used alone or as part of another substituent, and refers to cycloalkyl or aromatic ring groups in which one or more (in some embodiments 1 to 3) carbon atoms are replaced with heteroatoms such as, but not limited to N, O, S and P.
In the present application, the term "inert solvent" includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Compounds provided herein, including intermediates useful in the preparation of compounds provided herein, 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 protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like, as well as isotopes and the like. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxyl protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
In the present application, the term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, including deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable.
In the present application, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
In the present application, the term "optionally substituted" or "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the possible substituents. For example, "aryl optionally substituted with 1-4 substituents independently selected from halogen, cyano, hydroxy, C 1-6 alkyl" means that aryl is unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, and the description includes both substituted aryl and unsubstituted aryl.
In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
In the present application, the term "pharmaceutically acceptable acid addition salt" refers to a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present application. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the application.
In the present application, the term "amine salt" refers to a product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes an inorganic acid or an organic acid as described in the present application.
In the present application, the term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory.
When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985,62:114-120. The absolute configuration of a solid center is represented by wedge-shaped keys and dashed keys.
In the present application, the term "tautomer" refers to a functional group isomer generated by rapid movement of an atom in a molecule at two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while among phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.
In the present application, the term "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In the present application, 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, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent or emulsifier that is approved by the relevant government regulatory agency as acceptable for use in humans or domestic animals.
In the present application, the term "solvate" means that the compound of the present application or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent which is bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
In the present application, the term "prodrug" refers to a compound of the present application that can be converted into a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the application are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the application is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (2 H), tritium (3 H), iodine-125 (125 I) or C-14 (14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In the present application, the term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e. causing regression of the state of the disease or condition, or
(Iv) Alleviating symptoms caused by the disease or condition.
Advantageous effects
The present inventors have made extensive and intensive studies and have unexpectedly developed a compound having a structure shown in the present invention as an AT2R antagonist. The compound disclosed by the invention can be used for preventing or treating diseases or symptoms related to the A T2 receptor, has excellent pharmacokinetic properties, and has higher safety and pharmaceutical properties.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.
The application has the following definitions:
Symbol or unit:
IC 50 half inhibition concentration, which means the concentration at which half of the maximum inhibition effect is achieved
M: mol/L, for example n-butyllithium (14.56 mL,29.1mmol,2.5M in n-hexane) represents an n-hexane solution of n-butyllithium at a molar concentration of 2.5mol/L
N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT retention time
Reagent:
DMF N, N-dimethylformamide
DCM: dichloromethane
DIPEA N, N-diisopropylethylamine
MeOH methanol
EA ethyl acetate
PE Petroleum ether
HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
XPhos Pd G4 (SP-4-3) - [ dicyclohexyl [2',4',6 '-tris (isopropyl) [1,1' -biphenyl ] -2-yl ] phosphine ] (methanesulfonic acid) [2'- (methylamino) [1,1' -biphenyl ] -2-yl ] palladium
The test method comprises the following steps:
LCMS liquid chromatography-mass spectrometry
TLC thin layer chromatography
Intermediate A1 preparation of intermediate A1
Synthesis of 2, 6-difluoro-4-isobutylbenzonitrile
The synthetic route for intermediate A1 is shown below:
To a solution of 4-bromo-2, 6-difluorobenzonitrile (10 g,45.87 mmol) in dioxane (150 mL) were added isobutyl boric acid (7.01 g,68.81 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (3.36 g,4.59 mmol) and potassium carbonate (19.02 g,137.61 mmol), and the reaction was reacted at 115℃for 16h. After the reaction, diatomite is filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (pure petroleum ether) to give the product 2, 6-difluoro-4-isobutylbenzonitrile (7 g, yield 78.71%).
EXAMPLE 1 preparation of the target Compound I-3
(R) -3- ((4- (3-fluoro-5-isobutyl-2- (2H-tetrazol-5-yl) phenyl) -2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine
The synthetic route for the target compound I-3 is shown below:
first step of Synthesis of (R) -4-acetyl-3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (1 g,4.6 mmol) in dichloromethane (10 mL) was added triethylamine (1.4 g,13.8 mmol) and acetyl chloride (552 mg,6.9 mmol), followed by stirring at room temperature for 2h. The reaction solution was poured into water (50 mL), and extracted three times with methylene chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-1/1) to give the product (R) -4-acetyl-3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (800 mg, 67% yield).
Second step of synthesizing tert-butyl (R) -4-acetyl-3- (methoxymethyl) piperazine-1-carboxylate
To a solution of tert-butyl (R) -4-acetyl-3- (hydroxymethyl) piperazine-1-carboxylate (400 mg,1.5 mmol) in tetrahydrofuran (4 mL) at 0deg.C was added sodium hydrogen (144 mg,6mmol,60% purity) and stirred for 0.5h. Methyl iodide (284 mg,2 mmol) was then slowly added dropwise to the reaction mixture, and the mixture was stirred at 25℃for 5 hours. The reaction solution was slowly dropped into a saturated ammonium chloride solution (20 mL), followed by extraction with ethyl acetate (10 mL) three times. The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-0/1) to give the product (R) -4-acetyl-3- (methoxymethyl) piperazine-1-carboxylic acid tert-butyl ester (350 mg, 83% yield).
Third step of synthesizing (R) -3- (methoxymethyl) piperazine-1-tert-butyl formate
To a solution of tert-butyl (R) -4-acetyl-3- (methoxymethyl) piperazine-1-carboxylate (350 mg,1.3 mmol) in methanol (3.5 mL) was added 10M aqueous sodium hydroxide (1.3 mL,13 mmol) and the mixture was stirred at 90℃for 18h. The reaction solution was poured into water (50 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (dichloromethane/methanol (V/V) =1/0-10/1) to give the product (R) -3- (methoxymethyl) piperazine-1-carboxylic acid tert-butyl ester (130 mg, 43.9% yield).
Fourth step of Synthesis of tert-butyl (R) -3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylate
To a solution of 3- (chloromethyl) pyridazine (116 mg,0.9 mmol) in N, N-dimethylformamide (1.3 mL) were added triethylamine (182 mg,1.8 mmol) and tert-butyl (R) -3- (methoxymethyl) piperazine-1-carboxylate (130 mg,0.6 mmol), followed by stirring at 50℃for 18h. The reaction solution was poured into water (50 mL) and ethyl acetate (20 mL) was used three times. The organic phase was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/0-0/1) to give the product (R) -3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (120 mg, yield 65.9%).
LC-MS,M/Z(ESI):323.3[M+H]+
Fifth step (R) -3- ((2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine Synthesis
To a solution of tert-butyl (R) -3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylate (120 mg,0.4 mmol) in dioxane (1.2 mL) was added hydrochloric acid/1, 4-dioxane solution (1.2 mL, 4M) and the mixture was reacted at room temperature for 2h. The reaction solution was concentrated to give the product (R) -3- ((2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine (hydrochloride, 100 mg).
LC-MS,M/Z(ESI):223.3[M+H]+
Sixth step (R) -2-fluoro-4-isobutyl-6- (3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzonitrile synthesis
To a solution of 2, 6-difluoro-4-isobutylbenzonitrile (intermediate A1,80mg,0.4 mmol) in N, N-dimethylformamide (1 mL) were added (R) -3- ((2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine (89 mg,0.4 mmol) and N, N-diisopropylethylamine (146 mg,1.2 mmol), followed by stirring at 80 ℃ for 18h. The reaction solution was poured into water (50 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed five times with water (10 mL), twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (dichloromethane/methanol (V/V) =1/0-10/1) to give the product (R) -2-fluoro-4-isobutyl-6- (3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzonitrile (80 mg, yield 49.1%).
LC-MS,M/Z(ESI):398.3[M+H]+
Seventh step (R) -3- ((4- (3-fluoro-5-isobutyl-2- (2H-tetrazol-5-yl) phenyl) -2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine Synthesis
(R) -2-fluoro-4-isobutyl-6- (3- (methoxymethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzonitrile (80 mg,0.8 mmol), sodium azide (104 mg,1.6 mmol) and tributyltin chloride (521 mg,1.6 mmol) were dissolved in toluene (1.2 mL), and the solution was poured into a stainless steel jar liner and sealed and reacted at 140℃for 12h. The reaction solution was slowly poured into water (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by reverse phase preparative chromatography (column: phenomenex Synergi C < 100 > 25mm < 4 > um; solvent: a = water + 0.1% formic acid (99%), B = acetonitrile; gradient: 5% -95%,7 min) to give the product (R) -3- ((4- (3-fluoro-5-isobutyl-2- (2H-tetrazol-5-yl) phenyl) -2- (methoxymethyl) piperazin-1-yl) methyl) pyridazine (21.3 mg, 99.42% purity, 24% yield).
1H NMR(400MHz,DMSO)δ9.10(dd,1H),7.66(qd,2H),6.92–6.83(m,2H),4.14(d,1H),3.73(d,1H),3.47(dd,2H),3.17(dd,1H),3.12(s,3H),2.89(d,1H),2.76–2.51(m,6H),2.22–2.15(m,1H),1.90(dq,1H),0.89(d,6H).
LC-MS,M/Z(ESI):441.1[M+H]+
EXAMPLE 2 preparation of the target Compound I-5
(R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid
The synthetic route for the target compound I-5 is shown below:
First step Synthesis of tert-butyl (R) -3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylate
To a solution of tert-butyl (R) -3- (fluoromethyl) piperazine-1-carboxylate (1.2 g,5.5 mmol) in N, N-dimethylformamide (20 mL) was added 3- (chloromethyl) pyridazine (1 g,7.5 mmol) and triethylamine (2 g,15 mmol) and stirred at 60℃for 18 hours. The reaction solution is directly concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/1) to give tert-butyl (R) -3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylate (500 mg, yield 29%).
LC-MS,M/Z(ESI):311.2[M+H]+
Second step (R) -3- ((2- (fluoromethyl) piperazin-1-yl) methyl) pyridazine Synthesis
(R) -3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (500 mg,1.6 mmol) was dissolved in dichloromethane (10 mL), then 5mL of 4M dioxane hydrochloride solution was added and stirred at room temperature for 1h. Direct concentration gave the product (R) -3- ((2- (fluoromethyl) piperazin-1-yl) methyl) pyridazine (500 mg, 100% yield).
LC-MS,M/Z(ESI):211.2[M+H]+
Third step of synthesizing methyl (R) -4-bromo-2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzoate
A solution of methyl 4-bromo-2, 6-difluorobenzoate (575 mg,2.3 mmol), (R) -3- ((2- (fluoromethyl) piperazin-1-yl) methyl) pyridazine (500 mg,2.3 mol) and potassium carbonate (950 mg,6.9 mmol) in dimethyl sulfoxide (5 mL) was placed in a 100℃oil bath and reacted for 15h. The reaction was added dropwise to a saturated aqueous sodium chloride solution (50 mL), followed by extraction with ethyl acetate (20 mL) three times. Five times with water (10 mL), twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/1) to give the product (R) -methyl 4-bromo-2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzoate (150 mg, yield 15%).
LC-MS,M/Z(ESI):441.20/443.2[M+H]+
Fourth step of synthesizing methyl (R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoate
Methyl (R) -4-bromo-2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) benzoate (150 mg,0.34 mmol), potassium carbonate (94 mg,0.68 mmol), (SP-4-3) - [ dicyclohexyl [2',4',6 '-tris (isopropyl) [1,1' -biphenyl ] -2-yl ] phosphine ] (methanesulfonic acid) [2'- (methylamino) [1,1' -biphenyl ] -2-yl ] palladium (34 mg,0.04 mmol) and isobutylboronic acid (1.7 g,1.7 mmol) were added to anhydrous dioxane (5 mL) under nitrogen atmosphere and reacted at 90℃for 2h. Direct concentration gave the crude product which was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =1/1) to give the product (R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid methyl ester (120 mg, yield 84%).
LC-MS,M/Z(ESI):419.20[M+H]+
Fifth step (R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid synthesis
(R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid methyl ester (120 mg,0.29 mmol) was dissolved in methanol (4 mL) and water (1 mL), followed by addition of lithium hydroxide (21 mg,0.87 mmol) and reaction at room temperature for 18h. The reaction solution was concentrated to give a crude product, which was subjected to reverse phase preparative chromatography (column: phenomenex Synergi C18.100.25 mm.4 μm; solvent: a=water+0.1 vol% formic acid (99%), b=acetonitrile; gradient: 5% -95% for 7 min) to give the product (R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid (80 mg, yield 68%).
1H NMR(400MHz,dmso)δ13.50(s,1H),9.12(d,1H),7.74-7.65(m,2H),6.74-6.71(m,2H),4.87-4.59(m,3H),4.20-3.94(m,3H),3.19-2.87(m,5H),2.44-2.40(m,2H),1.82(m,1H),0.84(d,6H).
LC-MS,M/Z(ESI):405.2[M+H]+
EXAMPLE 3 preparation of the target Compound I-6
(R) -N- (ethylsulfonyl) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzamide
The synthetic route for the target compound I-6 is shown below:
First step Synthesis of (R) -N- (ethylsulfonyl) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzamide
(R) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzoic acid (80 mg,0.19 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (380 mg,1.98 mmol) and 4-dimethylaminopyridine (435 mg,3.56 mmol) were dissolved in dichloroethane (3 mL), then nitrogen was replaced, the reaction solution was stirred at room temperature for 10min, and then ethylsulfonamide (324 mg,2.98 mmol) was added, and the reaction solution was reacted at 50℃for 3h. The reaction solution was concentrated to give a crude product which was subjected to reverse phase preparative chromatography (column: phenomenex Synergi C18100 x 25mm x 4um; solvent: a=water+0.1 vol% formic acid (99%), b=acetonitrile; gradient: 5% -95% for 7 min) to give the product (R) -N- (ethylsulfonyl) -2-fluoro-6- (3- (fluoromethyl) -4- (pyridazin-3-ylmethyl) piperazin-1-yl) -4-isobutylbenzamide (8 mg, yield 8%).
1H NMR(400MHz,DMSO)δ9.13(d,1H),7.75-7.73(m,2H),7.69-7.67(m,2H),6.73-6.71(m,2H),4.83-4.74(m,3H),4.20-3.93(m,2H),3.21-2.43(m,8H),1.82(m,1H),1.24-1.23(m,3H),0.84(d,6H).
LC-MS,M/Z(ESI):496.2[M+H]+
EXAMPLE 4 preparation of the target Compound I-1
3- (((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) methyl) pyridazine
The synthetic route for the target compound I-1 is shown below:
First step Synthesis of 6- ((3R) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile
(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) under nitrogen, 2, 6-difluoro-4-isobutylbenzonitrile (intermediate A1,940mg,4.81 mmol) was added thereto and stirred at 80℃for 16h. After completion of the reaction, the mixture was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography to give 6- ((3R) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile (710 mg, yield 47%).
LC-MS,M/Z(ESI):312.1[M+H]+
Second step Synthesis of 6- ((3R) -4- (pyridazin-3-ylcarbonyl) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile
6- ((3R) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile (700 mg,2.25 mmol), HATU (1.076 g,2.70 mmol), 3-carboxypyridazine (308 mg,2.48 mmol) and DIPEA (552 mg,4.50 mmol) were dissolved in DMF (10 mL) and reacted at 25℃for 16h. After completion of the reaction, the mixture was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography to give 6- ((3R) -4- (pyridazin-3-ylcarbonyl) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile (415 mg, yield 44%).
LC-MS,M/Z(ESI):418.1[M+H)+
The third step is the synthesis of ((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) (pyridazin-3-yl) methanone
6- ((3R) -4- (pyridazin-3-ylcarbonyl) -3- (difluoromethyl) piperazin-1-yl) -2-fluoro-4-isobutylbenzonitrile (400 mg,0.96 mmol), sodium azide (624 mg,9.60 mmol) and tributyltin chloride (3.12 g,9.60 mmol) were dissolved in toluene (2 mL) and the pot was heated to 140℃and stirred for 12h. After completion of the reaction, the mixture was diluted with water (20 mL), extracted three times with methylene chloride (20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography to give ((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) (pyridazin-3-yl) methanone (233 mg, yield 53%).
LC-MS,M/Z(ESI):461.1[M+H]+
Fourth step, synthesis of 3- (((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) methyl) pyridazine
((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) (pyridazin-3-yl) methanone (200 mg,0.43 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of borane in tetrahydrofuran (3.44 mL,4.30mmol,1 mol/L) was added thereto at 0℃and after the completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water (10 mL) was added thereto at 0 ℃ and extracted three times with methylene chloride (10 mL), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography to give 3- (((2R) -2- (difluoromethyl) -4- (3-fluoro-2- (1H-1, 2,3, 4-tetrazol-5-yl) -5-isobutylphenyl) piperazin-1-yl) methyl) pyridazine (30 mg, yield 15%).
LC-MS,M/Z(ESI):447.1[M+H]+
1H NMR(400MHz,DMSO)δ9.05(s,1H),7.61(s,2H),6.88(d,J＝7.8Hz,2H),6.20(td,J＝55.7,4.1Hz,1H),4.02(dd,J＝38.7,14.7Hz,2H),2.95(d,J＝10.7Hz,1H),2.91–2.83(m,1H),2.82–2.75(m,1H),2.70(d,J＝8.0Hz,1H),2.66–2.53(m,2H),2.43(s,2H),2.24(d,J＝10.9Hz,1H),1.84(dt,J＝12.8,6.5Hz,1H),0.82(d,J＝6.2Hz,6H).
EXAMPLE 5 preparation of the target Compound I-7
2- ((3R) -3- (difluoromethyl) -4- ((pyridin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropanoic acid) benzoic acid
The synthetic route for the target compound I-7 is as follows:
First step (3R) -3- (difluoromethyl) piperazine-1-carboxylic acid tert-butyl ester synthesis
(2R) -2- (difluoromethyl) piperazine dihydrochloride (1.00 g,4.81 mmol), triethylamine (1.46 g,14.43 mmol) was dissolved in DCM (20 mL), and di-tert-butyl dicarbonate (1.05 g,4.81 mmol) was added thereto at 0℃and stirred at this temperature for 16h. After completion of the reaction, the mixture was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (PE/EA (v/v) =2/1) to give tert-butyl (3R) -3- (difluoromethyl) piperazine-1-carboxylate (920 mg, yield 81%).
LC-MS,M/Z(ESI):237.1[M+H]+
Second step of synthesizing (3R) -3- (difluoromethyl) -4- (pyridine-3-carbonyl) piperazine-1-carboxylic acid tert-butyl ester
(3R) -3- (difluoromethyl) piperazine-1-carboxylic acid tert-butyl ester (900 mg,3.81 mmol), HATU (1.82 g,4.57 mmol), 3-carboxypyridazine (473 mg,3.81 mmol) and N, N-diisopropylethylamine (1.18 g,9.14 mmol) were dissolved in DMF (10 mL) and reacted at 25℃for 16h. After completion of the reaction, the mixture was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (PE/EA (v/v) =1/1) to give tert-butyl (3R) -3- (difluoromethyl) -4- (pyridine-3-carbonyl) piperazine-1-carboxylate (977 mg, yield 75%).
LC-MS,M/Z(ESI):343.1[M+H]+
Third step of Synthesis of (3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester
Tert-butyl (3R) -3- (difluoromethyl) -4- (pyridine-3-carbonyl) piperazine-1-carboxylate (950 mg,2.78 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of borane in tetrahydrofuran (27.8 mL,27.8mmol,1 mol/L) was added thereto at 0℃and after the addition was completed, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction was quenched by addition of water (10 mL) thereto at 0 ℃, extracted three times with ethyl acetate (10 mL), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (PE/EA (v/v) =1/1) to give tert-butyl (3R) -3- (difluoromethyl) -4- ((pyridin-3-yl) methyl) piperazine-1-carboxylate (170 mg, yield 19%).
LC-MS,M/Z(ESI):329.1[M+H]+
Fourth step, synthesis of 3- (((2R) -2- (difluoromethyl) piperazin-1-yl) methyl) pyridine oxazine
Tert-butyl (3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazine-1-carboxylate (170 mg,0.52 mmol) was dissolved in dioxane (2 mL), and a dioxane solution (5 mL,20mmol,4 mol/L) of hydrogen chloride was added thereto, and after completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated to give 3- (((2R) -2- (difluoromethyl) piperazin-1-yl) methyl) pyridazine (118 mg, yield 99%).
LC-MS,M/Z(ESI):228.1[M+H]+
Fifth step, synthesis of methyl 4-bromo-2- ((3R) -3- (difluoromethyl) -4- (((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluorobenzoate
3- (((2R) -2- (difluoromethyl) piperazin-1-yl) methyl) pyridazine (118 mg,0.52 mmol), methyl 3, 5-difluoro-4-bromobenzoate (144 mg,0.57 mmol) and triethylamine (263 mg,2.6 mmol) were dissolved in DMF (5 mL) and reacted at 80℃for 16h. After completion of the reaction, the mixture was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (PE/EA (v/v) =1/1) to give methyl 4-bromo-2- ((3R) -3- (difluoromethyl) -4- (((pyridin-3-yl) methyl) piperazin-1-yl) -6-fluorobenzoate (167 mg, yield 70%).
LC-MS,M/Z(ESI):459.1[M+H]+
Sixth step Synthesis of methyl 2- ((3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropyl) benzoate
Methyl 4-bromo-2- ((3R) -3- (difluoromethyl) -4- (((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluorobenzoate (160 mg,0.35 mmol), isobutylboronic acid (72 mg,0.70 mmol), potassium carbonate (145 mg,1.05 mmol) and XPhos Pd G4 (30 mg,0.035 mmol) were dissolved in dioxane (5 mL), reacted at 90 ℃ for 3h after completion of the reaction, diluted with water (10 mL) and extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (PE/EA (v/v) =1/3) to give methyl 2- ((3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropyl) benzoate (99 mg, 65%) in yield.
LC-MS,M/Z(ESI):437.1[M+H]+
Seventh step Synthesis of 2- ((3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropionic acid) benzoic acid
Methyl 2- ((3R) -3- (difluoromethyl) -4- ((pyridazin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropyl) benzoate (99 mg,0.23 mmol), lithium hydroxide (83 mg,3.45 mmol) were dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) and reacted for 32h at 50 ℃. After completion of the reaction, the mixture was diluted with water (10 mL), the pH was adjusted to about 3 with 1N hydrochloric acid, extracted three times with ethyl acetate (10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (DCM/MeOH (v/v) =10/1) to give 2- ((3R) -3- (difluoromethyl) -4- ((pyridin-3-yl) methyl) piperazin-1-yl) -6-fluoro-4- (2-methylpropanoic acid) benzoic acid (45 mg, yield 47%).
LC-MS,M/Z(ESI):423.3[M+H]+
1H NMR(400MHz,dmso)δ13.34(s,1H),9.12(dd,J＝4.8,1.8Hz,1H),7.70(ddd,J＝13.2,8.4,3.3Hz,2H),6.81–6.70(m,2H),6.48(td,J＝55.7,5.0Hz,1H),4.23–4.10(m,2H),3.26–3.18(m,1H),3.15–3.01(m,2H),2.99–2.93(m,2H),2.94–2.83(m,1H),2.51–2.49(m,1H),2.42(d,J＝7.2Hz,2H),1.84(td,J＝13.3,6.6Hz,1H),0.83(d,J＝6.6Hz,6H).
Example 6 preparation of the following compounds can be obtained by reference to the preparation methods of the above compounds.
In the test examples of the present invention, reference was made to patent WO2023006893A1 for the preparation of control compound I, the structure of which is shown below,
Biological testing
The compounds prepared in the examples can be tested using the test methods described below.
Test example 1 Compounds bind to AT2R assay
According to the experimental instructions of the Angiotenin AT2 Receptor Ligand Binding Assay kit (#C1TT1AT2, cisbio). First 10mM compound stock was diluted in a gradient at 5 Xdilution (10 concentrations each repeated) and 160nL of different concentrations of compound were added to 384 well plates. 40. Mu.L of 1 XTLB was added to each well and shaken at room temperature for 15 minutes. A15 mL centrifuge tube with 5mL of 1 XTLB added was prepared in advance for use. The frozen labeled cells were thawed in a 37℃water bath (1-2 minutes), and the thawed cells were rapidly transferred to the 15mL centrifuge tube, mixed well, and centrifuged at 1000g for 5 minutes at room temperature. The supernatant was removed and 2.7mL of 1 XTLB resuspended cells were added. A new 384 well plate was prepared and 10. Mu.L of the well-mixed cells were added to the corresponding wells according to the assay design. mu.L of a 4 XCompound solution, 5. Mu.L of a 4 XTag-lite red fluorescent labeled ligand, was added to each well. After 1 hour incubation at room temperature, the data were read using the HTRF mode of EnVision. The excitation light intensities of 665nM and 615nM per well were read separately, the Ratio calculated (ratio=A665 nM/B615 nM), and the IC 50 value calculated using GRAPHPAD PRISM software, X: log compound concentration, Y: A665nM/B615nM Ratio. The results of some of the compounds are shown in the present examples, see in particular table 1.
TABLE 1 IC 50 values for Compounds tested for AT2R binding Activity
Compounds of formula (I) IC50(nM)
I-1 1.7
I-3 59
I-5 6.2
1-7 5.6
Experimental results show that in the binding test of the tested compound and the AT2R, the tested compound has stronger binding effect with the AT 2R.
Test example 2 pharmacokinetic test in rats
Rat pharmacokinetic experiments were performed using male SD rats, 3 in each group, 180-240g, and each group was orally administered with 10mg/kg by gavage overnight fast. Blood was collected 15, 30 minutes and 1,2, 4, 6, 8, 24 hours before and after dosing. Blood samples were centrifuged at 8000 rpm at 4℃for 6 minutes and plasma was collected and stored at-20 ℃. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model. The results of some of the compounds are shown in the present examples, see in particular table 2.
TABLE 2 results of pharmacokinetic experiments in rats
Experimental results show that the compound has good pharmacokinetic properties on rats compared with the control compound I.
Test example 3 mouse pharmacokinetic test
Mice pharmacokinetic experiments were performed using male ICR mice, 3 mice per group, 20-30g, overnight fasted, each orally administered 10mg/kg by gavage, respectively. Blood was collected 5, 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours before and after dosing. Blood samples were centrifuged at 6000 g/min at 2-8℃for 3 min and plasma was collected and stored at-20 ℃. Plasma at each time point was taken, 10 times of 50% methanol acetonitrile solution containing an internal standard was added and mixed, vortex mixing was performed for 5 minutes, centrifugation was performed for 10 minutes at 4000 rpm and 4 ℃, the supernatant was taken and mixed with 1 time of water, and a proper amount of the mixed solution was taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model. The results of some of the compounds are shown in the present examples, see in particular table 3.
TABLE 3 results of pharmacokinetic experiments in mice
Experimental results show that the compound has good pharmacokinetic properties on mice compared with the control compound I.
Test example 4 Manual patch clamp technique to test the effect of Compounds on hERG channel currents
Manual patch clamp assays were performed using HEK-293 cell lines stably expressing the hERG potassium channel, which were purchased from Creacell (cat# A-0320). The final concentrations of the test compounds were all formulated on the same day and re-dissolved in extracellular fluid. Extracellular fluid (mM) was :40mM NaCl,3.5mM KCl,1mM MgCl2·6H2O,2mM CaCl2·2H2O,10mM D-Glucose,10mM HEPES,1.25mM NaH2PO4·2H2O;pH 7.4(NaOH titrated). Intracellular fluid (mM) was ：20mM KCl,115mM K-Aspartic,1mM MgCl2·6H2O,5mM EGTA,10mM HEPES,2mM Na2-ATP;pH 7.4(KOH titrated).
Electrophysiological test, the cell membrane voltage is clamped at-80 mV after the whole cell is sealed. The clamp voltage is divided from-80 mV to-50 mV for 0.5s (used as leakage current detection), then is stepped to 30mV for 2.5s, and then is quickly restored to-50 mV for 4s, so that the tail current of the hERG channel can be excited. Data were collected repeatedly every 10s and the effect of the drug on hERG tail current (Peak tail current compound) was observed. The leakage current was measured with a stimulus of-50 mV for 0.5 s. Administration was initiated after stabilization of hERG current recorded by whole cells, and each drug concentration was applied to 5min (or current to stabilization) followed by detection of the next concentration, and each test compound was detected at one or more concentrations. The current (Peak tail current Control) detected by each cell in the compound-free external fluid served as its own control. Each concentration was assayed in duplicate using at least two independent cells. All electrophysiological experiments were performed at room temperature. Test data were collected by IPA amplifier (Sutter Instrument) and stored in Sutter Patch software.
Analysis of the data the corresponding inhibition rate for each drug concentration was calculated (1- (Peak tail current compound/Peak tail currentControl), and the IC 50 values for each compound were calculated in GRAPHPAD PRISM software using a non-linear fit to the concentration effect curve, y=1/(1+10 ((LogIC 50-X) HillSlope)). The results of some compounds are shown in an exemplary manner in accordance with the invention, see in particular table 4.
TABLE 4 inhibition of hERG by Compounds
Compounds of formula (I) IC50(μM)
Control Compound I 2.5
I-1 6.8
I-5 >30
1-7 >30
Experimental results show that compared with the control compound I, the compound has lower risk of inhibiting hERG in an in vitro system and lower risk of cardiac safety.
Test example 5 Chronic Constrictive Injury (CCI) model of rat sciatic nerve
And fixing the male SD rats with the weight of 200-250 g in a prone position after anesthesia. The method comprises shaving the outer side of the thigh of an animal to the femoral region, sterilizing, cutting 1.5cm of skin of the thigh, separating fascia, blunt separating biceps femoris to expose sciatic nerve, dissociating nerve at main trunk part before trigeminal branching of sciatic nerve by about 7mm, gently separating sciatic nerve, ligating 4 lanes of sciatic nerve with 5-0 suture line at a position 2mm before trigeminal branching, and spacing 1mm each lane to make the length of ligatured nerve about 4-5mm. The tightness of the ligation is based on slight twitching of the calf muscle or toe during knotting, and the muscle, subcutaneous tissue and skin are sutured in sequence, the wound is cleaned and disinfected with iodophor. Suturing the skin and sterilizing. The next day of modeling, animals were randomly grouped, 8 animals per group, each orally administered with a gastric lavage vehicle or corresponding compound solution, and the mechanical pain threshold of each animal was measured with Von-Frey fiber filaments before and after administration, respectively.
The mechanical pain threshold detection method comprises the steps of continuously stimulating the sole of a hind limb to be detected by using a Von-Frey fiber for a test animal to bend the fiber, and observing the foot contraction reaction of the animal. The test animals were stimulated one by one in the order of the gram number of fiber filaments from small to large, and the fiber filaments of each gram number were continuously stimulated 5 times. If the positive response occurred less than 3 times, the above procedure was repeated using a larger primary fiber, which was the pain threshold for the animal when 3 or more positive responses were first tested (3 tests per animal, averaged). The fiber gram number is 0.6,1.0,1.4,2.0,4.0,6.0,8.0,10.0,15.0, and the cutting value is 15.0g. Data statistics were performed using GRAPHPAD PRISM 8.0.0 for each group, using One-way analysis (One-way ANOVA) for the statistical method, and comparing whether there was a statistical difference between each group, with a statistical difference of P < 0.05.
Experimental results show that the compound can obviously improve the reduction of the mechanical pain threshold of animals caused by rat sciatic nerve modeling in a chronic constrictive injury model of the sciatic nerve of the rat, and has excellent analgesic effect.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (18)

1.式I所示化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：1. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: 其中，环A选自5-6元杂芳环；wherein Ring A is selected from a 5-6 membered heteroaromatic ring; R1选自卤素、羟基、氨基、氰基、氧代(＝O)、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基；所述C1-C6烷基、C1-C6烷氧基、C3-C7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、氧代； R1 is selected from halogen, hydroxyl, amino, cyano, oxo (=O), 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, amino, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C7 cycloalkyl, oxo; m选自0、1、2、3或4；当取代基R1为多个时，所述R1相同或不同；m is selected from 0, 1, 2, 3 or 4; when there are multiple substituents R 1 , the R 1 are the same or different; L不存在或者选自C0-C6亚烷基-O-C0-C6亚烷基、C1-C6亚烷基；所述C1-C6亚烷基-O-C1-C6亚烷基或C1-C6亚烷基任选地被1-4个选自下列基团的取代基取代：氘、氧代(＝O)、甲基、乙基、卤代甲基、卤代乙基；L is absent or selected from C 0 -C 6 alkylene-OC 0 -C 6 alkylene, C 1 -C 6 alkylene; the C 1 -C 6 alkylene-OC 1 -C 6 alkylene or C 1 -C 6 alkylene is optionally substituted with 1-4 substituents selected from the following groups: deuterium, oxo (=O), methyl, ethyl, halomethyl, haloethyl; R2选自C1-C6烷基、C3-C7环烷基、5-10元杂环、6-10元芳环；所述C1-C6烷基、C3-C6环烷基、5-10元杂环、6-10元芳环任选地被1、2、3、4个选自下列基团的取代基取代：卤素、羟基、氰基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基；且R2不为甲基、乙基、异丙基、-CF3；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选自1、2、3、4、5、6、7或8；当取代基R2为多个时，所述R2相同或不同；n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; when there are multiple substituents R 2 , the R 2 are the same or different; 环E选自苯环或6元杂芳环；Ring E is selected from a benzene ring or a 6-membered heteroaromatic ring; R3选自卤素、羟基、氰基、二甲基氨基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基；所述C1-C6烷基、C1-C6烷氧基、C3-C7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氰基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基； 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选自0、1、2、3或4；当取代基R3为多个时，所述R3相同或不同；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选自羧酸、-CONHSO2R5、-SO2NHCOR5、四氮唑或四氮唑生物电子等排体；所述生物电子等排体包括但不限于磷酸、 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, R5选自H、OH、NH2、ONa、OK(钾离子)、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基、5-6元杂环；所述C1-C8烷基、C3-C8环烷基、C1-C8烷氧基、5-6元杂环任选地被1-4个选自下列基团的取代基取代：卤素、氨基、C3-C7杂环烷基、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基。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. 2.如权利要求1所述的式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A为5-6元杂芳环，所述5-6元杂芳环含有1、2、3个杂原子；2. The compound of formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the ring A is a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms; 较佳地，所述杂原子选自N、O、S；Preferably, the heteroatom is selected from N, O, S; 更佳地，所述杂原子为N；More preferably, the heteroatom is N; 较佳地，环A选自：呋喃、吡咯、噻吩、噁唑、噁二唑、噻唑、吡唑、咪唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、三嗪；Preferably, ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, and triazine; 更佳地，环A选自：吡啶、嘧啶、哒嗪、吡嗪。More preferably, ring A is selected from: pyridine, pyrimidine, pyridazine, pyrazine. 3.如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环E为苯环或6元杂芳环；3. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the ring E is a benzene ring or a 6-membered heteroaromatic ring; 所述6元杂芳环含有1、2、3个杂原子；The 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms; 所述杂原子选自N、O、S；The heteroatom is selected from N, O, and S; 较佳地，所述环E选自苯环、吡啶、嘧啶、哒嗪；Preferably, the ring E is selected from benzene ring, pyridine, pyrimidine, pyridazine; 更佳地，所述环E选自苯环。More preferably, the ring E is selected from a benzene ring. 4.如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R1选自卤素、羟基、氨基、氰基、氧代(＝O)、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、C1-C3卤代烷氧基、C3-C7环烷基、C1-C3烷基-C1-C3烷氧基、C1-C3烷基-C3-C7环烷基；m选自0、1、2、3或4；4. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that R1 is selected from halogen, hydroxyl, amino, cyano, oxo (=O), C1 - C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1 - C3 haloalkoxy, C3 - C7 cycloalkyl, C1 - C3 alkyl- C1 - C3 alkoxy, C1 - C3 alkyl-C3- C7 cycloalkyl ; m is selected from 0, 1 , 2 , 3 or 4; 较佳地，所述R1选自卤素、甲基、卤代甲基、甲氧基；Preferably, the R 1 is selected from halogen, methyl, halomethyl, methoxy; m选自0。m is selected from 0. 5.如权利要求1所述的式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：5. The compound of formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound is selected from the following structures: 环A、M、L、R1、R3、m和p具有权利要求1所述的定义。Ring A, M, L, R 1 , R 3 , m and p have the same meanings as those defined in claim 1 . 6.如权利要求1所述的式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：6. The compound of formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound is selected from the following structures: 环A、M、R1、R3、m和p具有权利要求1所述的定义。Ring A, M, R 1 , R 3 , m and p have the same meanings as those defined in claim 1 . 7.如权利要求1所述的式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物具有如下结构：7. The compound of formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound has the following structure: M、R2具有权利要求1所述的定义；M and R2 have the definitions in claim 1; 较佳地，具有结构IVa、IVb：Preferably, it has structures IVa and IVb: 8.如权利要求1或权利要求7所述的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R2选自C1-C3烷基、C3-C6环烷基、5-6元杂环、苯环；所述C1-C3烷基、C3-C6环烷基、5-6元杂环、苯环任选地被1、2、3、4个选自下列基团的取代基取代：卤素、羟基、氰基、氨基、C1-C3烷基、C1-C6烷氧基、C3-C6环烷基；且R2不为甲基、乙基、异丙基、-CF3；和/或8. The compound according to claim 1 or claim 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that R2 is selected from C1 - C3 alkyl, C3- C6 cycloalkyl, 5-6 -membered heterocycle, benzene ring; the C1 - C3 alkyl, C3- C6 cycloalkyl, 5-6-membered heterocycle, benzene ring is optionally substituted by 1, 2 , 3, 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C1 - C3 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl; and R2 is not methyl, ethyl, isopropyl, -CF3 ; and/or n选自1、2、3；和/或n is selected from 1, 2, 3; and/or n为1。n is 1. 9.如权利要求1或权利要求7所述的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R2选自CH2F、CHF2、C1-C3烷基-C1-C6烷氧基、C3-C7环烷基、C1-C3烷基-C3-C7环烷基；9. The compound according to claim 1 or claim 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that 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; 较佳地，所述R2选自CH2F、CHF2、C1-C3烷基-C1-C3烷氧基、C3-C4环烷基、C1-C3烷基-C3-C4环烷基；n选自1、2、3；Preferably, R 2 is selected from CH 2 F, CHF 2 , C 1 -C 3 alkyl-C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl, C 1 -C 3 alkyl-C 3 -C 4 cycloalkyl; n is selected from 1, 2, 3; 较佳地，所述R2选自CH2F、CHF2、甲基-甲氧基、乙基-甲氧基、环丙基、甲基-环丙基；n选自1；较佳地，所述R2选自CH2F、CHF2、 Preferably, R 2 is selected from CH 2 F, CHF 2 , methyl-methoxy, ethyl-methoxy, cyclopropyl, methyl-cyclopropyl; n is selected from 1; Preferably, R 2 is selected from CH 2 F, CHF 2 , 较佳地，所述R2选自CH2F、CHF2；Preferably, said R 2 is selected from CH 2 F, CHF 2 ; 较佳地，所述R2选自CHF2。Preferably, the R 2 is selected from CHF 2 . 10.如权利要求1所述的式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R3选自卤素、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基；所述C1-C6烷基、C1-C6烷氧基、C3-C7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氰基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基；10. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that R3 is selected from halogen, C1- C6 alkyl, C1 - C6 alkoxy, C3 - C7 cycloalkyl; the C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C7 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxyl, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C7 cycloalkyl; p选自0、1、2、3或4；p is selected from 0, 1, 2, 3 or 4; 较佳地，所述R3选自F、C1-C5烷基、C1-C5卤代烷基、甲基-环丙基；p选自1、2、3；Preferably, 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; 更佳地，所述R3选自F、甲基、三氟甲基、异丁基、F取代的异丁基、甲基-环丙基；p选自2。More preferably, R 3 is selected from F, methyl, trifluoromethyl, isobutyl, isobutyl substituted with F, methyl-cyclopropyl; and p is selected from 2. 11.如权利要求1、权利要求5-7中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述M选自羧酸、-CONHSO2R5、-SO2NHCOR5、四氮唑或四氮唑生物电子等排体；11. The compound according to claim 1, or any one of claims 5 to 7, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein M is selected from carboxylic acid, -CONHSO 2 R 5 , -SO 2 NHCOR 5 , tetrazole or tetrazole bioisostere; 较佳地，M选自羧酸、-CONHSO2R5、-SO2NHCOR5、四氮唑；所述R5选自C1-C3烷基、C3-C5环烷基；Preferably, M is selected from carboxylic acid, -CONHSO 2 R 5 , -SO 2 NHCOR 5 , tetrazole; said R 5 is selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl; 更佳地，M选自羧酸、四氮唑、-CONHSO2CH2CH3；More preferably, M is selected from carboxylic acid, tetrazole, -CONHSO 2 CH 2 CH 3 ; 更佳地，M选自羧酸、四氮唑；More preferably, M is selected from carboxylic acid and tetrazole; 更佳地，M选自四氮唑。More preferably, M is selected from tetrazole. 12.如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，L不存在或选自羰基、亚甲基、-CH2CH2-、-CH(CH3)-、-CH2CH2CH2-、-CH2CH(CH3)-、-O-CH2-；12. The compound of formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that L is absent or selected from carbonyl, methylene, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -O-CH 2 -; 较佳地，L选自亚甲基、-CH2CH2-、-CH(CH3)-、-O-CH2-；Preferably, L is selected from methylene, -CH 2 CH 2 -, -CH(CH 3 )-, -O-CH 2 -; 更佳的，L选自亚甲基。More preferably, L is selected from methylene. 13.如权利要求1所述的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物包括：13. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound comprises: 14.如权利要求1所述的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物包括：14. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound comprises: 15.一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-14中任一所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和任选地药学上可接受的载体。15. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: a compound according to any one of claims 1 to 14, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; and optionally a pharmaceutically acceptable carrier. 16.一种如权利要求1-14中任一所述的化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或权利要求15所述的药物组合物的用途，所述用途包括：16. Use of a compound according to any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 15, comprising: 作为AT2R拮抗剂；Acts as an AT2R antagonist; 和/或，预防和/或治疗AT2R介导的疾病；and/or, preventing and/or treating AT2R-mediated diseases; 和/或，预防和/或治疗期望或需要AngⅡ作用减少的疾病；and/or, preventing and/or treating diseases in which a reduction in the action of Ang II is desired or required; 和/或，制备作为AT2R拮抗剂的药物、药物组合物或制剂；and/or, preparing a medicament, pharmaceutical composition or formulation as an AT2R antagonist; 和/或，制备预防和/或治疗AT2R在其中表达并且期望或必需对其进行抑制的疾病的药物、药物组合物或制剂。And/or, preparing a medicament, pharmaceutical composition or formulation for preventing and/or treating a disease in which AT2R is expressed and its inhibition is desired or necessary. 17.如权利要求16所述的用途，其特征在于，所述疾病为神经病或神经性疼痛。17. The use according to claim 16, wherein the disease is neuropathy or neuropathic pain. 18.如权利要求17所述的用途，其特征在于，所述疾病为原发性神经病、继发性神经病、周围神经病、由机械性神经损伤或生化神经损伤引起的神经病、带状疱疹后遗神经痛、糖尿病性神经痛或糖尿病相关神经性疾病。18. The use according to claim 17, characterized in that the disease is primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, postherpetic neuralgia, diabetic neuropathy or diabetes-related neuropathies.
CN202410774534.3A 2023-06-16 2024-06-14 Heterocyclic compounds as AT2R antagonists and uses thereof Pending CN119143734A (en)

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