Angiotensin ii receptor antagonist and use thereof in treatment of peripherally-induced neuropathic pain

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

Angiotensin II receptor antagonists and their use in treating peripheral neuropathic pain Technical Field

[0001] The present invention relates to angiotensin II type 2 (AT2) receptor antagonists and their use in preventing or treating peripheral neuropathic pain and related disorders. Background Art

[0002] The renin-angiotensin system (RAS) plays an important role in neuroprotection and neuroregeneration, regulating arterial blood pressure and ion homeostasis. There are two main receptors for AngII, AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R). Both AT1R and AT2R are seven-transmembrane receptors with similar affinity to Ang II. In the rat brain, AngII receptors are mainly AT2 receptor subtypes. AT2 receptor-specific antagonists are valuable in the treatment of various cerebrovascular, cognitive and central nervous system (CNS) diseases. In addition, AT2 receptors are found in neuronal tumor cells and transformed human neural cells. AT2 receptors are also involved in the differentiation and regeneration of neuronal tissue and the maintenance of bone. AT2R is expressed in damaged nerves and invasive immune cells and is associated with neurological pain.

[0003] The International Society for the Study of Pain defines neuropathic pain as pain caused by damage or disease of the somatosensory system (Jensen TS, Baron R, M, et al. A new definition of neuropathic pain [J]. Pain, 2011, 152(10): 2204-2205). According to the anatomical location of the injury or disease, neuropathic pain can be divided into peripherally-induced neuropathic pain (pNP) and central neuropathic pain (Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations [J]. Arch Neurol, 2003, 60: 1524-1534).

[0004] According to the International Classification of Diseases 11th version (ICD-11), peripheral neuropathic pain refers to chronic pain caused by damage or disease of the peripheral sensory nervous system. Peripheral neuropathic pain can be divided into five subtypes: trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. (Chronic neuropathic pain, Chinese Journal of Pain Medicine 2021, 27(7)).

[0005] Peripheral neuropathic pain is common in clinical practice. Common syndromes include painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (such as carpal tunnel syndrome), cranial neuralgia, postoperative or post-traumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0006] After peripheral nerve damage and lesions lead to pNP, the course of the disease is long and the clinical manifestations are complex, such as sensory impairment, movement disorders, autonomic dysfunction, and pain symptoms in the corresponding nerve innervation area. The pain can be spontaneous, persistent pain, or paroxysmal pain. In addition, patients may experience symptoms such as muscle spasms, stiffness, weakness, and atrophy. Physical examination can show decreased muscle tone, muscle atrophy, weakened or absent tendon reflexes, and paresthesia. Even if the original cause is removed, the injury heals, or is effectively controlled, the pain persists, seriously affecting the patient's quality of life and accompanied by emotional disorders (Editorial Committee of the Chinese Expert Consensus on Peripheral Neuropathic Pain. Chinese Expert Consensus on the Diagnosis and Treatment of Peripheral Neuropathic Pain. Chinese Journal of Pain Medicine. 2020, 26(05):321–328). Clinical characteristics include: spontaneous pain, allodynia, hyperalgesia, and paresthesia.

[0007] Painful diabetic peripheral neuropathy (PDPN) is the most common chronic complication of diabetes. It affects 16% of diabetic patients, many of whom remain undiagnosed (12.5%) and untreated (39%). In 2013, the prevalence of type 2 diabetes in my country reached 10.4%, translating to an estimated 22 million patients suffering from PDPN.

[0008] Postherpetic neuralgia (PHN) is also a common form of postherpetic neuralgia, with an annual incidence of 3.9 to 42.0 cases per 100,000 people. PHN occurs in 9% to 34% of patients with herpes zoster. Among patients aged 40 years and older visiting dermatology, neurology, and pain management departments in urban hospitals in my country, the overall prevalence of herpes zoster is 7.7%, and the overall prevalence of PHN is 2.3%. The prevalence of both conditions increases with age.

[0009] Trigeminal neuralgia is a common cranial nerve disease in clinical practice, with a prevalence of 182 people per 100,000 and an annual incidence of 3 to 5 per 100,000. It mostly occurs in adults and the elderly, with the peak age being 48 to 59 years old.

[0010] Therefore, peripheral neuropathic pain has a profound emotional and socioeconomic impact on patients, while existing therapeutic drugs and treatments have limited efficacy and relatively large side effects. Therefore, there is a significant unmet medical need for pNP.

[0011] Specifically, medication is currently the main treatment for pNP, but current drug treatments have limited efficacy and safety risks. The most commonly used drugs to relieve chronic peripheral neuropathic pain are opioids, anticonvulsants, and antidepressants. Opioids are effective for acute pain, but due to the high risk of abuse and potential serious adverse reactions, they are limited treatment options for chronic peripheral neuropathic pain. Anticonvulsants such as gabapentin and pregabalin, as well as tricyclic antidepressants, have significant central nervous system side effects.

[0012] Currently, the most widely used central analgesics for the clinical treatment of peripheral neuropathic pain (pNP) are gabapentin and pregabalin. Extensive clinical data demonstrate that gabapentin and pregabalin have significant central side effects. Fatigue and dizziness are the most common side effects of these drugs. Other side effects include headache, anxiety, and digestive-related nausea, constipation, bloating, and stomach pain. Opioid analgesics, which are clinically effective, have serious side effects such as respiratory depression and addiction, in addition to nausea, vomiting, and dizziness.

[0013] Therefore, there is still a need in the art for more effective drugs with fewer side effects for treating peripheral neuropathic pain, and the present invention solves this need to a large extent. Summary of the Invention

[0014] The present invention provides compounds useful as AT2 receptor antagonists, which have excellent inhibitory activity on AT2 receptors, better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and / or fewer side effects, wider therapeutic window), and other superior properties.

[0015] The present invention particularly provides the use of AT2 receptor antagonist compounds in preventing or treating peripheral neuropathic pain (pNP).

[0016] The mechanism of the present invention is that Ang II acts on AT2 receptors, producing inflammatory factors such as reactive oxygen species (ROS) in the skin and surrounding macrophages of damaged nerves. ROS act on the dorsal root ganglion, causing calcium ion influx in the neurons of the dorsal root ganglion and producing hyperalgesia. AT2 receptor antagonists can reduce the recruitment of macrophages to the painful area, inhibit the high expression of AT2 receptors in macrophages, and by inhibiting AT2 receptors, suppress the production of reactive oxygen and nitrogen species, thereby inhibiting pain signal transmission. The present invention exerts its analgesic effect through immune cells in the peripheral nervous system, rather than through the central nervous system, thus avoiding the central nervous system side effects associated with previous drugs.

[0017] Therefore, more specifically, the present invention provides the use of compounds that are AT2 receptor antagonists in preventing or treating peripheral neuropathic pain associated with macrophages, in particular preventing or treating peripheral neuropathic pain associated with the recruitment / aggregation of macrophages, peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages, and / or peripheral neuropathic pain associated with increased levels of reactive oxygen species / nitrogen species produced by macrophages.

[0018] The inventors discovered that experiments evaluating the effects of AT2 receptor antagonists on angiotensin II (AngII)-induced reactive oxygen species (ROS) production in isolated mouse peritoneal macrophages showed that AT2 receptor antagonists can reduce the increase in reactive oxygen species (ROS) in mouse macrophages caused by AngII by inhibiting AT2 receptors. Furthermore, in vivo efficacy studies have shown that, utilizing the aforementioned mechanism, AT2 receptor antagonists produce a significant analgesic effect. AT2 receptor antagonists have a significant analgesic effect in rat models of diabetic foot pain, rat models of chronic sciatic nerve compression, rat spinal nerve ligation, and mouse models of sciatic nerve branch injury.

[0019] Therefore, in a first aspect, the present application provides the following embodiments of AT2 receptor antagonist compounds:

[0020] 1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein the compound has the structure of formula (IV):

[0021] in:

[0022] U is C 1-3 alkylene;

[0023] R 1a Selected from: C 2-8 Alkenyl and C 2-8 Alkynyl, wherein the C 2-8 Alkenyl and C 2-8 Alkynyl groups are each replaced by a C 6-10 Aryl or 5-14 membered heteroaryl substituted; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; -C 1-6 Alkylene-saturated or partially unsaturated 3-10 membered heterocyclic group; -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl);

[0024] R 1b Absent or selected from: H; optionally replaced by 1, 2, 3 or more R 13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3- 10 Cycloalkyl; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-C 6-10 aryl;

[0025] X 1 Does not exist or is CR 10 or N;

[0026] X 4 Selected from: C(=O); and -OC(=O)- and -SC(=O)-, wherein O and S are the same as X 1 connect;

[0027] R 2a C 6-10 aryl;

[0028] R 2b C 6-10 aryl;

[0029] X 2 CR 10 or N;

[0030] R 3 -C(=O)OR 11 ;

[0031] R 4 is H;

[0032] R 10 At each occurrence, select from H, -OR 11 、-SR 11 and C 1-6 alkyl;

[0033] R 11 and R 12 Each occurrence is independently H or C 1-6 alkyl;

[0034] h and k are each independently 1;

[0035] The above alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R 13 replace;

[0036] The R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 11 、-SR 11 、-P(O)R 11 R 12 and -NR 11 R 12 , and wherein with respect to the substituent R 13 The alkyl, alkylene, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 The alkyl group is substituted with a substituent.

[0037] 2. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0038] R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10Aryl, 5-14 membered heteroaryl, -OR 11 、-SR 11 and -NR 11 R 12 , and wherein with respect to the substituent R 13 The alkyl, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 The alkyl group is substituted with a substituent.

[0039] 3. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein U is methylene or ethylene.

[0040] 4. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 3 is -COOH.

[0041] 5. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 10 Independently at each occurrence: H, C 1-4 Alkyl, OH or SH.

[0042] 6. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 11 and R 12 Each occurrence is independently selected from H and C 1-4 alkyl.

[0043] 7. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 or more substituents independently selected from halogen 1-4 Alkyl; C 5-7 Cycloalkyl; each optionally substituted by 1, 2, 3 or more independently selected from halogen, OH, amino, cyano and C 1-4 The substituents of the alkyl group are phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl; wherein R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; where R11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl-SR 11 ; and wherein R 11 and R 12 is independently at each occurrence C optionally substituted with 1, 2, 3 or more halogens 1-6 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 .

[0044] 8. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 F or Cl 1-4 Alkyl; wherein R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 -OR of alkyl 11 ; where R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 Alkyl-SR 11 ; where R 11 and R 12 C independently at each occurrence 1-3 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl, each optionally substituted by 1, 2, 3 or more substituents independently selected from F, Cl, Br, I and methyl.

[0045] 9. The compound of embodiment 8 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 1-3 The alkyl group is methyl, ethyl, propyl or isopropyl.

[0046] 10. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0047] R 1a Selected from: C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the C 2-6Alkenyl and C 2-6 Each alkynyl group is substituted by 1 phenyl group or 5-10 membered heteroaryl group; phenyl group; -C 1-3 Alkylene-C 3-7 Cycloalkyl; -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclyl); -C 1-3 Alkylene-(8-10 membered benzo-fused heterocyclic group); -C 1-3 Alkylene-phenyl; and -C 1-3 Alkylene-(5-10 membered heteroaryl);

[0048] R 1b Not present, or selected from: H; C 1-6 Alkyl; C 3-7 Cycloalkyl; phenyl; -C 1-3 Alkylene-C 3-7 Cycloalkyl; and -C 1-3 Alkylene-phenyl; and

[0049] The above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R groups as defined in embodiment 1. 13 replace.

[0050] 11. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1a Selected from phenyl, -C 1-3 Alkylene-C 3-7 Cycloalkyl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclic group), -C 1-3 Alkylene-(9-10 membered benzo-fused heterocyclic group), -C 1-3 Alkylene-(5-6 membered heteroaryl) and -C 1-3 Alkylene-(9-10 membered heteroaryl), each of which is optionally substituted by 1, 2, 3 or more R 13 replace.

[0051] 12. The compound of embodiment 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R 13 Selected from C 1-4 alkyl-O-; halogen; and C optionally substituted by 1, 2 or 3 substituents independently selected from halogen 1-4 alkyl.

[0052] 13. The compound of embodiment 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein X 4 is C(=O).

[0053] 14. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein:

[0054] R 1a Selected from:

[0055] C 2-6 Alkenyl and C 2-6 Alkynyl, the C 2-6 Alkenyl and C 2-6 Each alkynyl group is substituted with one phenyl group, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, each of which is optionally substituted with one, two, or three groups independently selected from F, Cl, Br, I, and C 1-4 Substitution of alkyl groups;

[0056] Optionally, 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 phenyl substituted with an alkyl substituent; and -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5- to 6-membered heteroaryl) and -C 1-3 Alkylene-(9- to 10-membered heteroaryl), wherein said alkylene is optionally substituted at each occurrence with one -NR 11 R 12 substituted, and the phenyl, 5- to 6-membered heteroaryl and 9- to 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 Substitution of alkyl groups;

[0057] R 1b does not exist;

[0058] X 1 does not exist; and

[0059] X 4 is C(=O) or -OC(=O)-.

[0060] 15. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl.

[0061] 16. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 2-6 Alkenyl is ethenyl, 1-propenyl or 2-propenyl.

[0062] 17. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 2-6 Alkynyl is vinyl, 1-propynyl or 2-propynyl.

[0063] 18. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 is phenyl, pyridyl, indolyl or furanyl, said phenyl, pyridyl, indolyl or furanyl being optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and methyl.

[0064] 19. The compound of embodiment 18, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a Selected from:

[0065] 20. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0066] R 1a is a group selected from the group consisting of: optionally substituted phenyl, - optionally substituted C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), -optionally substituted C 1-3 Alkylene-(optionally substituted 5-7 membered monocyclic heterocyclyl),-optionally substituted C 1-3 Alkylene-(optionally substituted 8-10 membered benzo-fused heterocyclic group), -optionally substituted C 1-3 Alkylene-optionally substituted phenyl, and -optionally substituted C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl);

[0067] R 1b selected from H, optionally 1, 2, 3 or more R 13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cycloalkyl; C6- 10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-C 6-10 aryl;

[0068] X 1 It's CR 10 or N;

[0069] X 4 is C(=O);

[0070] The "optionally substituted" refers to 1, 2, 3 or more R 13 Replacement; and

[0071] R 13 As defined in embodiment 1.

[0072] 21. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R 1b is a group selected from the group consisting of: H, optionally substituted C 1-4 Alkyl, optionally substituted C 3- 7-cycloalkyl, optionally substituted phenyl, -optionally substituted C 1-3 Alkylene-(optionally substituted C 3-7 cycloalkyl), and -optionally substituted C 1-3 Alkylene-optionally substituted phenyl;

[0073] The "optionally substituted" refers to 1, 2, 3 or more R 13 replace.

[0074] 22. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0075] R 2a is optionally substituted phenyl; and / or

[0076] R 2b is optionally substituted phenyl;

[0077] The "optionally substituted" refers to 1, 2, 3 or more R 13 replace.

[0078] 23. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II):

[0079] where R 1a 、R 1b 、X 1 、X 4 、R 2a 、R 2b 、X 2 、R 3 、R 4 , h and k are as defined in Embodiment 1.

[0080] 24. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein for:

[0081] 25. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein for:

[0082] 26. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 10 It is H or methyl.

[0083] 27. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a is selected from optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), -C 1-3 Alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclyl), -C 1-3 Alkylene-(optionally substituted 8- to 10-membered benzofused heterocyclic group), -C 1- 3 alkylene-optionally substituted phenyl, and -C 1-3 Alkylene-(optionally substituted 5- to 10-membered heteroaryl).

[0084] 28. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a Is selected from:

[0085] optionally substituted phenyl;

[0086] -C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0087] -C 1-3 Alkylene-(optionally substituted 8-10 membered benzofused heterocyclyl), wherein the heterocyclyl is

[0088] -C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is

[0089] 29. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 Selected from: halogen; wherein R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; wherein R 11 and R 12 Each independently selected from H and C 1-4 Alkyl-NR 11 R 12 ; and where R 11 and R 12 are each independently C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl -P(O)R 11 R 12 .

[0090] 30. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13Selected from: halogen; wherein R 11 is C optionally substituted with 1, 2 or 3 F or Cl 1-3 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2- 4 alkynyl; wherein R 11 and R 12 -NR, each independently selected from H and methyl 11 R 12 ; and where R 11 and R 12 are each independently C optionally substituted with 1, 2 or 3 F or Cl 1-3 Alkyl -P(O)R 11 R 12 .

[0091] 31. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from: F, Cl, Br, OH, -OC 1-4 Alkyl, -N(C 1-4 Alkyl)2, cyano, C 3-7 Cycloalkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; C optionally substituted by 1, 2, 3 or more F, Cl or Br 1-4 alkyl; and wherein R 11 and R 12 -P(O)R are each independently methyl, ethyl, propyl or isopropyl 11 R 12 .

[0092] 32. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 is selected from the group consisting of: F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, and CF3; and wherein R 11 and R 12 -P(O)R, each independently methyl 11 R 12 .

[0093] 33. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 1a Selected from: (include ),

[0094] 34. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1b Selected from: H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-7 Cycloalkyl, optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 The alkylene group is optionally substituted with the phenyl group.

[0095] 35. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 1b Selected from:

[0096] H, phenyl;

[0097] Optionally substituted C 1-4 Alkyl, wherein the alkyl is methyl, ethyl or isopropyl;

[0098] Optionally substituted C 3-7 Cycloalkyl and -C 1-3 Alkylene-(C 3-7 cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and

[0099] -C 1-3 Alkylene-phenyl.

[0100] 36. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from halogen and C 1-4 alkyl.

[0101] 37. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 13Selected from F, Cl, Br and methyl.

[0102] 38. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 1b Selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, Phenyl,

[0103] 39. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from halogen and -OR 11 , and where R 11 Selected from C 1-4 alkyl.

[0104] 40. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 13 Selected from F, Cl, Br and -OCH3.

[0105] 41. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 2a and R 2b Each selected from phenyl,

[0106] 42. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0107] U is ethylene;

[0108] R 1a Selected from: -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl);

[0109] R 1b Selected from: C 1-8 Alkyl; saturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-saturated C 3-10 Cycloalkyl;

[0110] X 1 N; X4 is C(=O); X 2 N; R 2a and R 2b All are phenyl;

[0111] R 3 is -C(=O)OH;

[0112] R 4 is H;

[0113] h and k are each independently 1; and

[0114] The above cycloalkyl, aryl and heteroaryl groups are each optionally substituted with one R 13 Substitution; said R 13 C 1-6 alkyl;

[0115] Preferably, the C 6-10 Aryl is phenyl, the saturated C 3-10 The cycloalkyl group is a cyclopropyl group, and the 5-14 membered heteroaryl group is a thienyl group or a benzothienyl group.

[0116] 43. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein the compound is selected from:

[0117] The corresponding relationships between the above compounds A1 to A8 and the following example compounds are as follows: A1 = C112, A2 = C246, A3 = C202, A4 = C196, A5 = C154, A6 = C155, A7 = C184, A8 = C207.

[0118] In a second aspect, the present application provides the following embodiments, which relate to the use of the compound described in the first aspect in the preparation of a drug for treating a disease.

[0119] 44. Use of a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, in the preparation of a medicament for preventing or treating peripheral neuropathic pain.

[0120] 45. Use of a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, in the preparation of a medicament for preventing or treating macrophage-associated peripheral neuropathic pain.

[0121] 46. ​​The use according to embodiment 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with recruitment / aggregation of macrophages.

[0122] 47. The use according to embodiment 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages.

[0123] 48. The use according to embodiment 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with elevated levels of reactive oxygen species / nitrogen species produced by macrophages.

[0124] 49. The use according to any one of embodiments 44 to 48, wherein the medicament is for preventing or treating peripheral neuropathic pain caused by secondary neuropathy.

[0125] 50. The use of embodiment 49, wherein the secondary neuropathy comprises: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerous lesions; nitrofurantoin neuropathy; sausage-shaped swelling neuropathy; neuropathy caused by nutritional deficiency; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).

[0126] 51. The use according to any one of embodiments 44-50, wherein the medicament is for preventing or treating a condition or symptoms associated therewith selected from the group consisting of trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0127] 51a. The use of any one of embodiments 44-50, wherein the medicament is for preventing or treating a condition or symptoms associated therewith selected from the group consisting of postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0128] 52. The use according to any one of embodiments 44-50, wherein the medicament is used to prevent or treat a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0129] 52a. The use according to any one of embodiments 44 to 50, wherein the medicament is used to prevent or treat a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0130] In a third aspect, the present application provides the following embodiments, which relate to a method for treating a disease, comprising administering a therapeutically effective amount of the compound according to the first aspect to a patient in need thereof.

[0131] 53. A method for preventing or treating peripheral neuropathic pain, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite, or prodrug thereof.

[0132] 54. A method for preventing or treating macrophage-associated peripheral neuropathic pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite, or prodrug thereof.

[0133] 55. The method of embodiment 53 or 54, wherein the disease is peripheral neuropathic pain associated with recruitment / aggregation of macrophages.

[0134] 56. The method of embodiment 53 or 54, wherein the disease is peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages.

[0135] 57. The method of embodiment 53 or 54, wherein the disease is peripheral neuropathic pain associated with elevated levels of reactive oxygen species / nitrogen species produced by macrophages.

[0136] 58. The method according to any one of embodiments 53 to 57, wherein the disease is peripheral neuropathic pain resulting from secondary neuropathy.

[0137] 59. The method of embodiment 58, wherein the secondary neuropathy comprises: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerative lesions; nitrofurantoin neuropathy; sausage-shaped swelling neuropathy; neuropathy caused by nutritional deficiencies; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).

[0138] 60. The method of any one of embodiments 53-59, wherein the disease is a condition or symptoms associated therewith selected from the group consisting of trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0139] 60a. The method of any one of embodiments 53-59, wherein the disease is a condition or symptoms associated therewith selected from the group consisting of postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0140] 61. The method according to any one of embodiments 53-59, wherein the disease is a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0141] 61a. The method of any one of embodiments 53-59, wherein the disease is a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0142] In a fourth aspect, the present application provides the following embodiments, which relate to the compound as described in the first aspect for treating a disease.

[0143] 62. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, for use in preventing or treating peripheral neuropathic pain.

[0144] 63. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, for use in preventing or treating macrophage-associated peripheral neuropathic pain.

[0145] 64. A compound of embodiment 62 or 63, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, for use in preventing or treating peripheral neuropathic pain associated with macrophage recruitment / aggregation.

[0146] 65. The compound of embodiment 62 or 63, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, for use in preventing or treating peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages.

[0147] 66. A compound of embodiment 62 or 63, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, for use in preventing or treating peripheral neuropathic pain associated with elevated levels of reactive oxygen species / nitrogen species produced by macrophages.

[0148] 67. A compound according to any one of embodiments 62-66, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, for use in preventing or treating peripheral neuropathic pain caused by secondary neuropathy.

[0149] 68. The compound of embodiment 67 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein the secondary neuropathy comprises: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcer lesions; nitrofurantoin neuropathy ; sausage-shaped swollen neuropathy; neuropathy caused by nutritional deficiencies; neuropathy and complex regional pain syndrome caused by kidney failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapy drugs (such as vincristine), alcohol, lead, arsenic, mercury, and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).

[0150] 69. A compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, for use in preventing or treating a condition or symptoms associated therewith selected from the group consisting of trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0151] 69a. A compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, for use in preventing or treating a condition or a symptom associated therewith selected from the group consisting of postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0152] 70. A compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, for use in preventing or treating a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0153] 70a. A compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, for use in preventing or treating a condition selected from the following or symptoms associated therewith: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0154] Detailed Description of the Invention

[0155] definition

[0156] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0157] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0158] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0159] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12 carbon atoms, particularly 1 to 8 ("C 1-8 alkyl”), for example 1 to 6 carbon atoms (“C 1-6 alkyl”), 1 to 4 carbon atoms (“C 1-4 alkyl”), more particularly having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. For example, as used herein, the term “C 1-8"Alkyl" refers to a linear or branched group of 1 to 8 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (for example, CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0160] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 8 carbon atoms ("C 2-8 Alkenyl", such as "C 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl and octenyl. When the compounds of the present invention contain an alkenylene group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0161] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6, 7 or 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, etc.

[0162] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6, such as 5-6 or 5-7) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, etc.

[0163] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or bicyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6; or, suitably 8-10, more suitably 9 or 10) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated monocyclic or bicyclic heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of monocyclic heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. Other examples of monocyclic heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (e.g., pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1,3-dioxolane, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (e.g., morpholino), thiomorpholinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiaz ... ane), hexahydropyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepane, 1,4-diazepane, 1,3-oxazepane, 1,3-thiazepane. Bicyclic heterocyclylene and heterocycle (group) include spiro ring systems, fused (e.g., benzofused) systems or bridged systems.Benzo-fused heterocyclylene and heterocyclyl refer to the monocyclic heterocyclylene and heterocyclyl described above fused to benzo, for example, a benzo derivative having 3-6 (suitably 4-6, more suitably 5-6) ring atoms, of which 1, 2, 3 or 4 are heteroatoms selected from N, O and S and the remaining ring atoms are C saturated or partially unsaturated monocyclic groups (i.e., "7-10 membered benzo-fused heterocyclyl"), including, for example, 2,3-dihydrobenzofuranyl. 1,3-Dihydroisobenzofuranyl 2,3-Dihydrobenzo[c]thienyl 1,3-Dihydrobenzo[c]thienyl (Iso)indolinyl (Iso)dihydroisoindole (Ethylenedi)benzo[d][1,3]dioxolyl (Ylene)benzo[d][1,3]dithiolene (Ylene)benzo[d][1,3]oxathiolene (Ylidene)3H-benzo[c][1,2]oxathiolene (Ylidene)3H-benzo[d][1,2]oxathiolene (Iso)2,3-dihydrobenzo[d]oxazolyl (Iso)2,3-dihydrobenzo[d]thiazolyl (Iso)2,3-dihydro-1H-benzo[d]imidazolyl 2,3-Dihydrobenzo[d]isoxazolyl (Iso)2,3-dihydrobenzo[d]isothiazolyl 1,3-Dihydrobenzo[c]isoxazolyl (Iso)1,3-dihydrobenzo[c]isothiazolyl (Iso)2,3-dihydro-1H-indazolyl (Asian) Semanki (Ethyl)2H-chromenyl (Ethyl)4H-chromenyl (Ide)dihydrobenzothiopyranyl (Sub)2H-thiochromene ), (sub) 4H-benzothiopyran (4H-thiochromene, ), (sub) 1,2,3,4,4a,8a-hexahydroquinolinyl (Ethyl)1,2,4a,8a-tetrahydroquinolinyl (Ethyl)1,4,4a,8a-tetrahydroquinolinyl (Iso)1,2,3,4,4a,8a-hexahydroisoquinolinyl (Ethyl)1,2,3,4,4a,8a-hexahydroquinoxalinyl (Ethyl)1,4,4a,8a-tetrahydroquinoxalinyl (Sub)1,2,3,4,4a,8a-hexahydroquinazolinyl (Ylidene) 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]oxazinyl (Ylidene) 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]oxazinyl (Ethyl)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]oxazinyl (Ylidene) 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]thiazinyl (Ylidene) 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]thiazinyl (Ethyl)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]thiazinyl and 2,3-dihydrobenzo[b][1,4]dioxin Such bridged systems include, for example, 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc. The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0164] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0165] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, and 5-pyrazolyl), isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl (e.g., 1-tetrazolyl or 5-tetrazolyl), thiadiazolyl, and the like, and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. Other examples of "heteroaryl(ene)" or "heteroaryl ring" include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, purinyl and the like.

[0166] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0167] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0168] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle being optionally benzo-fused and preferably linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0169] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0170] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0171] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0172] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0173] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0174] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring, including available atoms in the bridge when the substitutable ring is bridged.

[0175] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g.13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0176] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0177] In this article, solid lines can be used Solid wedge or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0178] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0179] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0180] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0181] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0182] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0183] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0184] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0185] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0186] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0187] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0188] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0189] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0190] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0191] Pharmaceutical compositions and methods of treatment

[0192] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. In some embodiments, the pharmaceutical composition may further comprise one or more other therapeutic agents.

[0193] In some embodiments, the present invention provides use of a compound of the present invention as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for the preparation of a medicament for use as an angiotensin II type 2 (AT2) receptor antagonist.

[0194] In some embodiments, the present invention provides a compound of the present invention as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use as angiotensin II type 2 (AT2) receptor antagonist.

[0195] In some embodiments, the present invention provides a method for preventing or treating AT2 receptor-mediated disorders or symptoms associated therewith, comprising administering to a subject in need thereof an effective amount of a compound of the present invention as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0196] In some embodiments, the disease is peripheral neuropathic pain.

[0197] In some embodiments, the disease is peripheral neuropathic pain associated with macrophage recruitment / accumulation.

[0198] In some embodiments, the disease is peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages.

[0199] In some embodiments, the disease is peripheral neuropathic pain associated with elevated levels of reactive oxygen and nitrogen species produced by macrophages.

[0200] In some embodiments, the disease is peripheral neuropathic pain caused by secondary neuropathy.

[0201] In some embodiments, the secondary neuropathy includes: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcer lesions; nitrofurantoin neuropathy; sausage-shaped swelling neuropathy; neuropathy caused by nutritional deficiency; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).

[0202] In some embodiments, the disease is a condition or symptoms associated therewith selected from the group consisting of trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0203] In some embodiments, the disease is a condition or symptoms associated therewith selected from the group consisting of postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

[0204] In some embodiments, the disease is a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

[0205] In some embodiments, the disease is a condition selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (e.g., chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy or symptoms associated therewith.

[0206] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0207] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0208] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0209] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0210] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0211] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0212] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0213] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0214] In some embodiments, the compound or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg or about 1 mg / kg to about 50 mg / kg per day, for example, at a dosage of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 10 0 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg g / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg , about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg body weight.

[0215] In some embodiments, the daily dose of the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered once or divided into two, three or four doses.

[0216] In some embodiments, the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

[0217] In some embodiments, the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) cycles of treatment, wherein each cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, At least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between each two courses of treatment.

[0218] The content or dosage of the compound of the present invention in the pharmaceutical composition can be 0.005 mg / day to about 5000 mg / day, suitably 0.01 mg to about 2000 mg, preferably 1-1500 mg, preferably 1-1200 mg, preferably 1-1000 mg, preferably 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-200 mg, 1-150 mg, 1-100 mg or 1-50 mg, for example about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day.

[0219] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0220] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0221] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0222] Figure 1 shows the effects of AT2R antagonists on AngII-induced reactive oxygen species (ROS) production in mouse peritoneal macrophages, as measured by ROS fluorescence intensity in different treatment groups. Note: ###p<0.001 compared with the Control group, ***p<0.001 compared with the AngII (0.2 μM) group.

[0223] FIG2 shows the changes in 50% PWT of each group of animals at different administration time points in the efficacy test of AT2R antagonist on diabetic foot pain model induced by high-fat and high-sugar diet combined with STZ in rats.

[0224] FIG3 shows the effect of AT2R antagonists on allodynia induced by spinal nerve ligation in SD rats.

[0225] FIG4 shows the results of the efficacy evaluation of AT2R antagonists in the rat sciatic nerve chronic constriction injury model.

[0226] FIG5 shows the paw withdrawal threshold (PWT) of each group of SNI mice in the efficacy test of AT2R antagonists on the sciatic nerve branch injury (SNI) model (Mean±SD, ***p<0.001, compared with the vehicle group at the corresponding time point).

[0227] Figure 6 shows typical images of macrophages co-stained with AT2R (AKA: AGTR2) and F4 / 80 on the injured and non-injured sides of the sciatic nerve of SNI mice (Bar=20 μm).

[0228] FIG7 shows the fluorescence intensity of AT2R and F4 / 80 co-stained macrophages on the injured side of the sciatic nerve of SNI mice, Note: ***p<0.001, compared with the vehicle group.

[0229] FIG8 shows the fluorescence intensity of AT2R and F4 / 80 co-stained macrophages on the non-injured side of the sciatic nerve of SNI model mice, Note: ***p<0.001, compared with the vehicle group.

[0230] FIG9 shows typical images of TRPA1 immunofluorescence staining of the injured-side DRG of SNI mice (Bar=20 μm).

[0231] FIG10 shows the mean fluorescence intensity of TRPA1 in DRG neurons on the injured side of SNI mice (***p<0.001, compared with the vehicle group).

[0232] Figure 11 shows that compared with the normal control group (Con) mice, the expression of TRPA1 on the injured side of the sciatic nerve in the SNI group mice was significantly increased; in the SNI mouse model, compared with the saline treatment group, the A1 200 mg / kg treatment group reduced the level of TRPA1, basically reaching the TRPA1 expression level of the normal control group.

[0233] FIG12 shows the inhibitory effects of A1, PD123319, and Olodanrigan on AT2R activated by AngII in R264.7 cells.

[0234] FIG13 shows the inhibitory effects of A1, PD123319, and Olodanrigan on the elevation of inflammatory factors in the supernatant of R264.7 cells induced by AngII stimulation.

[0235] FIG14 shows that A1, PD123319, and Olodanrigan inhibit the protein expression and mRNA transcription of TRPA1 and TRPV1.

[0236] FIG15 shows the in vitro cytotoxicity results, demonstrating that A1 has no cytotoxicity to RAW264.7 and HT22 cells. DETAILED DESCRIPTION

[0237] Compound Examples

[0238] The present application provides the following compounds known in the prior art, the preparation and identification of which are disclosed in the Examples section of WO2019179515A1. All the examples of WO2019179515A1 are incorporated herein by reference.

[0239] Biological Examples

[0240] In the following biological tests, the numbering relationship between compounds A1 to A8 and the example compounds is as follows: A1 = C112, A2 = C246, A3 = C202, A4 = C196, A5 = C154, A6 = C155, A7 = C184, and A8 = C207. It should be noted that compounds A1 to A8 are used as exemplary compounds in the following tests and do not limit the present invention to these compounds.

[0241] Example 1: Effects of AT2R antagonists on AngII-induced reactive oxygen species free radical production in mouse peritoneal macrophages

[0242] 1.1 Purpose of the Test

[0243] Mouse peritoneal macrophages express angiotensin II type 2 receptor (AT2R). Angiotensin II (AngII), as a ligand for AT2R, can induce an increase in reactive oxygen species (ROS) production in mouse peritoneal macrophages by binding to the AT2R. This study evaluated the ability of AT2R antagonists to inhibit AngII-induced ROS production in mouse peritoneal macrophages by inhibiting the AT2R receptor in mouse peritoneal macrophages.

[0244] 1.2 Instruments and Equipment

[0245] 1.3 Test methods

[0246] Six-week-old C57BL / 6 male mice were euthanized and primary peritoneal macrophages were obtained by intraperitoneal injection of phenol red-free medium. After centrifugation, the cells were suspended in RPMI1640 + 5% FBS (containing 50 ng / μl GM-CSF) medium and cultured in a 37°C, 5% CO2 incubator for 2 days. The macrophages were then seeded in 96-well plates. After 24 hours of adherence, the macrophages were stained with DCFH-DA, an indicator of reactive oxygen species (ROS), and then treated as follows: 1) blank solvent group; 2) AngII (0.2 μM) alone group; 3) PD123319 combined with AngII group (PD (1 μM) + AngII (0.2 μM)): PD123319 + AngII (1 μM) + AngII (0.2 μM) group. 319 was co-treated with AngII for 0.5 h; 4) A1 combined with AngII group (A1 (0.5 μM) + AngII (0.2 μM)): A1 (0.5 μM) was co-treated with AngII for 0.5 h; 5) A1 combined with AngII group (A1 (5 μM) + AngII (0.2 μM)): A1 (5 μM) was co-treated with AngII for 0.5 h, and the level of reactive oxygen species (ROS) produced by macrophages in each group was determined by real-time fluorescence scanning.

[0247] PD123319 di-trifluoroacetate (purchased from MCE, batch number: 14354)

[0248] 1.4 Statistics

[0249] Data were collected using Excel software and analyzed using Prism 6.01 (Graph Pad Software, Inc.) software (one-way analysis of variance). The results of each experimental group were statistically analyzed to compare whether there were statistical differences between the groups. P < 0.05 was considered statistically significant.

[0250] 1.5 Experimental Results

[0251] Figure 1 shows the ROS fluorescence intensity of different treatment groups. ### p<0.001 compared with the Control group, *** p<0.001 compared with the AngII (0.2μM) group. Compared with the blank solvent control group, the level of reactive oxygen species produced by macrophages after AngII treatment was significantly increased (p<0.05). Compared with the AngII-treated group, the A1 (0.5μM) combined with AngII (0.2μM) group and the A1 (5μM) combined with AngII (0.2μM) group significantly reduced the increase in reactive oxygen species caused by AngII (p<0.05). Therefore, A1 at concentrations of 0.5μM and 5μM can inhibit the increase in reactive oxygen species caused by AngII.

[0252] Example 2: Efficacy of AT2R antagonists on diabetic foot pain model in rats induced by high-fat and high-sugar diet combined with STZ

[0253] 2.1 Purpose of the Test

[0254] In this study, a diabetic foot pain model was established in rats by feeding them a high-fat and high-sugar diet combined with intraperitoneal injection of streptozotocin (STZ) to investigate the alleviating effect of AT2R antagonists on peripheral neuropathy induced by diabetes in rats.

[0255] 2.2 Test equipment

[0256] 2.3 Experimental animals

[0257] Species: SD rats;

[0258] Grade: SPF grade;

[0259] Number and sex of animals purchased: 220, all males;

[0260] Number and sex of animals included: 70, all males;

[0261] Source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0262] License number: SCXK(Beijing)2016-0006;

[0263] Certificate number: 110011211105511316;

[0264] IACUC approval number: IACUC-202104-r-001.

[0265] 2.4 Test methods

[0266] After one week of adaptive feeding and four weeks of high-fat, high-sugar diet, rats were subjected to plantar Von Frey fiber pain measurement once, and animals weighing more than 10g were screened out. After fasting for 16 hours but not water, a single intraperitoneal injection of 40mg / kg (animal weight 220-250g) or 50mg / kg (animal weight 180-220g) of STZ was given. After 72 hours, random blood glucose levels were tested, and a blood glucose level ≥16.7mmol / L was considered a successful diabetic model. Rats with successful diabetic modeling were trained with plantar Von Frey fiber pain measurement once a week. After 4 or 5 weeks, animals with 50% PWT values ​​within the range of 1-6g were selected as diabetic foot pain animals. The rats were randomly divided into 7 groups based on their pain threshold before administration: control solvent (ddH2O), gabapentin 100 mg / kg, and A1 (12.5, 25, 50, 100, and 200 mg / kg). Each group had 10 rats, and the administration volume was 10 mL / kg. The rats were given by oral gavage. Von Frey fiber pain measurement was performed 2, 4, and 6 hours after administration, and the drug efficacy was evaluated based on the change in 50% PWT of the rats. The 50% PWT value was calculated as follows: 50% g threshold = (10 [Xf+kδ] ) / 10000

[0267] where X f = the final Von Frey nylon thread log value used in the test; k = the positive / negative response pattern value; δ = the average difference in log value between nylon thread stimuli, here a constant of 0.224.

[0268] 2.5 Statistical analysis

[0269] The experimental data were statistically analyzed using EXCEL and Graph Pad Prism 8.

[0270] All quantitative data were expressed as Mean ± SEM. Graph Pad Prism 8 software was used to plot the parameters of animals in different groups before and after administration. Two-way Anova method was used to analyze and compare the differences in PWT 50% values ​​between different administration groups and at different pain measurement time points within the same group.

[0271] 2.5 Experimental Results

[0272] Figure 2 shows the changes in 50% PWT in each group of animals at different dosing time points. Animals were randomly divided according to pain threshold. 50% PWT values ​​were evenly distributed among the groups at 0 hour before dosing, with no significant differences. Compared with the vehicle control group, gabapentin 100 mg / kg, A1 100 mg / kg, and A1 200 mg / kg groups significantly alleviated diabetic peripheral neuropathy 2, 4, and 6 hours after administration; A1 50 mg / kg and A1 25 mg / kg groups significantly alleviated diabetic peripheral neuropathy 4 and 6 hours after administration; and A1 12.5 mg / kg group significantly alleviated diabetic peripheral neuropathy 6 hours after administration. Therefore, in this experimental system, A1 at doses of 12.5, 25, 50, 100, and 200 mg / kg significantly alleviated peripheral neuropathy in rats with a diabetic foot pain model established by feeding a high-fat, high-sugar diet combined with intraperitoneal injection of STZ.

[0273] Example 3: Efficacy of AT2R antagonists in the rat spinal nerve ligation model (SNL)

[0274] 3.1 The purpose of this study was to evaluate the pharmacological effects of AT2R antagonists in the spinal nerve ligation model of SD rats using the mechanical allodynia assay.

[0275] 3.2 Test equipment

[0276] 3.3 Experimental animals

[0277] Species: Sprague-Dawley rats;

[0278] Grade: SPF grade;

[0279] Number and sex of animals included: 100, male;

[0280] Source: Shanghai Slake Laboratory Animal Co., Ltd.

[0281] License number: SCXK(Shanghai)2017-0005;

[0282] Certificate number: 20170005023847;

[0283] IACUC protocol: GP02-021-2019v1.0.

[0284] 3.4 Experimental process

[0285] Sprague-Dawley rats were fully anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg / kg). The lumbar surgical area was shaved, and the skin was disinfected three times with iodine and 70% ethanol. After the skin dried, surgery began, performed under aseptic conditions. The left spinal nerves L5 and L6 were isolated, tightly ligated with 6-0 silk suture, and the wound sutured to complete the rat SNL model.

[0286] On the 11th day after surgery, the animals were placed in the experimental environment for acclimatization for 15 minutes per day for 3 consecutive days.

[0287] On the 13th day after surgery, the rats were subjected to the measurement of the basal value of mechanical allodynia. The animals without mechanical allodynia (with a paw withdrawal threshold greater than 5g) and with a paw withdrawal threshold less than 0.5g were excluded and randomly divided into 10 groups according to the basal paw withdrawal threshold: solvent control group (ddH2O), olodanrigan 200mg / kg, A1 200mg / kg, A2 200mg / kg, A3 200mg / kg, A4 200mg / kg, A5 200mg / kg, A6 200mg / kg, A7 200mg / kg, A8 200mg / kg, 10 rats / group, 5mL / kg of drug administered by gavage.

[0288] On the 14th day after surgery, mechanical allodynia was tested using Von Frey fibers at 0 hour before administration and 2, 4, and 6 hours after administration. Mechanical allodynia was expressed as the paw withdrawal threshold (PWT) in rat behavioral tests and was calculated according to the following formula: 50% response threshold (g) = (10 (Xf+kδ) ) / 10,000

[0289] Xf = final test fiber value used in the test, k = table value (Chaplan et al. 1994, page 62), δ = mean difference

[0290] 3.5 Statistical analysis

[0291] Data were collected using Excel software and analyzed using Prism 6.01 (Graph Pad Software, Inc.) software (two-way ANOVA with Bonferroni multiple comparison test).

[0292] 3.6 Test results

[0293] Figure 3 shows the effect of AT2R antagonists in the allodynia test induced by spinal nerve ligation in SD rats. The baseline value of mechanical allodynia withdrawal threshold (PWT) was tested for all model rats one day before administration, and there was no significant difference in the PWT values ​​of the test groups. After administration on the 14th day after surgery, compared with the solvent control group, Olodanrigan 200mg / kg 2h after administration, A1 200mg / kg, A6 200mg / kg, and A7 200mg / kg 2h and 4h after administration, all significantly inhibited the mechanical allodynia induced by spinal nerve ligation in rats.

[0294] Example 4: Efficacy of AT2R antagonists in rat sciatic nerve compression model (CCI)

[0295] 4.1 The purpose of this study was to evaluate the pharmacological effects of AT2R antagonists in the sciatic nerve compression model of SD rats using the mechanical allodynia assay.

[0296] 4.2 Test equipment

[0297] 4.3 Experimental animals

[0298] Species: Sprague-Dawley rats;

[0299] Grade: SPF grade;

[0300] Number and sex of animals included: 32, male;

[0301] Source: Shanghai Slake Laboratory Animal Co., Ltd.

[0302] License number: SCXK(Shanghai)2017-0005;

[0303] Certificate number: 20170005025163;

[0304] IACUC protocol: GP02-021-2019v1.0.

[0305] 4.4 Test process

[0306] Sprague-Dawley rats were fully anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg / kg). The lumbar surgical area was shaved, and the skin was disinfected three times with iodine and 70% ethanol. The surgery began after the skin dried, and aseptic techniques were performed throughout. The left sciatic nerve was isolated, and four loose ligatures were made with 4-0 chromic catgut approximately 7 mm upstream of the sciatic bifurcation, spaced approximately 1 mm apart. The wounds were sutured to complete the rat CCI model.

[0307] On the 11th day after surgery, the animals were placed in the experimental environment for acclimatization for 15 minutes per day for 3 consecutive days.

[0308] On the 13th day after surgery, the rats were subjected to the determination of the baseline value of mechanical allodynia. The animals without mechanical allodynia (with a foot withdrawal threshold greater than 5g) and those with a foot withdrawal threshold less than 0.5g were excluded and randomly divided into five groups according to the baseline foot withdrawal threshold: vehicle control group (ddH2O), olodanrigan 200mg / kg, A3 100mg / kg, A1 200mg / kg, 8 rats / group, and 5mL / kg was administered by gavage.

[0309] On the 14th day after surgery, mechanical allodynia was tested using Von Frey fibers at 0 hour before administration and 2, 4, and 6 hours after administration. Mechanical allodynia was expressed as the paw withdrawal threshold (PWT) in rat behavioral tests and was calculated according to the following formula: 50% response threshold (g) = (10 (Xf+kδ) ) / 10,000

[0310] Xf = final test fiber value used in the test, k = table value (Chaplan et al. 1994, page 62), δ = mean difference

[0311] 4.5 Statistical analysis

[0312] Data were collected using Excel software and analyzed using Prism 6.01 (Graph Pad Software, Inc.) software (two-way ANOVA with Bonferroni multiple comparison test).

[0313] 4.6 Test results

[0314] Figure 4 shows the efficacy of AT2R antagonists in a rat chronic sciatic nerve constriction injury model. Compared with the vehicle control group, A3 (100 mg / kg) at 2 and 4 hours after administration, and A1 (200 mg / kg) at 2 hours after administration, significantly inhibited mechanical allodynia induced by sciatic nerve constriction in rats. Olodanrigan (200 mg / kg) did not inhibit mechanical allodynia induced by sciatic nerve constriction in rats, either at 2 hours or 4 hours after administration.

[0315] Example 5: Efficacy of AT2R antagonists on the sciatic nerve branch injury model in mice

[0316] 5.1 Test Purpose:

[0317] The analgesic effect of AT2R antagonists on the sciatic nerve branch injury (SNI) model in mice was evaluated using a Von Frey electronic analgesia. The effects of AT2R antagonists on the co-staining of AT2R receptors and F4 / 80 on macrophages in the SNI model mice, as well as on the expression of transient receptor potential ion channel subunit 1 (TRPA1) in dorsal root ganglion (DRG) neurons were studied.

[0318] 5.2 Test equipment

[0319] Electronic analgesia (IITC, 2392), small animal anesthesia machine (R510-29), laser confocal microscope (Zeiss, LSM710), frozen section machine (ThermoFisher, NX70).

[0320] 5.3 Experimental Animals

[0321] Strain: C57BL / 6 mice

[0322] Age: 4-6 weeks

[0323] Gender: Male

[0324] Weight: 14-20 grams

[0325] Number of animals purchased: 70

[0326] Laboratory animal provider: Hunan Slake Jingda Laboratory Animal Co., Ltd.

[0327] Production license number: SCXK (Xiang) 2019-0004

[0328] 5.4 In vivo test process

[0329] 1) Mice were fully anesthetized by inhalation of isoflurane and fixed in a prone position on an operating table to fully expose the lateral buttocks. The left posterior branch was shaved and disinfected with alcohol. Aseptic techniques were performed during the surgery. SNI surgery group: The mouse skin was incised parallel to the sciatic nerve at the femur, exposing the sciatic nerve trunk until the tibial nerve, common peroneal nerve, and sural nerve were exposed. The tibial nerve and common peroneal nerve were tightly ligated with medical absorbable suture (8-0). A segment of the nerve (approximately 2-4 mm) was then cut from the ligation site to the distal nerve, ensuring the integrity of the sural nerve. The muscle and epidermis were sutured layer by layer to complete the mouse SNI model.

[0330] 2) On the 9th day after surgery, the animals were placed in the experimental environment for acclimatization for 15 minutes per day for 3 consecutive days.

[0331] 3) PWT was measured on the 11th day after surgery. Animals with abnormal PWT (mean PWT >4 g or <1 g) were excluded and randomly divided into five groups (SNI model group) according to body weight and PWT value: solvent control group (sterile water for injection), gabapetin 50 mg / kg, A1 50 mg / kg, A1 100 mg / kg, and A1 200 mg / kg, 12 mice per group, and 10 mL / kg was administered by gavage.

[0332] 4) On postoperative day 12, the paw withdrawal threshold was tested using a Von Frey electronic anesthesiometer at 0 h before administration and 2 and 4 h after administration. The animals were placed in a specially designed pain detection multi-unit metal mesh cage and acclimatized for 30 minutes. After the animals were acclimated to the test environment, the electronic von Frey Anesthesiometer (IITC Life Science Inc.) was used to stimulate the sole of the hind limb on the surgical side of the mouse. The pressure was continuously increased until the mouse showed a significant paw withdrawal reaction. The electronic anesthesiometer recorded the reading at this time, which was the threshold of the mechanical pain response. The test was repeated 6 times in g as the detection unit. The average value was then taken as the final test index.

[0333] 5.5 Tissue sampling and immunofluorescence staining process

[0334] 1) After pain measurement, the first six mice in the Vehicle group, A1 50 mg / kg, A1 100 mg / kg, and A1 200 mg / kg groups were anesthetized with isoflurane inhalation using a small animal anesthesia machine (R510-29) and euthanized by cervical dislocation. The sciatic nerves of the injured and non-injured sides and the DRG of the injured side were removed and fixed in 4% paraformaldehyde solution.

[0335] 2) Dehydrate, freeze-embed, and slice the fixed injured and uninjured sciatic nerves and dorsal root ganglia on the injured side.

[0336] 3) The immunofluorescence staining process is as follows:

[0337] The tissue sections were washed three times with PBS for 5 min each time; incubated with 0.3% Triton-X100 PBS for 20 min; washed three times with PBS for 5 min each time; and blocked with goat serum for 1 h at room temperature.

[0338] Then, the primary antibodies (AT2R: Rabbit, (LSBio, LS-A1322); TRPA1: Rabbit, (Invitrogen, PA1-46159); F4 / 80: Rat, (abcam, ab6640)) were diluted 1:200 with antibody diluent (New Saimei Biotechnology, Lot: 20220824) and incubated at 4°C overnight; then washed with PBS three times, 5 min each time;

[0339] Then the secondary antibody (Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rat ( 488) (abcam, ab150165)) was diluted with antibody diluent (New Saimei Biotechnology, Lot: 20220824) at a ratio of 1:2000 and incubated at room temperature for 30 minutes; then washed with PBS three times, each time for 5 minutes;

[0340] The sections were mounted with DAPI-containing mounting solution and photographed using a confocal microscope (Leica Microsystems, DCM8). The number of AT2R and F4 / 80 co-stained macrophages in sciatic nerve tissue was counted using the Find Maxima function of Image J, and the TRPA1 fluorescence intensity of DRG neuronal cells was calculated using Image J.

[0341] 4) Immunohistochemistry

[0342] The sections were removed from the -80°C freezer, fixed with 4% paraformaldehyde at 4°C for 10 minutes, and rinsed three times with 1× PBS. Endogenous peroxidase activity was blocked using a specific blocking buffer for 10 minutes, followed by three additional washes with 1× PBS. Subsequently, the sections were blocked with normal goat serum solution for 30 minutes. The primary antibody was incubated overnight at 4°C, and the secondary antibody was incubated at room temperature for 1 hour the next day. Finally, the sections were stained with AEC reagent and hematoxylin solution. TRPA1 antibody (orb374201, 1:2000, Biorbyt, UK), TRPV1 antibody (orb645490, 1:2000, Biorbyt, UK) and anti-rabbit antibody (1:1000) were used for immunohistochemical staining. Microscopic images were captured using a Leica Microsystems microscope and processed using Image-Pro Plus software.

[0343] 5.6 Statistics

[0344] The experimental results are expressed as "mean ± standard deviation". The data of each group were statistically analyzed using GraphPad Prism 8.0 software package. One-way ANOVA or two-way ANOVA was used according to the experiment to compare whether there were statistical differences between the groups. P < 0.05 was considered statistically significant.

[0345] 5.7 In vivo test results

[0346] In the SNI model, A1 50 mg / kg (4 hours after administration), A1 100 mg / kg (2 hours and 4 hours after administration), and A1 200 mg / kg (2 hours and 4 hours after administration) significantly inhibited sciatic nerve injury-induced mechanical allodynia in mice compared to the vehicle control group 2 and 4 hours after oral administration. Gabapentin 50 mg / kg (2 hours and 4 hours after administration) inhibited sciatic nerve injury-induced mechanical allodynia in mice. Figure 5 shows the paw withdrawal threshold (PWT) of each group of SNI mice (Mean ± SD, ***p < 0.001, compared with the vehicle group at the corresponding time points).

[0347] 5.8 Immunofluorescence staining results

[0348] Figure 6 shows typical images of macrophages co-stained with AT2R (AKA: AGTR2) and F4 / 80 on the injured and non-injured sides of the sciatic nerve of SNI mice (Bar=20 μm).

[0349] Figure 7 shows the fluorescence intensity of macrophages co-stained with AT2R and F4 / 80 on the injured side of the sciatic nerve in SNI mice. The results indicate that compared with the vehicle control group, A1 100 mg / kg and A1 200 mg / kg significantly reduced the number of macrophages co-stained with AT2R and F4 / 80 on the injured side of the sciatic nerve. Figure 8 shows the fluorescence intensity of macrophages co-stained with AT2R and F4 / 80 on the uninjured side of the sciatic nerve in SNI mice. The results indicate that the number of macrophages co-stained with AT2R and F4 / 80 on the uninjured side of the sciatic nerve was low in all experimental groups, and there was no significant difference in the number of AT2R and F4 / 80 co-stained cells among the groups. These results indicate that the injured side of the sciatic nerve recruits more peripheral macrophages than the uninjured side. The AT2R antagonist A1, administered orally at 100 mg / kg and 200 mg / kg, significantly reduced the number of peripheral macrophages and AT2R expression.

[0350] Figure 9 shows a typical image of TRPA1 immunofluorescence staining of the injured side DRG of SNI mice (Bar = 20 μm), and Figure 10 shows the average fluorescence intensity of TRPA1 in the injured side DRG neurons of SNI mice. The results indicate that compared with the vehicle control group, A1 100 mg / kg and A1 200 mg / kg can significantly reduce the expression of TRPA1 in DRG neurons.

[0351] 5.9 Immunohistochemistry Results

[0352] The results in Figure 11 show that compared with the normal control group mice, the expression of TRPA1 on the injured side of the sciatic nerve of SNI mice was significantly increased; in the SNI mouse model, compared with the saline treatment group, the A1 200 mg / kg treatment group reduced the level of TRPA1, basically reaching the TRPA1 expression level of the normal control group.

[0353] Example 6: Functional assay at the cellular level

[0354] 6.1 Experimental Objective: To evaluate the effects of A1 on AT2R and neuronal ion channel expression at the cellular level.

[0355] 6.2 Cell culture

[0356] Macrophages RAW264.7 were obtained from the Cell Resource Center of Peking Union Medical College, and mouse hippocampal neurons HT22 (CL-0697) were kindly provided by Procell Life Science Technology Co., Ltd.

[0357] RAW264.7 cells were cultured in DMEM supplemented with 10% FBS at 37°C. Experiments were performed when the cell density reached 70%. After the RAW264.7 cells were treated with different groups, the supernatant was collected, centrifuged at 4°C and 1000 g to remove the cell pellet, and the supernatant was added to HT22 cells in DMEM supplemented with 10% FBS and co-cultured at 37°C.

[0358] 6.3 Experimental methods

[0359] AT2R level method: When the RAW264.7 cell culture reached 70% density, Ang II (10, 30, 50, 100, and 200 nM) was added, and the negative control group was added with an equal volume of normal saline. After 24 h of treatment, the cells were collected to extract protein and RNA, and the AT2R expression level was evaluated.

[0360] A1 inhibition of AT2R receptor experimental method: When RAW264.7 cells reached 70% density, a certain concentration of AngII and the corresponding concentration of A1 (10, 30, 50, 100, and 200nM) were added. The negative control group was added with an equal volume of normal saline (without AngII). After 24 hours of treatment, the cells were collected to extract protein and RNA, and the AT2R expression level was evaluated. Furthermore, an appropriate concentration was selected. When RAW264.7 cells reached 70% density, a certain concentration of AngII and a certain concentration of A1, PD123319, and Olodanrigan were added. The negative control group was added with an equal volume of normal saline (without AngII). After 24 hours of treatment, the cells were collected to extract protein and RNA, and the AT2R expression level was evaluated.

[0361] ELISA: RAW264.7 cells were treated with normal saline (negative control group), AngII, AngII+A1, AngII+PD123319, and AngII+Olodanrigan for 24 hours, and the supernatant was collected. The cell pellet was removed by centrifugation at 4°C and 1000 g, and the sample concentration was determined using an ELISA kit at a wavelength of 450 nm. The supernatant after centrifugation was used to detect the concentrations of tumor necrosis factor TNF-α (cat. no. ml002095, Shanghai Enzyme-linked Biotechnology, China), IL-1 (cat. no. ml001816, Shanghai Enzyme-linked Biotechnology, China), serotonin (5-HT) (cat. no. ml001891, Shanghai Enzyme-linked Biotechnology, China), IL-8 (cat. no. ml063162, Shanghai Enzyme-linked Biotechnology, China), leukotrienes (LT) (cat. no. ml057907, Shanghai Enzyme-linked Biotechnology, China), and bradykinin (BK) (cat. no. ml063348, Shanghai Enzyme-linked Biotechnology, China).

[0362] Western blot (WB): 1) Proteins were extracted from RAW264.7 and HT22 cells after treatment with different groups using lysis buffer (10 μL PMSF (100x) and 10 μL phosphatase inhibitors per ml of lysis buffer). 2) The cells were then lysed on ice for 30 minutes and centrifuged at 12,000 rpm for 10 minutes at 4°C to collect total protein. 3) The protein content in the lysate was quantified using a BCA protein assay kit (Thermo Fisher Scientific). Equal amounts of protein were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred to a PVDF membrane. 4) The membrane was blocked with 5% skim milk for 1 hour at room temperature and then incubated with the primary antibody overnight at 4°C. 5) After incubation, the membrane was washed with TBST and then exposed to horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG (1:10,000 dilution; Zsbio, Beijing, China) or goat anti-rabbit IgG (1:10,000 dilution; Zsbio) for an additional hour at room temperature. 6) Signal detection was performed using an enhanced chemiluminescence (ECL) system, and images were analyzed using Image-Pro Plus version 6.0 software.

[0363] Real-time fluorescence PCR (RT-PCR): RNA was extracted from RAW264.7 and HT22 cells after different treatments using Trizol (Invitrogen, 15596-026), and then the extracted RNA was reverse transcribed into cDNA using the FastKing cDNA First-Strand Synthesis Kit (Tiangen, KR116). TM The differences in mRNA levels were determined using a multi-color real-time PCR detection system (Bio-Rad, Hercules, CA, USA) with GAPDH as the standard gene.

[0364] RT-PCR system and conditions: 10 μL 2X TransStart Green qPCR SuperMix (TransGen Biotech, Beijing, China), 3 μL cDNA template, 2 μL primers (1 μmol / L), and 5 μL ddH2O (nuclease-free). The RT-PCR program began with an initial denaturation at 95°C for 2 minutes, followed by 40 cycles of denaturation at 95°C for 15 seconds and annealing / extension at 60°C for 30 seconds.

[0365] 6.4 CCK-8 assay

[0366] RAW264.7 and HT22 cells were collected in the logarithmic growth phase, digested with trypsin, and centrifuged to prepare a single-cell suspension. The number of cells in the suspension was determined using a cell counting plate. Subsequently, 2 × 10 cells were added to each well. 3 The cell suspension was seeded into a 96-well plate at a specific density. At 0, 12, 24, and 48 hours after stimulation, 10 μL of CCK-8 solution was added to each well and incubated at 37°C for 1 to 4 hours. The absorbance at 450 nm was measured using a spectrophotometer.

[0367] Olodanrigan, Source: MCE, Item No.: HY-13106

[0368] 6.5 Statistical analysis

[0369] Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA). All data are presented as mean ± SD. Normal and lognormal values ​​were determined for all experiments. Statistical significance was calculated using two-way ANOVA when normal distribution was observed. Otherwise, statistical significance was calculated using the t-test. P < 0.05 was considered statistically significant.

[0370] 6.6 Results:

[0371] Figure 12 shows the inhibitory effect of A1 on AT2R activated by AngII in R264.7 cells. This suggests that A1 can significantly inhibit AT2R expression. WB and RT-PCR in Figures 12A, B, and C show that compared with the negative control, AngII at 10, 30, 50, 100, and 200 nM concentrations increased AT2R protein expression and mRNA levels in RAW264.7 cells in a concentration-dependent manner. WB and RT-PCR in Figures 12D, E, and F show that compared with the negative control, AngII treatment increased AT2R expression, but A1 at concentrations of 10, 30, 50, 100, and 200 nM dose-dependently inhibited AT2R expression in RAW264.7 cells. WB and RT-PCR in Figures 12G, H, and I show that compared with the negative control, AngII treatment increased AT2R expression, while A1, PD123319, and Olodanrigan treatment all inhibited AT2R expression.

[0372] Figure 13 shows that A1 reduced the increase in inflammatory factors in the supernatant of R264.7 cells induced by AngII stimulation. The results showed that A1 could reduce the increase in inflammatory factors mediated by AngII stimulation of RAW264.7 cells, including TNF-α, IL-1, 5-HT, IL-8, LT, and BK.

[0373] Figure 14 shows that A1 inhibits the protein expression and mRNA transcription of TRPA1 and TRPV1. Figure 14A shows a protein immunoblot of HT22 neuron lysates (TRPA1 and TRPV1); Figures 14B and C show quantitative analysis of TRPA1 protein expression and mRNA transcription levels in different treatment groups; Figures 14D and E show quantitative analysis of TRPV1 protein expression and mRNA transcription levels in different treatment groups; Figure 14F shows the ATP concentration in the supernatant of HT22 neurons in different treatment groups. *p<0.05, ***p<0.001, ****p<0.0001. These results suggest that A1 treatment reduces the protein expression and mRNA transcription of TRPA1 and TRPV1 when HT22 neurons are co-incubated with supernatant from macrophage R264.7 cells.

[0374] FIG15 shows that the in vitro cytotoxicity results indicate that A1 has no cytotoxicity to RAW264.7 and HT22 cells and does not inhibit neuronal activity.

[0375] In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of formula (IV): Wherein: U is C 1-3 an alkylene group; R 1a Selected from: C 2-8 alkenyl and C 2-8 alkynyl, wherein said C 2-8 alkenyl and C 2-8 alkynyl are each substituted by 1 C 6-10 aryl or 5- to 14-membered heteroaryl; C 6-10 aryl; -C 1-6 alkylene - saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1-6 alkylene - C 6-10 aryl; and -C 1-6 alkylene-(5- to 14-membered heteroaryl); R 1b is absent or selected from: H; C 13 alkyl optionally substituted with 1, 2, 3 or more R 1-8 groups; saturated or partially unsaturated C 3- 10 cycloalkyl; C 6-10 aryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; and -C 1-6 alkylene-C 6-10 aryl; X 1 Absent or CR 10 or N; X 4 Selected from: C(=O); and -O-C(=O)- and -S-C(=O)-, where O and S are linked to X 1 linked; R 2a is C 6-10 aryl; R 2b is C 6-10 aryl; X 2 is CR 10 or N; R 3 is -C(=O)OR 11 ; R 4 is H; R 10 is independently selected from H, -OR 11 , -SR 11 and C 1-6 alkyl each time it appears; R 11 and R 12 each independently represents H or C at each occurrence 1-6 alkyl; h and k are each independently 1; Each of the above-mentioned alkylene, cycloalkyl, heterocyclic, aryl and heteroaryl groups is optionally substituted, each time it appears, with one, two, three or more Rs 13 substituted; The R 13 is independently selected, at each occurrence, from: halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, -OR 11 , -SR 11 , -P(O)R 11 R 12 and -NR 11 R 12 , and wherein with respect to the substituent R 13 the alkyl, alkylene, aryl and heteroaryl as described are optionally further substituted by 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: R 13 is independently selected, at each occurrence, from: halogen, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -OR 11 , -SR 11 and -NR 11 R 12 , and wherein the alkyl, aryl and heteroaryl as described for substituent R 13 are optionally further substituted by 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein U is methylene or ethylene.

4. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 3 is -COOH.

5. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 10 is, independently at each occurrence: H, C 1-4 alkyl, OH or SH.

6. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 11 and R 12 are each independently selected from H and C 1-4 alkyl each time they occur.

7. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is independently selected, at each occurrence, from: F, Cl, Br, I, amino, cyano, nitro; C 1-4 alkyl optionally substituted with 1, 2, 3 or more substituents independently selected from halogen; C 5-7 cycloalkyl; phenyl, 5- to 6-membered heteroaryl and 9- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3 or more substituents independently selected from halogen, OH, amino, cyano and C 1-4 alkyl; wherein R 11 is -OR 1-6 wherein R 11 is C 11 alkyl optionally substituted with 1, 2, 3 or more halogens; wherein R 1-6 is -SR 11 wherein R 11 is C 12 alkyl optionally substituted with 1, 2, 3 or more halogens; and wherein R 1-6 and R 11 are independently, at each occurrence, -NR 12 R 11 R 12 or -P(O)R 11 R 12 wherein R 1-6 and R 11 are C 12 alkyl optionally substituted with 1, 2, 3 or more halogens.

8. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C 1-4 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 is C 1-3 alkyl optionally substituted with 1, 2, 3 F or Cl of -OR 11 ; wherein R 11 is C 1-3 alkyl optionally substituted with 1, 2, 3 F or Cl of -SR 11 ; wherein R 11 and R 12 are independently C 1-3 alkyl of -NR 11 R 12 or -P(O)R 11 R 12 ; phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl each optionally substituted with 1, 2, 3 or more substituents independently selected from F, Cl, Br, I and methyl.

9. The compound according to claim 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the C 1-3 alkyl group is methyl, ethyl, propyl or isopropyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: R 1a Selected from: C 2-6 alkenyl and C 2-6 alkynyl, wherein said C 2-6 alkenyl and C 2-6 alkynyl are each substituted by 1 phenyl or 5- to 10-membered heteroaryl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; -C 1-3 alkylene-(5- to 7-membered monocyclic heterocyclic group); -C 1-3 alkylene-(8- to 10-membered benzo-fused heterocyclic group); -C 1-3 alkylene-phenyl; and -C 1-3 alkylene-(5- to 10-membered heteroaryl); R 1b is absent or selected from: H; C 1-6 alkyl; C 3-7 cycloalkyl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; and -C 1-3 alkylene-phenyl; and Each occurrence of said alkyl, alkylene, cycloalkyl, heterocyclic group, aryl and heteroaryl is each optionally substituted by 1, 2, 3 or more Rs as defined in claim 1 13 substituted.

11. The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1a is selected from phenyl, -C 1-3 alkylene-C 3-7 cycloalkyl, -C 1-3 alkylene-phenyl, -C 1-3 alkylene-(5-7 membered monocyclic heterocyclic group), -C 1-3 alkylene-(9-10 membered benzo-fused heterocyclic group), -C 1-3 alkylene-(5-6 membered heteroaryl) and -C 1-3 alkylene-(9-10 membered heteroaryl), each of which is optionally substituted by 1, 2, 3 or more R 13 substituents.

12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from C 1-4 alkyl-O-; halogen; and C 1-4 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen.

13. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein X 4 is C(=O).

14. The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: R 1a Selected from: C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 2-6 alkenyl and C 2-6 alkynyl are each substituted by 1 phenyl, 5- or 6-membered heteroaryl or 9- or 10-membered heteroaryl, and the phenyl, 5- or 6-membered heteroaryl and 9- or 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I and C 1-4 alkyl; Optionally phenyl substituted with a substituent independently selected from one, two or three of F, Cl, Br, I and C 1-4 alkyl; and -C 1-3 alkylene-phenyl, -C 1-3 alkylene-(5- to 6-membered heteroaryl) and -C 1-3 alkylene-(9- to 10-membered heteroaryl), wherein said alkylene is optionally substituted by one -NR 11 R 12 substituent each time it appears, and said phenyl, 5- to 6-membered heteroaryl and 9- to 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I and C 1-4 alkyl; R 1b Does not exist; X 1 does not exist; and X 4 is C(=O) or -O-C(=O)-.

15. The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the C 1-6 alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl.

16. The compound of claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the C 2-6 alkenyl is vinyl, 1-propenyl or 2-propenyl.

17. The compound of claim 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the C 2-6 alkynyl group is vinyl, 1-propynyl or 2-propynyl.

18. The compound of claim 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is phenyl, pyridyl, indolyl or furyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and methyl.

19. The compound of claim 18 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1a is selected from:

20. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: R 1a is a group selected from the following: optionally substituted phenyl, - optionally substituted C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), - optionally substituted C 1-3 alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclic group), - optionally substituted C 1-3 alkylene-(optionally substituted 8- to 10-membered benzo-fused heterocyclic group), - optionally substituted C 1-3 alkylene-optionally substituted phenyl, and - optionally substituted C 1-3 alkylene-(optionally substituted 5- to 10-membered heteroaryl); R 1b selected from H, optionally substituted by 1, 2, 3 or more R 13 alkyl; saturated or partially unsaturated C 1-8 cycloalkyl; C 3-10 cycloalkyl; C 6- 10 aryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; and -C 1-6 alkylene-C 6-10 aryl; X 1 is CR 10 or N; X 4 is C(=O); wherein said "optionally substituted" means substituted with 1, 2, 3 or more Rs 13 and; R 13 As defined in claim 1.

21. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1b is a group selected from: H, optionally substituted C 1-4 alkyl, optionally substituted C 3- 7-cycloalkyl, optionally substituted phenyl, - optionally substituted C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), and - optionally substituted C 1-3 alkylene - optionally substituted phenyl; wherein said "optionally substituted" means substituted with 1, 2, 3 or more Rs 13 substituents.

22. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: R 2a is an optionally substituted phenyl group; and / or R 2b is an optionally substituted phenyl group; Wherein the "optionally substituted" means substituted by 1, 2, 3 or more R 13 substituents.

23. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of formula (II): where R 1a and R 1b and X 1 and X 4 and R 2a and R 2b and X 2 and R 3 and R 4 and h and k are as defined in claim 1.

24. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein is:

25. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein is:

26. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 10 is H or methyl.

27. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1a is selected from optionally substituted phenyl, -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), -C 1-3 alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclic group), -C 1-3 alkylene-(optionally substituted 8- to 10-membered benzo-fused heterocyclic group), -C 1- 3alkylene-optionally substituted phenyl, and -C 1-3 alkylene-(optionally substituted 5- to 10-membered heteroaryl).

28. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1a is selected from: Optionally substituted phenyl; -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; -C 1-3 alkylene-(optionally substituted 8- to 10-membered benzo-fused heterocyclic group), wherein said heterocyclic group is -C 1-3 alkylene-(optionally substituted 5- to 10-membered heteroaryl), wherein said heteroaryl is 29. The compound according to claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from: halogen; wherein R 11 is C 1-6 alkyl optionally substituted with 1, 2, 3 or more halogens, of -OR 11 ; cyano; C 3-7 cycloalkyl; C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, each optionally substituted with 1, 2, 3 or more halogens; wherein R 11 and R 12 are each independently selected from H and C 1-4 alkyl of -NR 11 R 12 ; and wherein R 11 and R 12 are each independently C 1-6 alkyl optionally substituted with 1, 2, 3 or more halogens, of -P(O)R 11 R 12 .

30. The compound according to claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from: halogen; wherein R 11 is -OR 1-3 wherein the alkyl is optionally substituted with 1, 2 or 3 F or Cl; cyano; C 11 cycloalkyl; C 3-7 alkyl, C 1-4 alkenyl and C 2-4 alkynyl, each optionally substituted with 1, 2, 3 or more halogens; -NR 2- wherein R 11 and R 12 are each independently selected from H and methyl; and -P(O)R 11 R 12 wherein R 11 and R 12 are each independently C 1-3 alkyl optionally substituted with 1, 2 or 3 F or Cl. 11 R 12 .

31. The compound according to claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from: F, Cl, Br, OH, -OC 1-4 alkyl, -N(C 1-4 alkyl)2, cyano, C 3-7 cycloalkyl, C 2-4 alkenyl and C 2-4 alkynyl; C 1-4 alkyl optionally substituted with 1, 2, 3 or more F, Cl or Br; and -P(O)R 11 and R 12 are each independently methyl, ethyl, propyl or isopropyl, R 11 R 12 .

32. The compound according to claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from: F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl and CF3; and wherein R 11 and R 12 each independently is methyl -P(O)R 11 R 12 .

33. The compound according to claim 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1a is selected from: (including )、 34. The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1b is selected from: H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, -C 1-3 alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 alkylene optionally substituted phenyl. The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1b is selected from: H, phenyl; Optionally substituted C 1-4 alkyl, wherein the alkyl is methyl, ethyl or isopropyl; Optionally substituted C 3-7 cycloalkyl and -C 1-3 alkylene-(C 3-7 cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and -C 1-3 Alkylene-phenyl.

36. The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from halogen and C 1-4 alkyl.

37. The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from F, Cl, Br and methyl.

38. A compound according to claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1b is selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, phenyl, 39. The compound of claim 22 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from halogen and -OR 11 , and wherein R 11 is selected from C 1-4 alkyl.

40. The compound of claim 22 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 13 is selected from F, Cl, Br, and -OCH3.

41. The compound of claim 22 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 2a and R 2b each independently selected from phenyl, 42. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof, wherein: U is ethylene; R 1a Selected from: -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5- to 14-membered heteroaryl); R 1b Selected from: C 1-8 alkyl; saturated C 3-10 cycloalkyl; and -C 1-6 alkylene-saturated C 3-10 cycloalkyl; X 1 is N; X 4 is C(=O); X 2 is N; R 2a and R 2b are both phenyl; R 3 is -C(=O)OH; R 4 is H; h and k are each independently 1; and Each of the above-mentioned cycloalkyl, aryl and heteroaryl groups is optionally substituted by one R each time it appears. 13 The R 13 is C 1-6 alkyl. Preferably, the C 6-10 aryl is phenyl, the saturated C 3-10 cycloalkyl group is cyclopropyl, and the 5- to 14-membered heteroaryl group is thienyl or benzothienyl.

43. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is selected from:

44. Use of the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof in the preparation of a medicament for preventing or treating peripheral neuropathic pain.

45. Use of the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N - oxide, isotope - labeled compound, metabolite or prodrug thereof in the preparation of a medicament for preventing or treating peripheral neuropathic pain associated with macrophages.

46. The use according to claim 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with macrophage recruitment / aggregation.

47. The use according to claim 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with high expression of AT2 receptor in macrophages.

48. The use according to claim 44 or 45, wherein the medicament is for preventing or treating peripheral neuropathic pain associated with elevated levels of reactive oxygen / nitrogen species produced by macrophages.

49. The use according to any one of claims 44 - 48, wherein the medicament is for preventing or treating peripheral neuropathic pain caused by secondary neuropathy. Use according to claim 49, wherein the secondary neuropathy comprises: Diabetic neuropathy; Herpes zoster - associated neuropathy; Uremia - associated neuropathy; Amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerative mutilation; furadantin neuropathy; neuropathy with sausage-like swelling; neuropathy caused by nutritional deficiency; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury, and organophosphate insecticides; and peripheral neuropathy associated with an infectious process (such as Guillain-Barré syndrome).

51. Use according to any one of claims 44 - 50, wherein the drug is for preventing or treating a disorder selected from the following or symptoms associated therewith: trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

52. Use according to any one of claims 44 - 50, wherein the drug is for preventing or treating a disorder selected from the following or symptoms associated therewith: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (such as carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain, chemotherapy-related neuropathic pain, and painful sensory neuropathy of HIV (human immunodeficiency virus).

53. A method for preventing or treating peripheral neuropathic pain, the method comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof.

54. A method for preventing or treating macrophage-related peripheral neuropathic pain, the method comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof.

55. The method of claim 53 or 54, wherein the disease is peripheral neuropathic pain associated with macrophage recruitment / aggregation.

56. The method of claim 53 or 54, wherein the disease is peripheral neuropathic pain associated with high expression of the AT2 receptor in macrophages.

57. The method of claim 53 or 54, wherein the disease is peripheral neuropathic pain associated with elevated levels of reactive oxygen / nitrogen species produced by macrophages.

58. The method of any one of claims 53 - 57, wherein the disease is peripheral neuropathic pain caused by secondary neuropathy.

59. The method of claim 58, wherein the secondary neuropathy comprises: Diabetic neuropathy; Herpes zoster-associated neuropathy; Uremia-associated neuropathy; Amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerative mutilation; furadantin neuropathy; sausage-shaped swelling neuropathy; neuropathy caused by nutritional deficiency; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury, and organophosphate pesticides; and peripheral neuropathy associated with an infectious process (such as Guillain-Barré syndrome).

60. The method of any one of claims 53-59, wherein the disease is a disorder selected from the following or a symptom associated therewith: trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

61. The method of any one of claims 53-59, wherein the disease is a disorder selected from the following or a symptom associated therewith: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve compression syndrome (such as carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain, chemotherapy-related neuropathic pain, and painful sensory neuropathy of HIV (human immunodeficiency virus).

62. The compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, for preventing or treating peripheral neuropathic pain.

63. The use of any one of claims 44-50, wherein the drug is used for preventing or treating a disorder selected from the following or a symptom associated therewith: postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

64. The use of any one of claims 44-50, wherein the drug is used for preventing or treating a disorder selected from the following or a symptom associated therewith: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve compression syndrome (such as carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and painful sensory neuropathy of HIV (human immunodeficiency virus).

65. The method of any one of claims 53-59, wherein the disease is a disorder selected from the following or a symptom associated therewith: postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy. The method according to any one of claims 53-59, wherein the disease is a disorder or a symptom associated therewith selected from the following: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (such as carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.