WO2025153011A1 - Angiotensin ii receptor antagonist and use thereof in treatment of peripherally-induced neuropathic pain - Google Patents

Abstract

The present invention relates to an angiotensin II receptor antagonist and a use thereof in the treatment of peripherally-induced neuropathic pain. In particular, the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a use thereof in the treatment of peripherally-induced neuropathic pain.

Description

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

The present invention relates to angiotensin II type 2 (AT ₂ ) receptor antagonists and their use in preventing or treating peripheral neuropathic pain and related disorders.

Background Art

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 AT ₂ receptor subtypes. AT ₂ receptor-specific antagonists are valuable in the treatment of various cerebrovascular, cognitive and central nervous system (CNS) diseases. In addition, AT ₂ receptors are found in neuronal tumor cells and transformed human neural cells. AT ₂ 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.

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 injury or disease, it 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).

According to the International Classification of Disease 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)).

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

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, weakening, disappearance of tendon reflexes, and paresthesia. Even if the original cause is removed, the injury is healed or effectively controlled, the pain will still persist, seriously affecting the patient's quality of life and accompanied by emotional disorders (Editorial Committee of Chinese Expert Consensus on Peripheral Neuropathic Pain. Chinese Expert Consensus on 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.

Painful diabetic peripheral neuropathy (PDPN) is the most common chronic complication of diabetes. 16% of diabetic patients are affected by it, and many patients are undiagnosed (12.5%) and untreated (39%). In 2013, the prevalence of type 2 diabetes in my country was as high as 10.4%, based on which it is estimated that about 22 million patients suffer from PDPN.

Postherpetic neuralgia (PHN) is also a common type of pNP, with an annual incidence of 3.9 to 42.0/100,000. 9% to 34% of herpes zoster patients will develop PHN. Among patients aged ≥40 years who visited the dermatology, neurology and pain departments of urban hospitals in my country, the overall prevalence of herpes zoster was 7.7%, and the overall prevalence of PHN was 2.3%. Both prevalences tended to increase gradually with age.

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 a peak age of 48 to 59 years old.

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, pNP has a significant unmet medical need.

Specifically, drugs are 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 have limited treatment options for chronic peripheral neuropathic pain. Anticonvulsants such as gabapentin and pregabalin and tricyclic antidepressants have significant central side effects.

At present, the most widely used central analgesics for the treatment of peripheral neuropathic pain (pNP) in clinical practice are gabapentin and pregabalin. A large amount of clinical data shows that gabapentin and pregabalin have obvious central side effects. Fatigue and dizziness are the most common side effects of this type of drug. Other side effects include headache, anxiety, and nausea, constipation, bloating, and stomach pain related to the digestive system. Opioid analgesics, which have good clinical analgesic effects, have serious side effects such as respiratory depression and addiction, in addition to nausea, vomiting, and dizziness.

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

The present invention provides compounds used as _AT2 receptor antagonists, which have excellent inhibitory activity on _AT2 receptors, better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window) and other more excellent properties.

The present invention particularly provides the use of _AT2 receptor antagonist compounds in preventing or treating peripheral neuropathic pain (pNP).

The mechanism of the present invention is that, due to the action of AngII on _AT2 receptors, inflammatory factors such as reactive oxygen free radicals (ROS) are produced in the skin/peripheral macrophages of damaged nerves, and ROS act on the dorsal root ganglion, causing calcium ion influx in the neurons of the dorsal root ganglion to produce hypersensitive pain. _AT2 receptor antagonists can reduce the recruitment of macrophages at the pain site, inhibit the high expression of _AT2 receptors in macrophages, inhibit the generation of reactive oxygen/nitrogen by inhibiting _AT2 receptors, and then inhibit pain signal transmission. The present invention exerts analgesic effects from the immune cells of the peripheral nervous system, rather than acting through the central nervous system, thereby avoiding the central side effects caused by previous drugs.

Therefore, more specifically, the present invention provides the use of compounds as _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/nitrogen produced by macrophages.

The inventors found that the test of evaluating the effect of _AT2 receptor antagonists on the generation of reactive oxygen free radicals induced by angiotensin II (AngII) in isolated mouse peritoneal macrophages showed that _AT2 receptor antagonists can reduce the increase of reactive oxygen species (ROS) in mouse macrophages caused by AngII by inhibiting _AT2 receptors. Moreover, in vivo efficacy studies showed that _AT2 receptor antagonists produced a good analgesic effect using the above mechanism. In the rat diabetic foot pain model, the rat sciatic nerve chronic compression model, the rat spinal nerve ligation model, and the mouse sciatic nerve branch injury model, _AT2 receptor antagonists all had significant analgesic effects.

Therefore, in the first aspect, the present application provides the following embodiments of _AT2 receptor antagonist compounds:

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

in:

U is a C _1-3 alkylene group;

R ^1a is selected from: C _2-8 alkenyl and C _2-8 alkynyl, wherein the C _2-8 alkenyl and C _2-8 alkynyl are each substituted with one C _6-10 aryl or 5-14 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 3-10 membered heterocyclyl; -C 1-6 alkylene} -C _6-10 aryl; and -C _1-6 alkylene-(5-14 membered heteroaryl);

R ^1b is absent or is selected from: H; C _1-8 alkyl optionally substituted by 1, ₂ , 3 or more R ¹³ ; 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 does not exist or is CR ¹⁰ or N;

^X4 is selected from: C(=O); and -OC(=O)- and -SC(=O)-, wherein O and S are connected to ^X1 ;

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 ;

^R4 is H;

R ¹⁰ , at each occurrence, is selected from H, -OR ¹¹ , -SR ¹¹ and C _1-6 alkyl;

R ¹¹ and R ¹² are each independently H or C _1-6 alkyl at each occurrence;

h and k are each independently 1;

The above alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1, 2, 3 or more R ¹³ at each occurrence;

Said 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 the alkyl, alkylene, aryl and heteroaryl described for the substituent R ¹³ are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C _1-6 alkyl.

2. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 described for the substituent R ¹³ are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C _1-6 alkyl.

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

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

5. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹⁰ at each occurrence is independently: H, C _1-4 alkyl, OH or SH.

6. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹¹ and R ¹² are each independently selected from H and C _1-4 alkyl at each occurrence.

7. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ at each occurrence is independently selected 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, 5-6 membered heteroaryl and 9-10 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 ¹¹ of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; wherein R ¹¹ is -SR ¹¹ of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; and wherein R ¹¹ and R ¹² is independently at each occurrence -NR ¹¹ R ¹² or -P(O)R ¹¹ R ¹² of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen.

8. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ at each occurrence 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 -OR ¹¹ of C _1-3 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R ¹¹ is -SR ¹¹ of C _1-3 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R ¹¹ and R ¹² at each occurrence are independently -NR ¹¹ R ¹² or -P(O)R ¹¹ R ¹² of C _1-3 alkyl ; 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.

9. The compound of embodiment 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the C _1-3 alkyl group is methyl, ethyl, propyl or isopropyl.

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

R ^1a is 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 with one phenyl or 5-10 membered heteroaryl; phenyl; -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 heterocyclyl); -C _1-3 alkylene-phenyl; and -C _1-3 alkylene-(5-10 membered heteroaryl);

R ^1b is absent or is 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

The above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1, 2, 3 or more R ¹³ as defined in Embodiment 1 at each occurrence.

11. The compound of embodiment 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, 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 heterocyclyl), -C _1-3 alkylene-(9-10 membered benzo-fused heterocyclyl), -C _1-3 alkylene-(5-6 membered heteroaryl) and -C _1-3 alkylene-(9-10 membered heteroaryl), each of which is optionally substituted with 1, 2, 3 or more R ¹³ .

12. The compound of embodiment 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ is selected from C _1-4 alkyl-O-; halogen; and C _1-4 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from halogen.

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

14. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein:

R ^1a is selected from:

_C2-6 alkenyl and _{C2-6 alkynyl} , each of which is substituted with 1 phenyl, _5-6 -membered heteroaryl or 9-10-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I and _C1-4 alkyl;

Phenyl optionally substituted with 1, 2 or 3 substituents independently selected from 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 the alkylene is optionally substituted at each occurrence with one -NR ¹¹ R ¹² , and the phenyl, 5 to 6 membered heteroaryl and 9 to 10 membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I and C _1-4 alkyl;

R ^1b does not exist;

^X1 does not exist; and

^X4 is C(=O) or -OC(=O)-.

15. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the C _1-6 alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl.

16. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the _C2-6 alkenyl group is ethenyl, 1-propenyl or 2-propenyl.

17. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the _C2-6alkynyl group is vinyl, 1-propynyl or 2-propynyl.

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

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

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

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 heterocyclyl), -optionally substituted C _1-3 alkylene-optionally substituted phenyl, and -optionally substituted C _1-3 alkylene-(optionally substituted 5-10 membered heteroaryl);

R ^1b is selected from H, C _1-8 alkyl optionally substituted by 1, 2, 3 or more R ¹³ ; 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 is CR ¹⁰ or N;

^X4 is C(=O);

wherein the "optionally substituted" refers to substitution by 1, 2, 3 or more R ¹³ ; and

R ¹³ is as defined in Embodiment 1.

21. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, 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;

The "optionally substituted" mentioned herein means substituted by 1, 2, 3 or more R ¹³ .

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

R ^2a is optionally substituted phenyl; and/or

R ^2b is optionally substituted phenyl;

The "optionally substituted" mentioned herein means substituted by 1, 2, 3 or more R ¹³ .

23. The compound of embodiment 1 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 (II):

wherein 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.

24. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein for:

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

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

27. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically 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 benzo-fused heterocyclyl), -C _1-3 alkylene-optionally substituted phenyl, and -C _1-3 alkylene-(optionally substituted 5 to 10-membered heteroaryl).

28. 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 ^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 8-10 membered benzo-fused heterocyclic group), wherein the heterocyclic group is

-C _1-3 alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is

29. A compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ is selected from: halogen; -OR ¹¹ wherein R ¹¹ is C _1-6 alkyl optionally substituted by 1, 2, 3 or more halogens; cyano; C _3-7 cycloalkyl; C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl optionally substituted by 1, 2, 3 or more halogens; -NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are each independently selected from H and C _1-4 alkyl; and -P(O)R ¹¹ R ¹² wherein R ¹¹ and R ¹² are each independently selected from C _1-6 alkyl optionally substituted by 1, 2, 3 or more halogens.

30. A compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ is selected from: halogen; -OR ¹¹ wherein R ¹¹ is C _1-3 alkyl optionally substituted by 1, 2 or 3 F or Cl; cyano; C _3-7 cycloalkyl; C _1-4 alkyl, C _2-4 alkenyl and C _{2-4 alkynyl} optionally substituted by 1, 2, 3 or more halogen; -NR ¹¹ R ¹² 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 selected from C _1-3 alkyl optionally substituted by 1, 2 or 3 F or Cl.

31. A compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, 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 R ¹² wherein R ¹¹ and R ¹² are each independently methyl, ethyl, propyl or isopropyl.

32. A compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ is selected from the group consisting of: F, Cl, Br, -OCH ₃ , -N(CH ₃ ) ₂ , cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl and CF ₃ ; and -P(O)R ¹¹ R ¹² wherein R ¹¹ and R ¹² are each independently methyl.

33. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R ^1a is selected from: (include ),

34. 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 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.

35. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, 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 embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R ¹³ is selected from halogen and C _1-4 alkyl.

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 ¹³ is selected from F, Cl, Br and methyl.

38. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ^1b is selected from H, methyl, ethyl, isopropyl, CF ₃ CH ₂ , cyclopropyl, Phenyl,

39. 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 is selected from halogen and -OR ¹¹ , and wherein R ¹¹ is selected from C _1-4 alkyl.

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 is selected from F, Cl, Br and -OCH ₃ .

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

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

U is ethylene;

R ^1a is selected from: -C _1-6 alkylene-C _6-10 aryl; and -C _1-6 alkylene-(5-14 membered heteroaryl);

R ^1b is selected from: C _1-8 alkyl; saturated C _3-10 cycloalkyl; and -C _1-6 alkylene-saturated C _3-10 cycloalkyl;

^X1 is N; ^X4 is C(=O); ^X2 is N; ^R2a and ^R2b are both phenyl;

^R3 is -C(=O)OH;

^R4 is H;

h and k are each independently 1; and

The above cycloalkyl, aryl and heteroaryl are each optionally substituted by 1 R ¹³ at each occurrence; said R ¹³ is C _1-6 alkyl;

Preferably, the C _6-10 aryl group is phenyl, the saturated C _3-10 cycloalkyl group is cyclopropyl, and the 5-14 membered heteroaryl group is thienyl or benzothienyl.

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

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

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

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, isotope-labeled substance, metabolite or prodrug thereof, in the preparation of a medicament for preventing or treating peripheral neuropathic pain.

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 substance, metabolite or prodrug thereof, in the preparation of a medicament for preventing or treating macrophage-associated peripheral neuropathic pain.

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

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.

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/nitrogen species produced by macrophages.

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

50. The use of embodiment 49, wherein 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 ulcerous lesions; nitrofurantoin neuropathy; sausage-like 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).

51. 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 trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.

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.

52. The use of any one of embodiments 44-50, wherein the medicament is used to prevent or treat a condition or symptoms associated therewith selected from the following: 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.

52a. The use of any one of embodiments 44-50, wherein the medicament is used to prevent or treat a condition or symptoms associated therewith selected from the following: 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.

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 as described in the first aspect to a patient in need thereof.

53. A method for preventing or treating peripheral neuropathic pain, the method 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.

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 of any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof.

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

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

57. The method of embodiment 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 according to any one of embodiments 53-57, wherein the disease is peripheral neuropathic pain caused by secondary neuropathy.

59. The method of embodiment 58, wherein 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 ulcerous lesions; nitrofurantoin neuropathy; sausage-like 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).

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.

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.

61. 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 posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

61a. The method of any one of embodiments 53-59, wherein the disease is 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 post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

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

62. 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, for use in preventing or treating peripheral neuropathic pain.

63. 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, for use in preventing or treating macrophage-associated peripheral neuropathic pain.

64. A compound of embodiment 62 or 63, 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 associated with the recruitment/aggregation of macrophages.

65. The compound of embodiment 62 or 63 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 associated with high expression of AT2 receptors in macrophages.

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/nitrogen species produced by macrophages.

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.

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-related neuropathy; uremia-related 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 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).

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

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

70. A compound according to any one of embodiments 62-68 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

70a. A compound of any one of embodiments 62-68 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

DETAILED DESCRIPTION OF THE INVENTION

definition

Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

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.

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.

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"), such as 1 to 6 carbon atoms ("C _1-6 alkyl"), 1 to 4 carbon atoms ("C _1-4 alkyl"), and more particularly 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 (e.g., 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 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , _CH2Cl or _-CH2CH2CF3 , etc.). The term _{" C1-4} 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).

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 8 carbon atoms (" _C2-8 alkenyl", for example " _C2-6 alkenyl"). 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 compound of the present invention contains an alkenylene group, the compound may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

As used herein, the term "alkynyl" means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6, 7 or 8 carbon atoms, for example ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, etc.

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 (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.

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 (sub)heterocyclyl" is a saturated or partially unsaturated monocyclic or bicyclic (sub)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-dioxolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (e.g., morpholino), thiomorpholinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiazinane, 1,3-thiazin ane), hexahydropyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepane, 1,4-diazepane, 1,3-oxazepane, 1,3-thiazepane. Bicyclic heterocyclylene and heterocycle (base) include spiro 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, such as benzo derivatives of saturated or partially unsaturated monocyclic groups having 3-6 (suitably 4-6, more suitably 5-6) ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms selected from N, O and S and the remaining ring atoms are C (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 (Ylene)benzo[d][1,3]dioxolyl (Ylidene)benzo[d][1,3]dithiolene (Ylidene)benzo[d][1,3]oxathiolene 3H-Benzo[c][1,2]oxathiolene 3H-Benzo[d][1,2]oxathiolene 2,3-Dihydrobenzo[d]oxazolyl 2,3-Dihydrobenzo[d]thiazolyl 2,3-Dihydro-1H-benzo[d]imidazolyl 2,3-Dihydrobenzo[d]isoxazolyl 2,3-Dihydrobenzo[d]isothiazolyl 1,3-Dihydrobenzo[c]isoxazolyl 1,3-Dihydrobenzo[c]isothiazolyl 2,3-Dihydro-1H-indazolyl (Asian) Semanki (Iso)2H-chromenyl 4H-chromenyl (Ide)dihydrobenzothiopyranyl 2H-thiochromene ), 4H-thiochromene, ), (sub) 1,2,3,4,4a,8a-hexahydroquinolinyl (Iso)1,2,4a,8a-Tetrahydroquinolinyl (Iso)1,4,4a,8a-Tetrahydroquinolinyl (Iso)1,2,3,4,4a,8a-Hexahydroisoquinolinyl (Iso)1,2,3,4,4a,8a-Hexahydroquinoxalinyl (Iso) 1,4,4a,8a-Tetrahydroquinoxalinyl (Iso)1,2,3,4,4a,8a-Hexahydroquinazolinyl 2,4,4a,8a-Tetrahydro-1H-benzo[d][1,3]oxazinyl 3,4,4a,8a-Tetrahydro-2H-benzo[b][1,4]oxazinyl 3,4,4a,8a-Tetrahydro-2H-benzo[e][1,3]oxazinyl 2,4,4a,8a-Tetrahydro-1H-benzo[d][1,3]thiazinyl 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 bridging 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 (eg, 1, 2, 3 or 4) suitable substituents.

As used herein, the terms "(ylidene)aryl" 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 terms "C _6-10 (ylidene)aryl" and "C _6-10 aromatic ring" mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring). The (ylidene)aryl group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

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 additionally may be benzo-fused. In particular, "heteroaryl" or "heteroaromatic ring" is selected from thiophenyl, 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, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof. Other examples of "heteroaryl" or "heteroaromatic ring" include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl and purinyl.

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

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

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 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 connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle is optionally benzo-fused, and is preferably connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.

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

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.

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

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

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, when the substitutable ring is bridged, an available atom in the bridge.

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 atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant 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 ( ^2H ), tritium ( ^3H )); isotopes of carbon (e.g., ^11C , ^13C , and ^14C ); isotopes of chlorine (e.g., ^36Cl ); isotopes of fluorine (e.g., ^18F ); isotopes of iodine (e.g., ^123I and ^125I ); isotopes of nitrogen (e.g., ^13N and ^15N ); isotopes of oxygen (e.g., ^15O , ^17O , and ^18O ); isotopes of phosphorus (e.g., ^32P ); and isotopes of sulfur (e.g., ^35S ). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because they are easily incorporated and easily detected. Substitution with positron emitting isotopes (e.g., ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

The term "stereoisomer" means 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, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. 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 the present application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

In this article, solid lines can be used Solid wedge Virtual wedge Carbon-carbon bonds of the compounds of the 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 stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include 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 invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

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

It should also be understood that certain compounds of the present invention may exist in free form for treatment, 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, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

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

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, hyaluronate, 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, toluenesulfonate, trifluoroacetate, and xinofoate.

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.

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.

As used herein, the term "ester" means an ester 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 free acid or alcohol form). The compounds of the present invention themselves may also be esters.

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

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, including 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: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; A.R.Katritzky and A.J.Boulton, Eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, Eds., Academic Press.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present 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 present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

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 less pharmacological activity or no pharmacological activity, which when administered into or onto the body can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity. Typically such prodrugs will be functional group derivatives of the compounds that are easily 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", Vol. 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)).

The present invention also encompasses compounds of the present invention containing protecting groups. In 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 by conventional protecting groups, for example, those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

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

Pharmaceutical compositions and methods of treatment

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, and 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 also include one or more other therapeutic agents.

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

In some embodiments, the present invention provides a compound of the present invention 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 as described above for use as angiotensin II type 2 (AT ₂ ) receptor antagonist.

In some embodiments, the present invention provides a method for preventing or treating an _AT2 receptor-mediated disorder or a symptom associated therewith, the method 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.

In some embodiments, the disease is peripheral neuropathic pain.

In some embodiments, the disease is peripheral neuropathic pain associated with the recruitment/aggregation of macrophages.

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

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

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

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 ulcerous lesions; nitrofurantoin neuropathy; sausage-like 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).

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.

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.

In some embodiments, the disease is 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, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

In some embodiments, the disease is 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 post-traumatic neuropathic pain (e.g., chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.

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

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 solutions of glucose and glycerol 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 preparations 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).

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, local, in the form of ophthalmic preparations or by inhalation.

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

The 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.

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

The dosage regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is 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 the composition or supervising the administration of the composition.

The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the 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 a 70kg person, 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, the dosage level not higher than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

In some embodiments, the compound or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-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, 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.

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.

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.

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) treatment courses, wherein each treatment course 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 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.

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.

As used herein, unless otherwise indicated, the terms "treating" and "treating" mean reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention 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.).

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

Figure 1 shows the effect of AT2R antagonists on the generation of reactive oxygen free radicals in mouse peritoneal macrophages induced by AngII through the ROS fluorescence intensity of different treatment groups. Note: ###p<0.001 compared with the Control group, ***p<0.001 compared with the AngII (0.2μM) group.

FIG. 2 shows the changes in 50% PWT of each group of animals at different administration time points in the efficacy test of AT2R antagonists on the diabetic foot pain model induced by high-fat and high-sugar diet combined with STZ in rats.

FIG. 3 shows the effect of AT2R antagonists in the allodynia test induced by spinal nerve ligation model in SD rats.

FIG4 shows the results of the efficacy evaluation of AT2R antagonists in the rat sciatic nerve chronic compression injury model.

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

FIG6 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).

FIG. 7 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.

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.

FIG. 9 shows typical images of TRPA1 immunofluorescence staining of the injured-side DRG of SNI mice (Bar=20 μm).

FIG. 10 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).

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.

FIG. 12 shows the inhibitory effects of A1, PD123319, and Olodanrigan on AT2R activated by AngII in R264.7 cells.

FIG. 13 shows the inhibitory effects of A1, PD123319, and Olodanrigan on the elevation of inflammatory factors in the supernatant of R264.7 cells caused by AngII stimulation.

FIG. 14 shows that A1, PD123319, and Olodanrigan inhibit the protein expression and mRNA transcription of TRPA1 and TRPV1.

FIG. 15 shows the in vitro cytotoxicity results, demonstrating that A1 is not cytotoxic to RAW264.7 and HT22 cells.

DETAILED DESCRIPTION

Compound Examples

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

Biological Examples

In the following biological tests, the numbering correspondence between the compounds A1 to A8 used and the example compounds is as follows: A1 = C112, A2 = C246, A3 = C202, A4 = C196, A5 = C154, A6 = C155, A7 = C184, A8 = C207. It should be noted that compounds A1 to A8 are used as exemplary compounds in the following tests, and it does not mean that the present invention is limited to the compounds A1 to A8.

Example 1: Effects of AT2R antagonists on AngII-induced generation of reactive oxygen free radicals in mouse peritoneal macrophages

1.1 Purpose of the experiment

Mouse peritoneal macrophages express angiotensin II type 2 receptor (AT2R). Angiotensin II (AngII), as a ligand of AT2R, can induce an increase in reactive oxygen free radicals (ROS) produced by mouse peritoneal macrophages by binding to AT2R receptors. This experiment evaluated whether AT2R antagonists inhibited AngII-induced ROS production in mouse peritoneal macrophages by inhibiting AT2R receptors in mouse peritoneal macrophages.

1.2 Instruments and Equipment

1.3 Test methods

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

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

1.4 Statistics

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

1.5 Experimental Results

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 treatment 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 concentrations of 0.5μM and 5μM can inhibit the increase in reactive oxygen species caused by AngII.

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

2.1 Purpose of the experiment

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

2.2 Test equipment

2.3 Experimental animals

Species: SD rats;

Grade: SPF grade;

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

Number and gender of animals included: 70, all males;

Source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.;

License number: SCXK(Beijing)2016-0006;

Certificate number: 110011211105511316;

IACUC approval number: IACUC-202104-r-001.

2.4 Test methods

After one week of adaptive feeding and four weeks of high-fat and high-sugar diet, rats were subjected to plantar Von Frey fiber pain measurement once to screen out animals weighing more than 10g. After fasting but not water deprivation for 16 hours, a single intraperitoneal injection of 40mg/kg (animal body weight 220-250g) or 50mg/kg (animal body weight 180-220g) STZ was given. Random blood glucose levels were tested 72 hours later, and a blood glucose level ≥16.7mmol/L indicated 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 in the range of 1-6g were selected as diabetic foot pain animals. The rats were randomly divided into 7 groups according to the pain threshold before administration: control solvent (ddH ₂ O), gabapentin 100 mg/kg, A1 (12.5, 25, 50, 100 and 200 mg/kg), 10 rats/group, the administration volume was 10 mL/kg, and the drug was administered by oral gavage. Von Frey fiber filament pain measurement was performed 2, 4 and 6 hours after administration, and the drug efficacy was evaluated based on the change of 50% PWT of rats.
50% PWT value, formula: 50% g threshold = (10 ^{[Xf + kδ]} )/10000

Where _Xf = the final Von Frey nylon yarn Log value used in the test; k = the positive/negative response mode value; δ = the average difference Log value between nylon yarn stimuli, here a constant of 0.224.

2.5 Statistical analysis

The data obtained from the experiment were statistically analyzed using EXCEL and Graph Pad Prism 8.

All measured 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 drug administration. Two-way Anova method was used to analyze and compare the differences in PWT 50% values between different drug administration groups and at different pain measurement time points within the same group.

2.5 Experimental Results

Figure 2 shows the changes in 50% PWT of each group of animals at different administration time points. The animals were randomly divided into groups according to the pain threshold, and the 50% PWT of each group was evenly dispersed at 0 hour before administration, with no significant difference. Compared with the vehicle control group, gabapentin 100 mg/kg and A1 100 mg/kg groups and A1 200 mg/kg groups could significantly relieve peripheral neuropathy caused by diabetes at 2, 4 and 6 hours after administration; A1 50 mg/kg group and A1 25 mg/kg group could significantly relieve peripheral neuropathy caused by diabetes at 4 and 6 hours after administration; A1 12.5 mg/kg group could significantly relieve peripheral neuropathy caused by diabetes at 6 hours after administration. Therefore, under this experimental system, A1 at doses of 12.5, 25, 50, 100 and 200 mg/kg can significantly relieve peripheral neuropathy in rat diabetic foot pain model animals established by high-fat and high-sugar diet feeding combined with intraperitoneal injection of STZ.

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

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 method.

3.2 Test equipment

3.3 Experimental animals

Species: Sprague-Dawley rats;

Grade: SPF grade;

Number and sex of animals included: 100, male;

Source: Shanghai Slake Laboratory Animal Co., Ltd.;

License number: SCXK(Shanghai)2017-0005;

Certificate number: 20170005023847;

IACUC protocol: GP02-021-2019v1.0.

3.4 Experimental process

The SD rats were completely anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg/kg). The animal's lumbar surgical area was shaved, and the skin was disinfected three times with iodine and 70% ethanol. The surgery began after the skin was dry, and the surgical procedure was performed aseptically. The left spinal nerves L5 and L6 were separated, tightly ligated with 6-0 silk thread, and the wound was sutured to complete the rat SNL model.

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.

On the 13th day after surgery, the basal value of mechanical allodynia was measured in the rats. The animals without mechanical allodynia (foot withdrawal threshold greater than 5g) and animals with foot withdrawal threshold less than 0.5g were eliminated and randomly divided into 10 groups according to the basal foot 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 administered by gavage.

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 the rat behavioral test and was calculated according to the following formula:
50% reaction threshold (g) = (10 ^{(Xf + kδ)} )/10,000

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

3.5 Statistical analysis

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).

3.6 Test results

Figure 3 shows the effect of AT2R antagonists in the allodynia test induced by spinal nerve ligation in SD rats. The basic 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 each test group. 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, A7 200mg/kg 2h and 4h after administration, all significantly inhibited the mechanical allodynia induced by spinal nerve ligation in rats.

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

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 method.

4.2 Test equipment

4.3 Experimental animals

Species: Sprague-Dawley rats;

Grade: SPF grade;

Number and sex of animals included: 32, male;

Source: Shanghai Slake Laboratory Animal Co., Ltd.;

License number: SCXK(Shanghai)2017-0005;

Certificate number: 20170005025163;

IACUC protocol: GP02-021-2019v1.0.

4.4 Experimental process

SD rats were completely anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg/kg). The animal's lumbar surgical area was shaved, and the skin was disinfected three times with iodine and 70% ethanol. The surgery began after the skin was dry, and the surgical procedure was performed aseptically. The left sciatic nerve was separated, and four 4-0 chromic gut sutures were used to loosely ligate the sciatic nerve about 7 mm upstream of the bifurcation of the sciatic nerve, with a spacing of about 1 mm. The wound was sutured to complete the rat CCI model.

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.

On the 13th day after surgery, the basal value of mechanical allodynia was measured in the rats. The animals without mechanical allodynia (foot withdrawal threshold greater than 5g) and animals with foot withdrawal threshold less than 0.5g were eliminated and randomly divided into 5 groups according to the basal foot withdrawal threshold: vehicle control group (ddH2O), Olodanrigan 200mg/kg, A3 100mg/kg, A1 200mg/kg, 8 rats/group, 5mL/kg was administered by gavage.

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 the rat behavioral test and was calculated according to the following formula:
50% reaction threshold (g) = (10 ^{(Xf + kδ)} )/10,000

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

4.5 Statistical analysis

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).

4.6 Test results

Figure 4 shows the efficacy evaluation of AT2R antagonists on the rat sciatic nerve chronic compression injury model. Compared with the solvent control group, A3 100 mg/kg 2h and 4h after administration, A1 200 mg/kg 2h after administration, can significantly inhibit the mechanical allodynia caused by sciatic nerve compression in rats. Olodanrigan 200 mg/kg 2h and 4h after administration did not inhibit the mechanical allodynia induced by sciatic nerve compression in rats.

Example 5: Efficacy test of AT2R antagonist on mouse sciatic nerve branch injury model

5.1 Test Purpose:

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

5.2 Test equipment

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

5.3 Experimental animals

Strain: C57BL/6 mice

Age: 4-6 weeks

Gender: Male

Weight: 14-20 g

Number of animals purchased: 70

Experimental animal provider: Hunan Slake Jingda Experimental Animal Co., Ltd.

Production license number: SCXK (Xiang) 2019-0004

5.4 In vivo test process

1) The mice were fully anesthetized by inhalation of isoflurane, and fixed on the operating table in a prone position to fully expose the lateral buttocks. The left posterior branch was shaved and disinfected with alcohol. The surgical procedure was performed aseptically. SNI surgical group: The mouse skin was cut in the direction of the femur parallel to the sciatic nerve to expose the sciatic nerve trunk until the tibial nerve, common peroneal nerve and sural nerve were exposed. The tibial nerve and common peroneal nerve of the mouse were tightly ligated with medical absorbable sutures (8-0), and then a section of nerve (about 2-4mm) was cut from the ligation site of the tibial nerve and common peroneal nerve to the distal nerve to ensure the integrity of the sural nerve. The muscles and epidermis were sutured layer by layer to complete the mouse SNI model.

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.

3) PWT was detected on the 11th day after surgery, and animals with abnormal PWT (PWT mean >4g or <1g) were eliminated. The mice were randomly divided into 5 groups (SNI model group) according to their body weight and PWT value: solvent control group (sterile water for injection), Gabapetin 50mg/kg, A1 50mg/kg, A1 100mg/kg, A1 200mg/kg, 12 mice/group, 10mL/kg was administered by gavage.

4) On the 12th day after surgery, the paw withdrawal threshold was tested using a Von Frey electronic analgesic at 0 h before administration and 2 and 4 h after administration. The animals were placed in a special multi-unit metal mesh cage for pain detection and adapted to the environment for 30 minutes. After the animals adapted to the test environment, an electronic analgesic (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, and the pressure was continuously increased until the mouse showed an obvious paw withdrawal reaction. The reading recorded by the electronic analgesic was the threshold of the mechanical pain reaction, with g as the detection unit, and the test was repeated 6 times. The average value was then taken as the final detection index.

5.5 Tissue sampling and immunofluorescence staining process

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

2) Dehydrate, freeze-embed, and slice the fixed injured-side sciatic nerve, non-injured-side sciatic nerve, and injured-side dorsal root ganglion respectively for later use;

3) The immunofluorescence staining process is as follows:

The tissue sections were washed 3 times with PBS, 5 min each time; incubated with 0.3% Triton-X100 PBS for 20 min; washed 3 times with PBS, 5 min each time; blocked with goat serum at room temperature for 1 h;

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 Bio, Lot: 20220824) and incubated at 4°C overnight; then washed with PBS three times, 5 min each time;

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 min; then washed with PBS three times, 5 min each time;

The sections were sealed with a sealing solution containing DAPI, and photographed with a confocal microscope (Leica Microsystems, DCM8). The Find Maxima function of Image J was used to count the number of AT2R and F4/80 co-stained cells of macrophages in the sciatic nerve tissue, and Image J was used to count the TRPA1 fluorescence intensity of DRG neuronal cells.

4) Immunohistochemistry

The sections were removed from the −80°C freezer, fixed with 4% paraformaldehyde at 4°C for 10 min, and rinsed three times with 1× PBS. Endogenous peroxidase activity was blocked for 10 min using a specific blocking buffer, followed by three additional washes with 1× PBS. Subsequently, the sections were blocked with normal goat serum solution for 30 min. The primary antibody was incubated overnight at 4°C, and the secondary antibody was incubated for 1 h at room temperature 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 taken using a Leica Microsystems microscope and processed with Image-Pro Plus software.

5.6 Statistics

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.

5.7 In vivo test results

2h and 4h after oral administration in the mouse SNI model, compared with the vehicle control group, A1 50mg/kg 4h after administration, A1 100mg/kg 2h and 4h after administration, A1 200mg/kg 2h and 4h after administration, can significantly inhibit the mechanical allodynia induced by sciatic nerve injury in mice. Gabapentin 50mg/kg 2h and 4h after administration can inhibit the mechanical allodynia induced by sciatic nerve injury 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 point).

5.8 Immunofluorescence staining results

FIG6 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).

Figure 7 shows the fluorescence intensity of AT2R and F4/80 co-stained macrophages on the injured side of the sciatic nerve of SNI mice. The results show that compared with the solvent control group, A1 100mg/kg and A1 200mg/kg can significantly reduce the number of AT2R and F4/80 co-stained macrophages on the injured side of the sciatic nerve. Figure 8 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. The results show that on the non-injured side of the sciatic nerve, the number of AT2R and F4/80 co-stained macrophages in each experimental group was low and there was no significant difference in the number of AT2R and F4/80 co-stained cells among the groups. The results show that the injured side of the sciatic nerve recruited more peripheral macrophages than the non-injured side. When the AT2R antagonist A1 was administered orally at 100mg/kg and 200mg/kg, it can significantly reduce the number of peripheral macrophages and the expression of AT2R.

Figure 9 shows a typical image of TRPA1 immunofluorescence staining of the injured DRG of SNI mice (Bar = 20 μm), and Figure 10 shows the average fluorescence intensity of TRPA1 in the DRG neurons on the injured side 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.

5.9 Immunohistochemistry results

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 in 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.

Example 6: Functional assay at the cellular level

6.1 Experimental purpose: To evaluate the effect of A1 on AT2R and on the expression of neuronal ion channels at the cellular level.

6.2 Cell culture

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.

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

6.3 Experimental methods

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

A1 inhibits AT2R receptors. Experimental method: When RAW264.7 cells reach 70% density, a certain concentration of AngII and a corresponding concentration of A1 (10, 30, 50, 100, and 200 nM) are added. An equal volume of saline (without AngII) is added to the negative control group. After 24 hours of treatment, cells are collected to extract protein and RNA to evaluate the expression level of AT2R. Further, a suitable concentration is selected. When RAW264.7 cells reach 70% density, a certain concentration of AngII and a certain concentration of A1, PD123319 and Olodanrigan are added. An equal volume of saline (without AngII) is added to the negative control group. After 24 hours of treatment, cells are collected to extract protein and RNA to evaluate the expression level of AT2R.

ELISA: After RAW264.7 cells were treated with normal saline (negative control group), AngII, AngII+A1, AngII+PD123319 and AngII+Olodanrigan for 24 hours, the supernatant was collected and centrifuged at 4°C and 1000 g to remove the cell pellet. 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), 5-hydroxytryptamine (5-HT) (cat. no. ml001891, Shanghai Enzyme-linked Biotechnology, China), IL-8 (cat. no. ml063162, Shanghai Enzyme-linked Biotechnology, China), leukotriene (LT) (cat. no. ml057907, Shanghai Enzyme-linked Biotechnology, China), and bradykinin (BK) (cat. no. ml063348, Shanghai Enzyme-linked Biotechnology, China).

Western blot (WB): 1) RAW264.7 and HT22 cells treated with different groups were used to extract proteins using lysis buffer (10 μL PMSF (100x) and 10 μL phosphatase inhibitor 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 another hour at room temperature. 6) Signal detection was performed using an enhanced chemiluminescence (ECL) system, and image analysis was performed using image-pro Plus version 6.0 software.

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 FastKing cDNA First-Strand Synthesis Kit (Tiangen, KR116). The iQ5 ^TM multi-color real-time PCR detection system (Bio-Rad, Hercules, CA, USA) was used to determine the difference in mRNA levels using GAPDH as a standard gene.

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 first performed an initial denaturation at 95°C for 2 min, followed by 40 cycles of amplification: denaturation at 95°C for 15 s and annealing/extension at 60°C for 30 s.

6.4 CCK-8 Experiment

RAW264.7 and HT22 cells were collected in the logarithmic growth phase, and single-cell suspensions were prepared by trypsin digestion and centrifugation. The number of cells in the suspension was determined using a cell counting plate. Subsequently, the cell suspension was seeded in a 96-well plate at a density of 2×10 ³ cells per well. 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. Finally, the absorbance at 450 nm was measured using a spectrophotometer.

Olodanrigan, source manufacturer: MCE, item number: HY-13106

6.5 Statistical analysis

Statistical analyses were performed using GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA). All data are presented as mean ± SD. In all experiments, normal and log-normal values were determined. When normal distribution was met, statistical significance was calculated using two-way analysis of variance. Otherwise, statistical significance was calculated using t-test. P < 0.05 was considered statistically significant.

6.6 Results:

Figure 12 shows the inhibitory effect of A1 on AT2R activated by AngII in R264.7 cells. It indicates that A1 can significantly inhibit the expression of AT2R. 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 increases the AT2R protein expression level and mRNA level 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 increases the expression of AT2R, but A1 at concentrations of 10, 30, 50, 100, and 200 nM dose-dependently inhibits the expression of AT2R in RAW264.7 cells. WB and RT-PCR in Figures 12G, H, and I show that compared with the negative control, AngII treatment increases the expression of AT2R, and A1, PD123319, and Olodanrigan treatment all inhibit the expression of AT2R.

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

Figure 14 shows that A1 inhibits the protein expression and mRNA transcription of TRPA1 and TRPV1. Figure 14A shows the protein immunoblot (TRPA1 and TRPV1) of the cell lysate of HT22 neurons; Figures 14B and C show the quantitative analysis of the protein expression and mRNA transcription levels of TRPA1 in different treatment groups; Figures 14D and E show the quantitative analysis of the protein expression and mRNA transcription levels of TRPV1 in different treatment groups; Figure 14F shows the concentration of ATP in the supernatant of HT22 neurons in different treatment groups. *p＜0.05,***p＜0.001,****p＜0.0001. The results suggest that under the condition of co-incubation of HT22 neurons and macrophage R264.7 supernatant, A1 treatment can reduce the protein expression and mRNA transcription of TRPA1 and TRPV1.

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.

In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art based on 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 (66)

A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has the structure of formula (IV):
in: U is a C _1-3 alkylene group; R ^1a is selected from: C _2-8 alkenyl and C _2-8 alkynyl, wherein the C _2-8 alkenyl and C _2-8 alkynyl are each substituted with one C _6-10 aryl or 5-14 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 3-10 membered heterocyclyl; -C 1-6 alkylene} -C _6-10 aryl; and -C _1-6 alkylene-(5-14 membered heteroaryl); R ^1b is absent or is selected from: H; C _1-8 alkyl optionally substituted by 1, ₂ , 3 or more R ¹³ ; 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 does not exist or is CR ¹⁰ or N; ^X4 is selected from: C(=O); and -OC(=O)- and -SC(=O)-, wherein O and S are connected to ^X1 ; 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 ; ^R4 is H; R ¹⁰ , at each occurrence, is selected from H, -OR ¹¹ , -SR ¹¹ and C _1-6 alkyl; R ¹¹ and R ¹² are each independently H or C _1-6 alkyl at each occurrence; h and k are each independently 1; The above alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1, 2, 3 or more R ¹³ at each occurrence; Said 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 the alkyl, alkylene, aryl and heteroaryl described for the substituent R ¹³ are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C _1-6 alkyl. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 described for the substituent R ¹³ are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C _1-6 alkyl. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein U is methylene or ethylene. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ³ is -COOH. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹⁰ is independently H, C _1-4 alkyl, OH or SH at each occurrence. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled product, metabolite or prodrug thereof, wherein R ¹¹ and R ¹² are each independently selected from H and C _1-4 alkyl at each occurrence. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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, 5-6 membered heteroaryl and 9-10 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 ¹¹ of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; wherein R ¹¹ is -SR ¹¹ of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; and wherein R ¹¹ and R ¹² is independently at each occurrence -NR ¹¹ R ¹² or -P(O)R ¹¹ R ¹² of C _1-6 alkyl optionally substituted with 1, 2, 3 or more halogen. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, 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 by 1, 2, 3 F or Cl; wherein R ¹¹ is -OR ¹¹ of C _1-3 alkyl optionally substituted by 1, 2, 3 F or Cl; wherein R ¹¹ is -SR ¹¹ of C _1-3 alkyl optionally substituted by 1, 2, 3 F or Cl; wherein R ¹¹ and R ¹² are independently selected at each occurrence from -NR ¹¹ R ¹² or -P(O)R ¹¹ R ¹² of C _1-3 alkyl ; 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. The compound of claim 8 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the C _1-3 alkyl group is methyl, ethyl, propyl or isopropyl. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein: R ^1a is 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 with one phenyl or 5-10 membered heteroaryl; phenyl; -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 heterocyclyl); -C _1-3 alkylene-phenyl; and -C _1-3 alkylene-(5-10 membered heteroaryl); R ^1b is absent or is 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 The above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by 1, 2, 3 or more R ¹³ as defined in claim 1 at each occurrence. The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 heterocyclyl), -C _1-3 alkylene-(9-10 membered benzo-fused heterocyclyl), -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 . The compound of claim 11 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from C _1-4 alkyl-O-; halogen; and C _1-4 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from halogen. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein X ⁴ is C(═O). The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein: R ^1a is selected from: _C2-6 alkenyl and _{C2-6 alkynyl} , each of which is substituted with 1 phenyl, _5-6 -membered heteroaryl or 9-10-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I and _C1-4 alkyl; phenyl optionally substituted with 1, 2 or 3 substituents independently selected from 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 the alkylene group is optionally substituted at each occurrence with one -NR ¹¹ R ¹² , and the phenyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heteroaryl groups are each optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, I, and C _1-4 alkyl; R ^1b does not exist; ^X1 does not exist; and ^X4 is C(=O) or -OC(=O)-. The compound of claim 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the C _1-6 alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl. The compound of claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein the _C2-6 alkenyl is ethenyl, 1-propenyl or 2-propenyl. The compound of claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein the _C2-6 alkynyl is vinyl, 1-propynyl or 2-propynyl. The compound of claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is phenyl, pyridyl, indolyl or furanyl, and the phenyl, pyridyl, indolyl or furanyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and methyl. The compound of claim 18 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ^1a is selected from:
The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein: 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 heterocyclyl), -optionally substituted C _1-3 alkylene-optionally substituted phenyl, and -optionally substituted C _1-3 alkylene-(optionally substituted 5-10 membered heteroaryl); R ^1b is selected from H, C _1-8 alkyl optionally substituted by 1, 2, 3 or more R ¹³ ; 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 is CR ¹⁰ or N; ^X4 is C(=O); wherein the "optionally substituted" refers to substitution by 1, 2, 3 or more R ¹³ ; and R ¹³ is as defined in claim 1. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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; The "optionally substituted" mentioned herein means substituted by 1, 2, 3 or more R ¹³ . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein: R ^2a is optionally substituted phenyl; and/or R ^2b is optionally substituted phenyl; The "optionally substituted" mentioned herein means substituted by 1, 2, 3 or more R ¹³ . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has the structure of formula (II):
wherein 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 claim 1 . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein for:
The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein for:
The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹⁰ is H or methyl. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 benzo-fused heterocyclyl), -C 1-3 alkylene} -optionally substituted phenyl, and -C _1-3 alkylene-(optionally substituted 5 to 10-membered heteroaryl). The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 8-10 membered benzo-fused heterocyclic group), wherein the heterocyclic group is -C _1-3 alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from: halogen; wherein R ¹¹ is -OR ¹¹ of a C _1-6 alkyl group optionally substituted by 1, 2, 3 or more halogens; cyano; C _3-7 cycloalkyl; C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups optionally substituted by 1, 2, 3 or more halogens; wherein R ¹¹ and R ¹² are each independently selected from H and -NR ¹¹ R ¹² of a C _1-4 alkyl group; and wherein R ¹¹ and R ¹² are each independently selected from -P(O)R ¹¹ R ¹² of a C _1-6 alkyl group optionally substituted by 1, 2, 3 or more halogens. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from: halogen; -OR ¹¹ wherein R ¹¹ is a C _1-3 alkyl group optionally substituted with 1, 2 or 3 F or Cl; cyano; C _3-7 cycloalkyl; C _1-4 alkyl, C _2-4 alkenyl and C _{2-4 alkynyl} groups optionally substituted with 1, 2, 3 or more halogens; -NR ¹¹ R 12 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 selected from C _1-3 alkyl group optionally substituted with 1, 2 or ³ F or Cl. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, 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 R ¹² wherein R ¹¹ and R ¹² are each independently methyl, ethyl, propyl or isopropyl. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from the group consisting of: F, Cl, Br, -OCH ₃ , -N(CH ₃ ) ₂ , cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl and CF ₃ ; and -P(O)R ¹¹ R ¹² wherein R ¹¹ and R ¹² are each independently methyl. The compound of claim 20 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ^1a is selected from: (include ), The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, 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, isotope-labeled substance, 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. The compound of claim 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from halogen and C _1-4 alkyl. The compound of claim 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ¹³ is selected from F, Cl, Br and methyl. The compound of claim 21 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ^1b is selected from H, methyl, ethyl, isopropyl, CF ₃ CH ₂ , cyclopropyl, Phenyl, The compound of claim 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled product, 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. The compound of claim 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled product, metabolite or prodrug thereof, wherein R ¹³ is selected from F, Cl, Br and -OCH ₃ . The compound of claim 22 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein R ^2a and R ^2b are each selected from phenyl, The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein: U is ethylene; R ^1a is selected from: -C _1-6 alkylene-C _6-10 aryl; and -C _1-6 alkylene-(5-14 membered heteroaryl); R ^1b is selected from: C _1-8 alkyl; saturated C _3-10 cycloalkyl; and -C _1-6 alkylene-saturated C _3-10 cycloalkyl; ^X1 is N; ^X4 is C(=O); ^X2 is N; ^R2a and ^R2b are both phenyl; ^R3 is -C(=O)OH; ^R4 is H; h and k are each independently 1; and The above cycloalkyl, aryl and heteroaryl are each optionally substituted by 1 R ¹³ at each occurrence; said R ¹³ is C _1-6 alkyl; Preferably, the C _6-10 aryl group is phenyl, the saturated C _3-10 cycloalkyl group is cyclopropyl, and the 5-14 membered heteroaryl group is thienyl or benzothienyl. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound is selected from:
Use 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 substance, metabolite or prodrug thereof in the preparation of a medicament for preventing or treating peripheral neuropathic pain. Use of a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof in the preparation of a medicament for preventing or treating macrophage-associated peripheral neuropathic pain. The use of claim 44 or 45, wherein the medicament is used to prevent or treat peripheral neuropathic pain associated with the recruitment/aggregation of macrophages. The use of claim 44 or 45, wherein the medicament is used to prevent or treat peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages. The use of claim 44 or 45, wherein the medicament is used to prevent or treat peripheral neuropathic pain associated with increased levels of reactive oxygen/nitrogen produced by macrophages. The use according to any one of claims 44 to 48, wherein the drug is used to prevent or treat peripheral neuropathic pain caused by secondary neuropathy. The use of claim 49, wherein the secondary neuropathy includes: diabetic neuropathy; herpes zoster-related neuropathy; uremia-related 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-like 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). The use of any one of claims 44 to 50, wherein the medicament is used to prevent or treat 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. The use of any one of claims 44-50, wherein the drug is used to prevent or treat 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, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy. A method for preventing or treating 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 claims 1 to 43 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof. 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 claims 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof. The method of claim 53 or 54, wherein the disease is peripheral neuropathic pain associated with the recruitment/aggregation of macrophages. The method of claim 53 or 54, wherein the disease is peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages. 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. The method of any one of claims 53-57, wherein the disease is peripheral neuropathic pain caused by secondary neuropathy. 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 ulcerous lesions; nitrofurantoin neuropathy; sausage-like 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). The method of any one of claims 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. The method of any one of claims 53-59, wherein the disease is 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, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy. A compound according to any one of claims 1 to 43, 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. The use of any one of claims 44 to 50, wherein the medicament is used to prevent or treat 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. The use of any one of claims 44-50, wherein the drug is used to prevent or treat 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 post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy. The method of any one of claims 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. The method of any one of claims 53-59, wherein the disease is 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.