Angiotensin ii type 2 receptor antagonist and use thereof for treating cancerous pain

Abstract

An angiotensin II receptor antagonist and the use thereof for treating cancerous pain. Specifically, the present invention relates to a compound of formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopic label, metabolite or prodrug thereof, and the use thereof for treating cancerous pain, preferably cancerous ostalgia.

Description

Angiotensin II type 2 receptor antagonists and their use in treating cancer pain Technical Field

[0001] The present invention relates to angiotensin II type 2 (AT2) receptor antagonists and their use in preventing or treating cancer pain, in particular bone cancer pain. Background Art

[0002] The renin-angiotensin system (RAS) is a crucial system in the body that regulates water, electrolyte, and fluid balance, as well as blood pressure. Renin breaks down angiotensinogen to produce angiotensin I, which, through the action of angiotensin-converting enzyme, forms angiotensin II (AngII), exerting its physiological effects by constricting blood vessels and stimulating aldosterone secretion. Local RAS also exist in the cardiovascular and central nervous systems. These RAS, independent of the kidneys, can synthesize and release renin and angiotensin, participating in the regulation of local blood flow and vascular tone, and promoting the growth and metabolism of cardiac and vascular smooth muscle. AngII has two major receptors: the AngII type 1 receptor (AT1R) and the AngII type 2 receptor (AT2R). Both AT1R and AT2R belong to the family of seven-transmembrane G protein-coupled receptors. AngII, through the AT1R receptor, exerts its effects on the cardiovascular and renal systems, tumorigenesis, tissue remodeling, cognition, embryonic development, reproduction, and bone homeostasis. AngII acts on AT2R and is valuable in the treatment of various cerebrovascular, cognitive and central nervous system (CNS) diseases. It is also related to a variety of inflammatory pain and neuropathic pain.

[0003] The International Society for the Study of Pain defines neuropathic pain as pain caused by damage or disease of the somatosensory system (Jensen TS, Baron R, M, et al. A new definition of neuropathic pain [J]. Pain, 2011, 152(10): 2204-2205). According to the anatomical location of the injury or disease, 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 Diseases 11th version (ICD-11), peripheral neuropathic pain refers to chronic pain caused by damage or disease of the peripheral sensory nervous system.

[0004] All patients with advanced cancer and about 30%-50% of cancer patients will experience cancer pain, and the pain will increase as the cancer progresses. About 70% of cancer pain is caused by the cancer itself, such as nerve, bone and mucosal invasion; about 20% is caused by surgery, chemotherapy and radiotherapy-related tissue damage. Regardless of the cause, cancer-related neuropathic pain is described as needle-like, burning, discharge-like or impact-like pain or tingling, corresponding to the site of nerve damage (Liviu Feller et al., Pain: Persistent postsurgery and bone cancer-related pain, Journal of International Medical Research, Volume 47, Issue 2, February 2019, Pages 528-543).

[0005] Solid tumors such as breast, prostate, kidney, thyroid, lung, colorectal, gynecological, and melanoma can metastasize to multiple bones throughout the body, including the spine, ribs, hip, femur, and tibia (Bone cancer pain: Causes, consequences, and therapeutic opportunities, Patrick Mantyh, PAIN, 25 July 2013). Seventy percent of patients with metastatic prostate and breast cancer have bone metastases. Cancer that spreads to the bones is rarely curable and can lead to associated conditions such as severe bone cancer pain, increased risk of fractures, and hypercalcemia (Jaime Fornetti et al., Understanding the Bone in Cancer Metastasis, Journal of Bone and Mineral Research, Vol. 33, No. 12, December 2018, pp. 2099–2113). Cancer-induced bone pain (CIBP) initially presents as dull, persistent pain that intensifies as the disease progresses, eventually developing into breakthrough pain or severe, episodic pain (Bone cancer pain: Causes, consequences, and therapeutic opportunities Patrick Mantyh, PAIN, 25 July 2013).

[0006] Many factors can cause bone cancer pain, including pain-causing biological factors in the metastatic microenvironment, increased bone and nerve compression, and periosteum stretching caused by the growth of metastatic tumors in the bone, microfractures of trabeculae, pathological fractures caused by the gradual reduction of bone structural integrity due to tumor growth, and direct damage to sensory nerve fibers in the bone by the tumor and infiltration of tumor cells into the nerve roots (Liviu Feller et al., Pain: Persistent postsurgery and bone cancer-related pain, Journal of International Medical Research, Volume 47, Issue 2, February 2019, Pages 528-543). In patients with bone cancer pain, the dorsal horn of the spinal cord associated with the nerves at the site of metastatic bone disease shows neurochemical changes, morphological function and structural plasticity, accompanied by the sprouting of new nerve endings, upregulation of receptors and their related neurotransmitters and reactive glial cell expression. In the tumor microenvironment, malignant tumor cells and immune inflammatory cells release proteases, bradykinins, prostaglandins, endothelins, cytokines, chemokines, growth factors, ATP, and H, which can excite primary afferent nociceptors and cause cancer pain.

[0007] Currently, bone cancer pain is largely managed using the WHO's three-step analgesic ladder. Mild pain is treated with nonsteroidal anti-inflammatory drugs (NSAIDs), moderate pain with NSAIDs plus weak opioid analgesics, and severe pain with strong opioid analgesics, optionally combined with NSAIDs. Other adjunctive therapies include antiepileptic drugs (such as gabapentin and carbamazepine), antidepressants (such as amitriptyline and imipramine), and corticosteroids. However, these analgesics are prone to various adverse reactions, such as addiction, tolerance, respiratory depression, and gastrointestinal adverse reactions.

[0008] Therefore, there is still a need in the art for more effective drugs with fewer side effects for treating bone cancer pain. Summary of the Invention

[0009] The inventors found that AT2R antagonists can reduce the increase of macrophage reactive oxygen species (ROS) free radicals caused by AngII by inhibiting AT2 receptors. In another in vitro experiment, they can significantly reduce the calcium ion concentration in DRG neurons co-cultured with macrophages RAW264.7 in vitro after AngII treatment. In addition, in the mouse sciatic nerve branch injury model, they can reduce the macrophage AT2R expression of the injured side sciatic nerve and the transient receptor site ion channel subunit (TRPA1) of the dorsal root ganglion, and show significant analgesic effects in the mouse sciatic nerve branch injury model and the rat breast cancer bone cancer metastasis model.

[0010] Without wishing to be bound by any theory, the analgesic mechanism of the AT2R antagonist in the present invention is that bone cancer pain involves damage to bone tissue and physiological and biochemical changes in the local tumor microenvironment and dorsal root ganglion. Immune cells including macrophages in the tumor microenvironment are involved in inducing the occurrence of bone cancer pain. The renin-angiotensin system is involved in the regulation of immune response and T cells and macrophages, and Ang II can be considered as a pro-inflammatory factor in macrophage response. AT2R is expressed on macrophages. After macrophages infiltrate the injury site, AngII activates AT2R on macrophages, causing macrophages to produce inflammatory factors such as reactive oxygen species (ROS) / reactive nitrogen species (RNS). The generated ROS and / or RNS act on the TRPA1 receptors on dorsal root ganglion (DRG) neurons. TRPA1 receptors are expressed on resident macrophages / macrophage-colony stimulating factor TRPA1 plays an important role in mediated cancer pain. Furthermore, TRPA1 has good permeability to calcium ions and can be activated by endogenous electrophilic groups (such as ROS / RNS), causing calcium ion influx and enhanced neuronal excitability, thereby producing hyperalgesia. AT2R antagonists can reduce the recruitment of macrophages to painful areas and the high expression of AT2R within macrophages. By inhibiting AT2R, they inhibit the production of ROS and / or RNS, suppress neuronal excitability, and thus inhibit pain signal transmission. In the present invention, AT2R antagonists exert analgesic effects through immune cells in the peripheral nervous system, rather than through the central nervous system, thus avoiding central side effects.

[0011] Therefore, in one aspect, the present invention provides the use of an AT2R antagonist compound (or "AT2R antagonist compound") in preventing or treating cancer pain.

[0012] In a preferred embodiment, the present invention provides the use of AT2R antagonist compounds in preventing or treating cancer pain associated with peripheral macrophage function.

[0013] As used herein, the term "cancer" includes but is not limited to: blood cancers, such as leukemias; and solid tumors, such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, bone cancer. In preferred embodiments, the cancer is bone cancer. In some embodiments, the bone cancer is primary bone cancer. In some embodiments, the bone cancer is metastatic bone cancer, such as bone metastasis of blood cancer (such as leukemia) and solid tumors (such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma), more preferably bone metastasis of breast cancer, lung cancer, kidney cancer, rectal cancer, pancreatic cancer, gastric cancer, colon cancer or ovarian cancer.

[0014] As used herein, "peripheral" and "peripheral" are used interchangeably to refer to tissues and organs outside the brain and spinal cord, including but not limited to the peripheral nervous system, skin, bones, heart, lungs and other organs, peritoneum, abdominal cavity, etc. The peripheral nervous system includes sensory nerves or sensory nerve fibers, motor nerves or motor nerve fibers, and mixed nerves. In some preferred embodiments, the peripheral nerves are sensory nerves or sensory nerve fibers (e.g., dorsal root ganglia), and mixed nerves (e.g., sciatic nerves).

[0015] As used herein, "peripheral macrophages" and "peripheral macrophages" are used interchangeably to refer to macrophages in tissues and organs outside the brain and spinal cord.

[0016] As used herein, "macrophage function" refers to one or more of the recruitment / aggregation of macrophages (e.g., at peripheral nerves), the expression of AT2R in macrophages (e.g., high expression), and the production of inflammatory factors such as ROS and / or RNS by macrophages (e.g., elevated levels of ROS and / or RNS).

[0017] Thus, in some particular embodiments, the present invention provides the use of AT2R antagonist compounds in preventing or treating cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0018] In some more preferred embodiments, the present invention provides use of an AT2R antagonist compound in preventing or treating bone cancer pain.

[0019] In some more preferred embodiments, the present invention provides the use of AT2R antagonist compounds in preventing or treating bone cancer pain associated with peripheral macrophage function.

[0020] In particular, the present invention provides the use of AT2R antagonist compounds in preventing or treating bone cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0021] In another aspect, the present invention provides AT2R antagonist compounds for use in preventing or treating cancer pain.

[0022] In some embodiments, the AT2R antagonist compounds are used to prevent or treat cancer pain associated with peripheral macrophage function.

[0023] In some embodiments, the AT2R antagonist compounds are used to prevent or treat cancer pain associated with one or more of the recruitment / accumulation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0024] In some preferred embodiments, the AT2R antagonist compound is used to prevent or treat bone cancer pain.

[0025] In some preferred embodiments, the AT2R antagonist compound is used to prevent or treat bone cancer pain associated with peripheral macrophage function.

[0026] In particular, the AT2R antagonist compounds are useful for preventing or treating bone cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0027] In yet another aspect, the present invention provides a method for preventing or treating cancer pain, comprising administering a prophylactically or therapeutically effective amount of an AT2R antagonist compound to a subject in need thereof.

[0028] In some embodiments, the present invention provides methods for preventing or treating cancer pain associated with peripheral macrophage function, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of an AT2R antagonist compound.

[0029] In some embodiments, the present invention provides a method for preventing or treating cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of an AT2R antagonist compound.

[0030] In some preferred embodiments, the present invention provides a method for preventing or treating bone cancer pain, comprising administering a preventively or therapeutically effective amount of an AT2R antagonist compound to an individual in need thereof.

[0031] In some preferred embodiments, the present invention provides a method for preventing or treating bone cancer pain associated with peripheral macrophage function, comprising administering to an individual in need thereof a preventively or therapeutically effective amount of an AT2R antagonist compound.

[0032] In particular, the present invention provides a method for preventing or treating bone cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of an AT2R antagonist compound.

[0033] In another aspect, the present invention provides use of an AT2R antagonist compound in preparing a pharmaceutical composition for preventing or treating cancer pain.

[0034] In some preferred embodiments, the present invention provides use of an AT2R antagonist compound in the preparation of a pharmaceutical composition for preventing or treating cancer pain associated with peripheral macrophage function.

[0035] In particular, the present invention provides the use of an AT2R antagonist compound in the preparation of a pharmaceutical composition for preventing or treating cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0036] In some more preferred embodiments, the present invention provides use of an AT2R antagonist compound in preparing a pharmaceutical composition for preventing or treating bone cancer pain.

[0037] In some more preferred embodiments, the present invention provides use of an AT2R antagonist compound in the preparation of a pharmaceutical composition for preventing or treating bone cancer pain associated with peripheral macrophage function.

[0038] In particular, the present invention provides the use of an AT2R antagonist compound in the preparation of a pharmaceutical composition for preventing or treating bone cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0039] As used herein, the term "treating" means to reverse, alleviate, inhibit the progress of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0040] As used herein, the term "individual" includes humans or non-human mammals, such as non-human primates, livestock and / or domesticated animals (eg, sheep, dogs, cats, cows, pigs, etc.). Preferably, the individual is a human.

[0041] In any of the aspects described herein and in embodiments according to any of the aspects, the AT2R antagonist compound is a compound having a structure of Formula (IV) as described in the "AT2R Antagonist Compounds" section below, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof.

[0042] AT2R antagonist compounds

[0043] The present application provides the following embodiments of AT2R antagonist compounds:

[0044] 1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein the compound has the structure of formula (IV):

[0045] in:

[0046] U is C 1-3 alkylene;

[0047] R 1a Selected from: C 2-8 Alkenyl and C 2-8 Alkynyl, wherein the C 2-8 Alkenyl and C 2-8 Alkynyl groups are each replaced by a C 6-10 Aryl or 5-14 membered heteroaryl substituted; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; -C 1-6 Alkylene-saturated or partially unsaturated 3-10 membered heterocyclic group; -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl);

[0048] R 1b Absent or selected from: H; optionally replaced by 1, 2, 3 or more R13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cycloalkyl; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-C 6-10 aryl;

[0049] X 1 Does not exist or is CR 10 or N;

[0050] X 4 Selected from: C(=O); and -OC(=O)- and -SC(=O)-, wherein O and S are the same as X 1 connect;

[0051] R 2a C 6-10 aryl;

[0052] R 2b C 6-10 aryl;

[0053] X 2 CR 10 or N;

[0054] R 3 -C(=O)OR 11 ;

[0055] R 4 is H;

[0056] R 10 At each occurrence, select from H, -OR 11 、-SR 11 and C 1-6 alkyl;

[0057] R 11 and R 12 Each occurrence is independently H or C 1-6 alkyl;

[0058] h and k are each independently 1;

[0059] The above alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R 13 replace;

[0060] The R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 11 、-SR 11 、-P(O)R 11 R 12 and -NR 11 R 12 , and wherein with respect to the substituent R 13 The alkyl, alkylene, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 The alkyl group is substituted with a substituent.

[0061] 2. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0062] 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 with respect to the substituent R 13 The alkyl, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 The alkyl group is substituted with a substituent.

[0063] 3. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein U is methylene or ethylene.

[0064] 4. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 3 is -COOH.

[0065] 5. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 10 Independently at each occurrence: H, C 1-4 Alkyl, OH or SH.

[0066] 6. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 11 and R 12 Each occurrence is independently selected from H and C 1-4 alkyl.

[0067] 7. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 or more substituents independently selected from halogen 1-4 Alkyl; C 5-7 Cycloalkyl; each optionally substituted by 1, 2, 3 or more independently selected from halogen, OH, amino, cyano and C 1-4 The substituents of the alkyl group are phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl; wherein R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; where R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl-SR 11 ; and wherein R 11 and R 12 is independently at each occurrence C optionally substituted with 1, 2, 3 or more halogens 1-6 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 .

[0068] 8. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 F or Cl 1-4 Alkyl; wherein R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 -OR of alkyl 11 ; where R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 Alkyl-SR 11 ; where R 11 and R12 C independently at each occurrence 1-3 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl, each optionally substituted by 1, 2, 3 or more substituents independently selected from F, Cl, Br, I and methyl.

[0069] 9. The compound of embodiment 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 1-3 The alkyl group is methyl, ethyl, propyl or isopropyl.

[0070] 10. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0071] R 1a Selected from: C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the C 2-6 Alkenyl and C 2-6 Each alkynyl group is substituted by 1 phenyl group or 5-10 membered heteroaryl group; phenyl group; -C 1-3 Alkylene-C 3-7 Cycloalkyl; -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclyl); -C 1-3 Alkylene-(8-10 membered benzo-fused heterocyclic group); -C 1-3 Alkylene-phenyl; and -C 1-3 Alkylene-(5-10 membered heteroaryl);

[0072] R 1b Not present, or selected from: H; C 1-6 Alkyl; C 3-7 Cycloalkyl; phenyl; -C 1-3 Alkylene-C 3-7 Cycloalkyl; and -C 1-3 Alkylene-phenyl; and

[0073] The above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R groups as defined in embodiment 1. 13 replace.

[0074] 11. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R 1a Selected from phenyl, -C 1-3 Alkylene-C 3-7 Cycloalkyl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclic group), -C 1-3 Alkylene-(9-10 membered benzo-fused heterocyclic group), -C 1-3 Alkylene-(5-6 membered heteroaryl) and -C 1-3 Alkylene-(9-10 membered heteroaryl), each of which is optionally substituted by 1, 2, 3 or more R 13 replace.

[0075] 12. The compound of embodiment 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R 13 Selected from C 1-4 alkyl-O-; halogen; and C optionally substituted by 1, 2 or 3 substituents independently selected from halogen 1-4 alkyl.

[0076] 13. The compound of embodiment 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein X 4 is C(=O).

[0077] 14. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein:

[0078] R 1a Selected from:

[0079] C 2-6 Alkenyl and C 2-6 Alkynyl, the C 2-6 Alkenyl and C 2-6 Each alkynyl group is substituted with one phenyl group, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, each of which is optionally substituted with one, two, or three groups independently selected from F, Cl, Br, I, and C 1-4 Substitution of alkyl groups;

[0080] Optionally, 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 a phenyl group substituted with an alkyl substituent; and

[0081] -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5- to 6-membered heteroaryl) and -C 1-3 Alkylene-(9- to 10-membered heteroaryl), wherein said alkylene is optionally substituted at each occurrence with one -NR 11 R 12 substituted, and the phenyl, 5- to 6-membered heteroaryl and 9- to 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 Substitution of alkyl groups;

[0082] R 1b does not exist;

[0083] X 1 does not exist; and

[0084] X 4 is C(=O) or -OC(=O)-.

[0085] 15. The compound of embodiment 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl.

[0086] 16. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 2-6 Alkenyl is ethenyl, 1-propenyl or 2-propenyl.

[0087] 17. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein said C 2-6 Alkynyl is vinyl, 1-propynyl or 2-propynyl.

[0088] 18. The compound of embodiment 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 is phenyl, pyridyl, indolyl or furanyl, said phenyl, pyridyl, indolyl or furanyl being optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and methyl.

[0089] 19. The compound of embodiment 18, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a Selected from:

[0090] 20. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0091] R 1a is a group selected from the group consisting of: optionally substituted phenyl, - optionally substituted C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), -optionally substituted C 1-3 Alkylene-(optionally substituted 5-7 membered monocyclic heterocyclyl),-optionally substituted C 1-3 Alkylene-(optionally substituted 8-10 membered benzo-fused heterocyclic group), -optionally substituted C 1-3 Alkylene-optionally substituted phenyl, and -optionally substituted C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl);

[0092] R 1b selected from H, optionally 1, 2, 3 or more R 13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cycloalkyl; 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;

[0093] X 1 It's CR 10 or N;

[0094] X 4 is C(=O);

[0095] The "optionally substituted" refers to 1, 2, 3 or more R 13 Replacement; and

[0096] R 13 As defined in embodiment 1.

[0097] 21. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled form, metabolite or prodrug thereof, wherein R 1bis 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;

[0098] The "optionally substituted" refers to 1, 2, 3 or more R 13 replace.

[0099] 22. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0100] R 2a is optionally substituted phenyl; and / or

[0101] R 2b is optionally substituted phenyl;

[0102] The "optionally substituted" refers to 1, 2, 3 or more R 13 replace.

[0103] 23. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II):

[0104] where R 1a 、R 1b 、X 1 、X 4 、R 2a 、R 2b 、X 2 、R 3 、R 4 , h and k are as defined in Embodiment 1.

[0105] 24. The compound of embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein for:

[0106] 25. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein for:

[0107] 26. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 10 It is H or methyl.

[0108] 27. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a is selected from optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), -C 1-3 Alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclyl), -C 1-3 Alkylene-(optionally substituted 8- to 10-membered benzofused heterocyclic group), -C 1-3 Alkylene-optionally substituted phenyl, and -C 1-3 Alkylene-(optionally substituted 5- to 10-membered heteroaryl).

[0109] 28. The compound of embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1a Is selected from:

[0110] optionally substituted phenyl;

[0111] -C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0112] -C 1-3 Alkylene-(optionally substituted 8-10 membered benzofused heterocyclyl), wherein the heterocyclyl is

[0113] -C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is

[0114] 29. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 Selected from: halogen; wherein R 11is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; wherein R 11 and R 12 Each independently selected from H and C 1-4 Alkyl-NR 11 R 12 ; and where R 11 and R 12 are each independently C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl -P(O)R 11 R 12 .

[0115] 30. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from: halogen; wherein R 11 is C optionally substituted with 1, 2 or 3 F or Cl 1-3 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; wherein R 11 and R 12 -NR, each independently selected from H and methyl 11 R 12 ; and where R 11 and R 12 Each is independently C optionally substituted with 1, 2 or 3 F or Cl 1-3 Alkyl -P(O)R 11 R 12 .

[0116] 31. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from: F, Cl, Br, OH, -OC 1-4 Alkyl, -N(C 1-4 Alkyl)2, cyano, C 3-7 Cycloalkyl, C 2-4 Alkenyl and C2-4 Alkynyl; C optionally substituted by 1, 2, 3 or more F, Cl or Br 1-4 alkyl; and wherein R 11 and R 12 -P(O)R are each independently methyl, ethyl, propyl or isopropyl 11 R 12 .

[0117] 32. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 13 is selected from the group consisting of: F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, and CF3; and wherein R 11 and R 12 -P(O)R, each independently methyl 11 R 12 .

[0118] 33. The compound according to embodiment 20, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein R 1a Selected from:

[0119] (include ),

[0120] 34. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 1b Selected from: H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-7 Cycloalkyl, optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 The alkylene group is optionally substituted with the phenyl group.

[0121] 35. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 1b Selected from:

[0122] H, phenyl;

[0123] Optionally substituted C 1-4 Alkyl, wherein the alkyl is methyl, ethyl or isopropyl;

[0124] 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

[0125] -C 1-3 Alkylene-phenyl.

[0126] 36. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from halogen and C 1-4 alkyl.

[0127] 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 Selected from F, Cl, Br and methyl.

[0128] 38. The compound of embodiment 21, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 1b Selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, Phenyl,

[0129] 39. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 13 Selected from halogen and -OR 11 , and where R 11 Selected from C 1-4 alkyl.

[0130] 40. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein R 13 Selected from F, Cl, Br and -OCH3.

[0131] 41. The compound of embodiment 22, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof, wherein R 2a and R 2b Each selected from phenyl,

[0132] 42. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite or prodrug thereof, wherein:

[0133] U is ethylene;

[0134] R 1a Selected from: -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl);

[0135] R 1b Selected from: C 1-8 Alkyl; saturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-saturated C 3-10 Cycloalkyl;

[0136] X 1 N; X 4 is C(=O); X 2 N; R 2a and R 2b All are phenyl;

[0137] R 3 is -C(=O)OH;

[0138] R 4 is H;

[0139] h and k are each independently 1; and

[0140] The above cycloalkyl, aryl and heteroaryl groups are each optionally substituted with one R 13 Substituted; said R 13 C 1-6 alkyl;

[0141] Preferably, the C 6-10 Aryl is phenyl, the saturated C 3-10 The cycloalkyl group is a cyclopropyl group, and the 5-14 membered heteroaryl group is a thienyl group or a benzothienyl group.

[0142] 43. The compound of embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled form, metabolite, or prodrug thereof, wherein the compound is selected from:

[0143] The corresponding relationships between the above compounds A1 to A9 and the example compounds listed in Table A below are as follows: A1 = C112, A2 = C246, A3 = C202, A4 = C196, A5 = C154, A6 = C155, A7 = C184, A8 = C207, A9 = C159.

[0144] definition

[0145] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0146] 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.

[0147] 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.

[0148] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12 carbon atoms, particularly 1 to 8 ("C 1-8 alkyl”), for example 1 to 6 carbon atoms (“C 1-6 alkyl”), 1 to 4 carbon atoms (“C 1-4 alkyl”), more particularly having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. For example, as used herein, the term “C 1-8"Alkyl" refers to a linear or branched group of 1 to 8 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (for example, CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0149] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 8 carbon atoms ("C 2-8 Alkenyl", such as "C 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl, and octenyl. When the compounds described herein contain an alkenylene group, the compounds may be present in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0150] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6, 7 or 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, etc.

[0151] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6, such as 5-6 or 5-7) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, etc.

[0152] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or bicyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6; or, suitably 8-10, more suitably 9 or 10) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated monocyclic or bicyclic heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of monocyclic heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. Other examples of monocyclic heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (e.g., pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1,3-dioxolane, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (e.g., morpholino), thiomorpholinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiaz ... ane), hexahydropyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepane, 1,4-diazepane, 1,3-oxazepane, 1,3-thiazepane. Bicyclic heterocyclylene and heterocycle (group) include spiro ring systems, fused (e.g., benzofused) systems or bridged systems.Benzo-fused heterocyclylene and heterocyclyl refer to the monocyclic heterocyclylene and heterocyclyl described above fused to benzo, for example, a benzo derivative having 3-6 (suitably 4-6, more suitably 5-6) ring atoms, of which 1, 2, 3 or 4 are heteroatoms selected from N, O and S and the remaining ring atoms are C saturated or partially unsaturated monocyclic groups (i.e., "7-10 membered benzo-fused heterocyclyl"), including, for example, 2,3-dihydrobenzofuranyl. 1,3-Dihydroisobenzofuranyl 2,3-Dihydrobenzo[c]thienyl 1,3-Dihydrobenzo[c]thienyl (Iso)indolinyl (Iso)dihydroisoindole (Ethylenedi)benzo[d][1,3]dioxolyl (Ylene)benzo[d][1,3]dithiolene (Ylene)benzo[d][1,3]oxathiolene (Ylidene)3H-benzo[c][1,2]oxathiolene (Ylidene)3H-benzo[d][1,2]oxathiolene (Iso)2,3-dihydrobenzo[d]oxazolyl (Iso)2,3-dihydrobenzo[d]thiazolyl (Iso)2,3-dihydro-1H-benzo[d]imidazolyl 2,3-Dihydrobenzo[d]isoxazolyl (Iso)2,3-dihydrobenzo[d]isothiazolyl 1,3-Dihydrobenzo[c]isoxazolyl (Iso)1,3-dihydrobenzo[c]isothiazolyl (Iso)2,3-dihydro-1H-indazolyl (Asian) Semanki (Ethyl)2H-chromenyl (Ethyl)4H-chromenyl (Ide)dihydrobenzothiopyranyl (Sub)2H-thiochromene ), (sub) 4H-benzothiopyran (4H-thiochromene, ), (sub) 1,2,3,4,4a,8a-hexahydroquinolinyl (Ethyl)1,2,4a,8a-tetrahydroquinolinyl (Ethyl)1,4,4a,8a-tetrahydroquinolinyl (Iso)1,2,3,4,4a,8a-hexahydroisoquinolinyl (Ethyl)1,2,3,4,4a,8a-hexahydroquinoxalinyl (Ethyl)1,4,4a,8a-tetrahydroquinoxalinyl (Sub)1,2,3,4,4a,8a-hexahydroquinazolinyl (Ylidene) 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]oxazinyl (Ylidene) 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]oxazinyl (Ethyl)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]oxazinyl (Ylidene) 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]thiazinyl (Ylidene) 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]thiazinyl (Ethyl)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]thiazinyl and 2,3-dihydrobenzo[b][1,4]dioxin Such bridged systems include, for example, 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc. The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0153] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0154] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, and 5-pyrazolyl), isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl (e.g., 1-tetrazolyl or 5-tetrazolyl), thiadiazolyl, and the like, and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. Other examples of "heteroaryl(ene)" or "heteroaryl ring" include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, purinyl and the like.

[0155] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0156] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0157] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle being optionally benzo-fused and preferably linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0158] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0159] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0160] 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.

[0161] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0162] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0163] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring, including available atoms in the bridge when the substitutable ring is bridged.

[0164] The present application also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds described above, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g.13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0165] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds described herein can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0166] In this article, solid lines can be used Solid wedge or virtual wedge Carbon-carbon bonds of the compounds described herein are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds described herein are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds described herein may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0167] The present application encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0168] It should also be understood that certain compounds described herein may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In this application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound described herein or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound described herein," the various derivative forms of the compounds described above are also intended to be encompassed.

[0169] Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

[0170] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0171] 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.

[0172] Suitable salts are reviewed in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0173] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds described herein in the form of the free acid or alcohol). The compounds described herein themselves may also be esters.

[0174] The compounds described herein may exist in the form of solvates (preferably hydrates), wherein the compounds described herein contain a polar solvent, such as water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio.

[0175] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0176] The present application also includes metabolites of the compounds described herein, i.e., substances formed in vivo upon administration of the compounds. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compounds. Thus, the present application includes metabolites of the compounds, including compounds produced by methods that contact the compounds with a mammal for a sufficient period of time to produce a metabolic product thereof.

[0177] The present application further includes prodrugs of the compounds, which are certain derivatives of the compounds that may have little or no pharmacological activity themselves, which can be converted into the compounds with the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are 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", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs can be prepared, for example, by replacing appropriate functional groups present in the compounds described herein 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)).

[0178] This application also encompasses compounds containing protecting groups. In any process for preparing the compounds described herein, 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 compound. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0179] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0180] Pharmaceutical composition

[0181] The AT2R antagonist compounds described herein can be administered in the form of a pharmaceutical composition comprising the AT2R antagonist compound and one or more pharmaceutically acceptable carriers. The pharmaceutical composition can be a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation. In some embodiments, the pharmaceutical composition may further comprise one or more other therapeutic or prophylactic agents.

[0182] The term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0183] The pharmaceutically acceptable carrier includes, but is not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0184] The pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0185] For these administration routes, the pharmaceutical composition can be administered in suitable dosage forms.

[0186] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0187] As used herein, the term "effective amount" refers to an amount of the AT2R antagonist compound that, when administered, prevents or delays the onset, shortens the duration, reduces the severity or eliminates the pain, and / or slows down the progression of cancer pain, preferably bone cancer pain.

[0188] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0189] The amount of the AT2R antagonist compound administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. In general, an effective dose is from about 0.0001 to about 50 mg per kg of body weight per day, for example, from about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would amount to from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, a dosage level not exceeding the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0190] In some embodiments, the AT2R antagonist compound is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg per day, for example, at a dose of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg per unit dose. / 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, about 575 μg / kg, about 600 μg / kg 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 15 mg / kg, about 1 0 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.

[0191] In some embodiments, the daily dose of the AT2R antagonist compound is administered once or divided into two, three, or four doses.

[0192] In some embodiments, the AT2R antagonist compound 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 day, 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.

[0193] In some embodiments, the AT2R antagonist compound is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment, wherein each course of treatment 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 day, 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 wherein each course of treatment is separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.

[0194] The AT2R antagonist compound may be present in an amount of 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, 15 0, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0195] Figure 1 shows the ROS fluorescence intensity of different treatment groups, which shows the effect of AT2R antagonists on AngII-induced ROS free radical generation in mouse peritoneal macrophages. ###p<0.001, compared with the blank solvent group (Control); ***p<0.001, compared with the AngII (0.2 μM) group.

[0196] FIG2 shows the relative fluorescence intensity of calcium ions in DRG neurons in different treatment groups when DRG neurons were co-cultured with Raw264.7 cells. ### p<0.001, compared with the vehicle group (Control); **p<0.01, *** p<0.001, compared with the AngII (200 nM) group.

[0197] FIG3 shows the paw withdrawal threshold (PWT) of each group of SNI mice in the efficacy test of AT2R antagonists on the sciatic nerve branch injury (SNI) model (Mean±SD, ***p<0.001, compared with the vehicle group at the corresponding time point).

[0198] Figure 4 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).

[0199] FIG5 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.

[0200] FIG6 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.

[0201] FIG7 shows typical images of TRPA1 immunofluorescence staining of the injured-side DRG of SNI mice (Bar=20 μm).

[0202] FIG8 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).

[0203] FIG9 shows the changes in 50% PWT of different treatment groups at different administration time points in the rat bone cancer pain model. DETAILED DESCRIPTION

[0204] Compound Examples

[0205] The present application provides the compounds known in the prior art listed in Table A below, whose preparation and identification are disclosed in the Examples section of WO2019179515A1. All the examples of WO2019179515A1 are incorporated herein by reference.

[0206] Table A

[0207] Biological Examples

[0208] In the following biological tests, the compound A1 used corresponds to compound C112 shown in Table A. It should be noted that compound A1 is used as an exemplary compound in the following tests and does not mean that the present invention is limited to the compound A1.

[0209] Experimental Example 1: Effects of AT2R antagonists on AngII-induced reactive oxygen species free radical production in mouse peritoneal macrophages

[0210] 1.1 Purpose of the Test

[0211] Mouse peritoneal macrophages express AT2R. AngII, as a ligand for AT2R, can induce an increase in ROS production in mouse peritoneal macrophages by binding to the AT2R receptor. This study evaluated the ability of AT2R antagonists to inhibit AngII-induced ROS production in mouse peritoneal macrophages by inhibiting the AT2R receptor in mouse peritoneal macrophages.

[0212] 1.2 Instruments and Equipment

[0213] 1.3 Test methods

[0214] Six-week-old C57BL / 6 male mice were euthanized and primary peritoneal macrophages were obtained by intraperitoneal injection of phenol red-free medium. After centrifugation, the cells were suspended in RPMI1640 + 5% FBS (containing 50 ng / μl GM-CSF) medium and cultured in a 37°C, 5% CO2 incubator for 2 days. The macrophages were then seeded in 96-well plates. After 24 hours of adherence, the macrophages were stained with the ROS indicator DCFH-DA and treated as follows: 1) blank solvent group; 2) AngII (0.2 μM) treatment group; 3) PD123319 combined with AngII group (PD (1 μM) + AngII (0.2 μM)): PD123319 + AngII (0.2 μM) 319 were 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 ROS production level of macrophages in each group was determined by real-time fluorescence scanning.

[0215] PD123319 di-trifluoroacetate (purchased from MCE, batch number: 14354)

[0216] 1.4 Statistics

[0217] Data were collected using Excel software and analyzed using Prism 6.01 (Graph Pad Software, Inc.) software (one-way analysis of variance). The results of each experimental group were statistically analyzed to compare whether there were statistical differences between the groups. P < 0.05 was considered statistically significant.

[0218] 1.5 Experimental Results

[0219] Figure 1 shows the ROS fluorescence intensity of different treatment groups. ### p<0.001 indicates that compared with the blank solvent group, *** p<0.001 indicates comparison with the AngII (0.2μM) group. Compared with the blank solvent group, the level of reactive oxygen species produced by macrophages after AngII treatment was significantly increased (p<0.05). Compared with the AngII-treated group, the A1 (0.5μM) combined with AngII (0.2μM) group and the A1 (5μM) combined with AngII (0.2μM) group significantly reduced the AngII-induced increase in reactive oxygen species (p<0.05). Therefore, both 0.5μM and 5μM concentrations of A1 inhibited the increase in reactive oxygen species induced by AngII.

[0220] Experimental Example 2: Effects of AT2R Antagonists on Neuronal Excitability in Co-culture of DRG Neurons and Raw264.7 Cells

[0221] 2.1 Test equipment

[0222] Microplate reader (Promega, Discover System 4.92.0)

[0223] 2.2 Cell sources and culture conditions

[0224] DRG neurons (catalog number: BNCC360471, batch number: 23072601) and RAW264.7 cells (catalog number: BNCC354753, batch number: 23072601) were purchased from Beina Biotechnology. The culture conditions were DMEM (high glucose medium) + 10% FBS + penicillin-streptomycin (S / P) double antibody, among which DMEM high glucose medium was purchased from Keygen Biotechnology (batch number: 20230629), FBS was purchased from Eva Biopharmaceutical Technology Co., Ltd. (batch number: 22EG01105), S / P double antibody was purchased from Nanjing Shenghang Biotechnology Co., Ltd. (batch number: BC20221202), and trypsin was purchased from Suzhou Xinsaimei Biotechnology Co., Ltd. (batch number: 20230607).

[0225] 2.3 Experimental Procedure

[0226] (1) DRG neurons and Raw264.7 were cultured separately in separate cell culture flasks and grown to a certain density (>1×10 6 / ml) and then the cell density was adjusted to 3×10 5 / ml (Raw264.7) and 1×10 5 / ml (DRG neurons);

[0227] (2) DRG neurons were co-cultured with RAW264.7 (1×10 4 :3×10 4 ), DRG neurons (1×10 4 ) alone, R264.7 cells (3×10 4 ) Single culture: cells were cultured in 96-well plates (n=8 for each condition) overnight until adhered;

[0228] (3) After the cells adhered, the culture medium was discarded, and the 96-well plate was washed three times with 1× HHBS buffer (containing 20 mM Hepes). 5 μM Fluo-8, AM dye was added and incubated at 37°C for 30 min. The 96-well plate was then washed three times with 1× HHBS buffer (containing 20 mM Hepes).

[0229] (4) Different cells were treated with the following groups: PBS blank control group, AngII (200 nM), Ang II (200 nM) + PD123319 (1 μM), AngII (200 nM) + A1 (0.1 μM), AngII (200 nM) + A1 (1 μM), Ang II (200 nM) + A1 (10 μM), n = 8 per group, treated for 30 minutes;

[0230] (5) Record the fluorescence intensity at 475 / 500-550 nm on a microplate reader.

[0231] 2.4 Data Statistics

[0232] The experimental results are expressed as "mean ± standard deviation". The data of each group were statistically analyzed using GraphPad Prism 8.0 software package, and the one-way ANOVA method was used to compare whether there were any statistical differences between the groups. P < 0.05 was considered statistically significant.

[0233] 2.5 Experimental Results

[0234] When DRG neurons were co-cultured with Raw264.7 macrophages, AngII (200 nM) treatment for 30 minutes significantly increased calcium concentration in DRG neurons (by approximately 135.8%, p < 0.001) compared to the vehicle (PBS) blank control group. Compared to the AngII (200 nM) group, A1 (0.1 μM), A1 (1 μM), A1 (10 μM), and PD123319 (1 μM) reduced calcium concentration by 16.4% (p < 0.01), 41.4% (p < 0.001), 49.6% (p < 0.001), and 48.2% (p < 0.001), respectively. Compared to the AngII (200 nM) treatment group, A1 at both 1 μM and 10 μM concentrations significantly inhibited the AngII (200 nM)-induced increase in intracellular calcium concentration in DRG neurons. The results are shown in Table 1 and Figure 2.

[0235] Table 1. Relative fluorescence intensity of intracellular calcium ions in DRG neurons in different treatment groups Note: ### p < 0.001, compared with the vehicle group; ** p<0.01, *** p<0.001, compared with the AngII (200 nM) group.

[0236] Experimental Example 3: Efficacy of AT2R antagonists on the sciatic nerve branch injury model in mice

[0237] 3.1 Test Purpose:

[0238] The analgesic effect of AT2R antagonists on the sciatic nerve branch injury (SNI) model in mice was evaluated using a Von Frey electronic analgesia. The effects of AT2R antagonists on the co-staining of AT2R receptors and F4 / 80 on macrophages in the SNI model mice, as well as on the expression of transient receptor potential ion channel subunit 1 (TRPA1) in dorsal root ganglion (DRG) neurons were studied.

[0239] 3.2 Test instruments

[0240] Electronic analgesia (IITC, 2392), small animal anesthesia machine (R510-29), laser confocal microscope (Zeiss, LSM710), frozen section machine (ThermoFisher, NX70).

[0241] 3.3 Experimental animals

[0242] Strain: C57BL / 6 mice

[0243] Age: 4-6 weeks

[0244] Gender: Male

[0245] Weight: 14-20 grams

[0246] Number of animals purchased: 70

[0247] Laboratory animal provider: Hunan Slake Jingda Laboratory Animal Co., Ltd.

[0248] Production license number: SCXK (Xiang) 2019-0004

[0249] 3.4 In vivo test process

[0250] 1) Mice were fully anesthetized by inhalation of isoflurane and secured in a prone position on an operating table to fully expose the lateral buttocks. The left posterior ramus was shaved and disinfected with alcohol. Aseptic techniques were followed during the surgery. For the SNI surgery group: The skin was incised parallel to the sciatic nerve at the femur, exposing the sciatic nerve trunk until the tibial, common peroneal, and sural nerves were exposed. The tibial and common peroneal nerves were tightly ligated with absorbable medical sutures (8-0). A segment (approximately 2-4 mm) was then cut from the ligation site to the distal nerve, ensuring the integrity of the sural nerve. The muscle and epidermis were then sutured layer by layer to complete the SNI model.

[0251] 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.

[0252] 3) PWT was measured on the 11th day after surgery. Animals with abnormal PWT (mean PWT >4 g or <1 g) were excluded and randomly divided into five groups (SNI model group) according to body weight and PWT value: solvent control group (sterile water for injection), gabapetin 50 mg / kg, A1 50 mg / kg, A1 100 mg / kg, and A1 200 mg / kg, 12 mice per group, and 10 mL / kg was administered by gavage.

[0253] 4) On postoperative day 12, the paw withdrawal threshold was tested using a Von Frey electronic anesthesiometer at 0 h before administration and 2 and 4 h after administration. The animals were placed in a specially designed pain detection multi-unit metal mesh cage and acclimatized for 30 minutes. After the animals were acclimated to the test environment, the electronic anesthesiometer (Electronic von Frey Anesthesiometer, IITC Life Science Inc.) was used to stimulate the sole of the hind limb on the surgical side of the mouse. The pressure was continuously increased until the mouse showed a significant paw withdrawal reaction. The electronic anesthesiometer recorded the reading at this time, which was the threshold of the mechanical pain response. The test was repeated 6 times in g as the detection unit. The average value was then taken as the final test index.

[0254] 3.5 Tissue sampling and immunofluorescence staining process

[0255] 1) After pain measurement, the first six mice in the Vehicle group, A1 50 mg / kg, A1 100 mg / kg, and A1 200 mg / kg groups were anesthetized with isoflurane inhalation using a small animal anesthesia machine (R510-29) and euthanized by cervical dislocation. The sciatic nerves of the injured and non-injured sides and the DRG of the injured side were removed and fixed in 4% paraformaldehyde solution.

[0256] 2) Dehydrate, freeze-embed, and slice the fixed injured and uninjured sciatic nerves and dorsal root ganglia on the injured side.

[0257] 3) The immunofluorescence staining process is as follows:

[0258] The tissue sections were washed three times with PBS for 5 min each time; incubated with 0.3% Triton-X100 PBS for 20 min; washed three times with PBS for 5 min each time; and blocked with goat serum for 1 h at room temperature.

[0259] Then, the primary antibodies (AT2R: Rabbit, (LSBio, LS-A1322); TRPA1: Rabbit, (Invitrogen, PA1-46159); F4 / 80: Rat, (abcam, ab6640)) were diluted 1:200 with antibody diluent (New Saimei Biotechnology, Lot: 20220824) and incubated at 4°C overnight; then washed with PBS three times, 5 min each time;

[0260] Then the secondary antibody (Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rat ( 488) (abcam, ab150165)) was diluted with antibody diluent (New Saimei Biotechnology, Lot: 20220824) at a ratio of 1:2000 and incubated at room temperature for 30 minutes; then washed with PBS three times, each time for 5 minutes;

[0261] The sections were mounted with DAPI-containing mounting solution and photographed using a confocal microscope (Leica Microsystems, DCM8). The number of AT2R and F4 / 80 co-stained macrophages in sciatic nerve tissue was counted using the Find Maxima function of Image J, and the TRPA1 fluorescence intensity of DRG neuronal cells was calculated using Image J.

[0262] 3.6 Data Statistics

[0263] 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.

[0264] 3.7 In vivo test results

[0265] In the SNI model, A1 (50 mg / kg) significantly inhibited mechanical allodynia induced by sciatic nerve injury in mice 2 and 4 hours after oral administration, compared with the vehicle control group. Gabapentin (50 mg / kg) also inhibited mechanical allodynia induced by sciatic nerve injury in mice 2 and 4 hours after oral administration. Figure 3 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).

[0266] 3.8 Immunofluorescence staining results

[0267] Figure 4 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).

[0268] Figure 5 shows the fluorescence intensity of macrophages co-stained for AT2R and F4 / 80 on the injured side of the sciatic nerve in SNI mice. The results indicate that compared with the vehicle control group, both A1 (100 mg / kg) and A1 (200 mg / kg) significantly reduced the number of macrophages co-stained for AT2R and F4 / 80 on the injured side of the sciatic nerve. Figure 6 shows the fluorescence intensity of macrophages co-stained for AT2R and F4 / 80 on the uninjured side of the sciatic nerve in SNI model mice. The results indicate that the number of macrophages co-stained for AT2R and F4 / 80 on the uninjured side of the sciatic nerve was low in all experimental groups, and there was no significant difference in the number of macrophages co-stained for AT2R and F4 / 80 between groups. These results indicate that the injured side of the sciatic nerve recruits more peripheral macrophages than the uninjured side. The AT2R antagonist A1, administered orally at 100 mg / kg and 200 mg / kg, significantly reduced the number of peripheral macrophages and AT2R expression.

[0269] Figure 7 shows a typical image of TRPA1 immunofluorescence staining of the injured side DRG of SNI mice (Bar = 20 μm), and Figure 8 shows the average fluorescence intensity of TRPA1 in the injured side DRG neurons of SNI mice. The results indicate that compared with the vehicle control group, A1 (100 mg / kg) and A1 (200 mg / kg) can significantly reduce the expression of TRPA1 in DRG neurons.

[0270] Experimental Example 4: Efficacy of a single oral gavage of an AT2R antagonist in a rat bone cancer pain model

[0271] 4.1 Test equipment

[0272] 4.2 Experimental animals

[0273] Species: Sprague–Dawley rats

[0274] Number and sex of animals purchased: 80 females

[0275] Laboratory animal provider: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0276] Production license number: SCXK (Beijing) 2016-0006

[0277] Quality certificate number: 1100112011012856

[0278] 4.3 Test methods

[0279] Breast cancer cell culture: Rat breast cancer MRMT-1 cells (Guangzhou Geneo Biotechnology Co., Ltd., catalog number: JNO-M0051) were cultured in RPMI 1640 medium containing 10% FBS, 1% L-glutamine, and 2% penicillin / streptomycin. When the cells reached 80%-90% of the bottom of the culture flask, they were digested with 0.25% trypsin and centrifuged at 1200 rpm for 3 minutes. The cell pellet was resuspended in PBS and then centrifuged at 1200 rpm for 3 minutes. Finally, the pellet was resuspended in PBS and counted to obtain a cell concentration of 1.6 x 10 8 pieces / mL.

[0280] SD rats were acclimated for one week. Rats were anesthetized with a mixture of 10% chloral hydrate and 25% urethane (1:1) by intraperitoneal injection with the abdomen facing upwards, and the left leg was disinfected with 70% ethanol. A transverse incision of approximately 1 cm was made in the skin above the left tibia to expose the tibial articular surface. The tibia was fixed and a 5 mL syringe needle was used to punch a hole into the bone marrow cavity on the articular surface. 6 μL of MRMT-1 cell suspension (1.6×10 8 The drug was injected slowly and evenly into the rat's bone marrow cavity. The bone marrow cavity was then sealed with bone wax. The skin was then sutured and disinfected with iodine. The entire surgical procedure was performed under sterile conditions. Thus, a bone cancer pain model was established in SD rats. Fourteen days after modeling, plantar von Frey fiber analgesia was performed, and animals with 50% PWT values ​​between 1 and 6 g were selected as bone cancer pain model rats. Sixty SD rats with bone cancer pain models were randomly divided into five groups based on pain threshold and body weight: vehicle control (ddH2O), gabapentin 100 mg / kg, and A1 (50, 100, and 200 mg / kg), with 12 rats per group. The drug was administered via oral gavage at a volume of 10 mL / kg. Von Frey fiber analgesia was performed 2, 4, and 6 hours after administration, and drug efficacy was evaluated based on changes in the rats' 50% PWT.

[0281] 50% PWT value, the formula is: 50% g threshold = (10 [Xf+kδ] ) / 10000

[0282] Where Xf = the final Von Frey nylon filament log value used in the test; k = the positive / negative response pattern value; δ = the mean difference in log values ​​between nylon filament stimuli, here a constant of 0.224.

[0283] 4.4 Statistical analysis

[0284] Data were collected using Excel software and analyzed using Prism 6.01 (Graph pad software, Inc.) software (two-way analysis of variance). The experimental results of each group were statistically analyzed to compare whether there were statistical differences between the groups. P < 0.05 was considered statistically significant.

[0285] 4.5 Experimental Results

[0286] 50% PWT was evenly dispersed among the groups at 0 hour before administration, with no significant difference. Compared with the vehicle control group, A1 (50 mg / kg) had a significant alleviating effect on the mechanical allodynia in rats with bone cancer pain model 2 hours and 4 hours after oral administration. A1 (100 mg / kg) had a significant alleviating effect on the mechanical allodynia in rats with bone cancer pain model 4 hours after oral administration. A1 (200 mg / kg) had a significant alleviating effect on the mechanical allodynia in rats with bone cancer pain model 2 hours and 4 hours after oral administration. Therefore, under this experimental system, A1 can significantly relieve bone cancer pain in rats at doses of 50, 100 and 200 mg / kg. The experimental results are also shown in Figure 9.

[0287] In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

Use of angiotensin II type 2 receptor (AT2R) antagonist compound in preparing a pharmaceutical composition for preventing or treating cancer pain. Use of an AT2R antagonist compound in preparing a pharmaceutical composition for preventing or treating cancer pain associated with peripheral macrophage function. The use according to claim 1 or 2, wherein the cancer pain is cancer pain associated with one or more of the following: recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and increased levels of reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) produced by macrophages. Preferably, the cancer is selected from the group consisting of: blood cancers, such as leukemia; and solid tumors, such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, stomach cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma and bone cancer. The use according to claim 1, wherein the cancer pain is bone cancer pain, Preferably, the cancer pain is bone cancer pain associated with peripheral macrophage function, More preferably, the bone cancer pain is bone cancer pain associated with one or more of the following: recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages. Still more preferably, the bone cancer is primary bone cancer or metastatic bone cancer, wherein the metastatic bone cancer is preferably selected from bone metastases of blood cancer (such as leukemia) and solid tumors (such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma), more preferably bone metastases of breast cancer, lung cancer, kidney cancer, rectal cancer, pancreatic cancer, gastric cancer, colon cancer, or ovarian cancer. AT2R antagonist compounds for use in preventing or treating cancer pain. The AT2R antagonist compound for use according to claim 5, for preventing or treating cancer pain associated with peripheral macrophage function, Preferably, it is used for preventing or treating cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages. More preferably, the cancer is selected from the group consisting of: blood cancers, such as leukemia; and solid tumors, such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, stomach cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma and bone cancer. The AT2R antagonist compound for use according to claim 5, which is used for preventing or treating bone cancer pain, Preferably, it is used to prevent or treat bone cancer pain associated with peripheral macrophage function, More preferably, it is used for preventing or treating bone cancer pain associated with one or more of the recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages. Still more preferably, the bone cancer is primary bone cancer or metastatic bone cancer, wherein the metastatic bone cancer is preferably selected from bone metastases of blood cancer (such as leukemia) and solid tumors (such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma), more preferably bone metastases of breast cancer, lung cancer, kidney cancer, rectal cancer, pancreatic cancer, gastric cancer, colon cancer, or ovarian cancer. A method for preventing or treating cancer pain, comprising administering a preventively or therapeutically effective amount of an AT2R antagonist compound to an individual in need thereof. The method of claim 8, wherein the cancer pain is cancer pain associated with peripheral macrophage function, Preferably, the cancer pain is cancer pain associated with one or more of the following: recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) produced by macrophages. More preferably, the cancer is selected from the group consisting of: blood cancers, such as leukemia; and solid tumors, such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, stomach cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma and bone cancer. The method of claim 8, wherein the cancer pain is bone cancer pain, Preferably, the cancer pain is bone cancer pain associated with peripheral macrophage function. More preferably, the bone cancer pain is bone cancer pain associated with one or more of the following: recruitment / aggregation of macrophages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages. Still more preferably, the bone cancer is primary bone cancer or metastatic bone cancer, wherein the metastatic bone cancer is preferably selected from bone metastases of blood cancer (such as leukemia) and solid tumors (such as breast cancer, lung cancer, prostate cancer, kidney cancer, thyroid cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, ovarian cancer, cervical cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma), more preferably bone metastases of breast cancer, lung cancer, kidney cancer, rectal cancer, pancreatic cancer, gastric cancer, colon cancer, or ovarian cancer. The use according to any one of claims 1 to 4, the AT2R antagonist compound according to any one of claims 5 to 7, or the method according to any one of claims 8 to 10, wherein the AT2R antagonist compound is a compound of formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof: in: U is C 1-3 alkylene; R 1a Selected from: C 2-8 Alkenyl and C 2-8 Alkynyl, wherein the C 2-8 Alkenyl and C 2-8 Alkynyl groups are each replaced by a C 6-10 Aryl or 5-14 membered heteroaryl substituted; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; -C 1-6 Alkylene-saturated or partially unsaturated 3-10 membered heterocyclic group; -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl); R 1b Absent or selected from: H; optionally replaced by 1, 2, 3 or more R 13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cycloalkyl; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-C 6-10 aryl; X 1 Does not exist or is CR 10 or N; X 4 Selected from: C(=O); and -OC(=O)- and -SC(=O)-, wherein O and S are the same as X 1 connect; R 2a C 6-10 aryl; R 2b C 6-10 aryl; X 2 CR 10 or N; R 3 is -C(=O)OR 11 ; R 4 is H; R 10 At each occurrence, select from H, -OR 11 、-SR 11 and C 1-6 alkyl; R 11 and R 12 Each occurrence is independently H or C 1-6 alkyl; h and k are each independently 1; The above alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R 13 replace; The R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 11 、-SR 11 、-P(O)R 11 R 12 and -NR 11 R 12 , and wherein with respect to the substituent R 13 The alkyl, alkylene, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 The alkyl group is substituted with a substituent. The use, compound, or method of claim 11, 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 with respect to the substituent R 13 The alkyl, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more groups independently selected from halogen and C 1-6 Substitution of the alkyl group; and / or wherein U is methylene or ethylene; and / or where R 3 is -COOH; and / or where R 10 Independently at each occurrence: H, C 1-4 Alkyl, OH or SH; and / or where R 11 and R 12 Each occurrence is independently selected from H and C 1-4 alkyl. The use, compound, or method of claim 11, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 or more substituents independently selected from halogen 1-4 Alkyl; C 5-7 Cycloalkyl; each optionally substituted by 1, 2, 3 or more independently selected from halogen, OH, amino, cyano and C 1-4 The substituents of the alkyl group are phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl; wherein R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; where R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl-SR 11 ; and wherein R 11 and R 12 is independently at each occurrence C optionally substituted with 1, 2, 3 or more halogens 1-6 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 . The use, compound, or method of claim 11, wherein R 13 is independently selected at each occurrence from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, 3 F or Cl 1-4 Alkyl; wherein R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 -OR of alkyl 11 ; where R 11 is C optionally substituted by 1, 2, 3 F or Cl 1-3 Alkyl-SR 11 ; where R 11 and R 12 C independently at each occurrence 1-3 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl, each optionally substituted by 1, 2, 3 or more substituents independently selected from F, Cl, Br, I and methyl, Preferably, wherein the C 1-3 The alkyl group is methyl, ethyl, propyl or isopropyl. The use, compound, or method of claim 11, wherein: R 1a Selected from: C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the C 2-6 Alkenyl and C 2-6 Each alkynyl group is substituted by 1 phenyl group or 5-10 membered heteroaryl group; phenyl group; -C 1-3 Alkylene-C 3-7 Cycloalkyl; -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclyl); -C 1-3 Alkylene-(8-10 membered benzo-fused heterocyclic group); -C 1-3 Alkylene-phenyl; and -C 1-3 Alkylene-(5-10 membered heteroaryl); R 1b Not present, or selected from: H; C 1-6 Alkyl; C 3-7 Cycloalkyl; phenyl; -C 1-3 Alkylene-C 3-7 Cycloalkyl; and -C 1-3 Alkylene-phenyl; and The above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2, 3 or more R groups as defined in claim 11. 13 replace. The use, compound, or method of claim 15, wherein R 1a Selected from phenyl, -C 1-3 Alkylene-C 3-7 Cycloalkyl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclic group), -C 1-3 Alkylene-(9-10 membered benzo-fused heterocyclic group), -C 1-3 Alkylene-(5-6 membered heteroaryl) and -C 1-3 Alkylene-(9-10 membered heteroaryl), each of which is optionally substituted by 1, 2, 3 or more R 13 replace, Preferably, wherein R 13 Selected from C 1-4 alkyl-O-; halogen; and C optionally substituted by 1, 2 or 3 substituents independently selected from halogen 1-4 alkyl. The use, compound, or method of claim 16, wherein X 4 is C(=O). The use, compound, or method of claim 15, wherein: R 1a Selected from: C 2-6 Alkenyl and C 2-6 Alkynyl, the C 2-6 Alkenyl and C 2-6 Each alkynyl group is substituted with one phenyl group, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, each of which is optionally substituted with one, two, or three groups independently selected from F, Cl, Br, I, and C 1-4 Substitution of alkyl groups; Optionally, 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 a phenyl group substituted with an alkyl substituent; and -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-(5- to 6-membered heteroaryl) and -C 1-3 Alkylene-(9- to 10-membered heteroaryl), wherein said alkylene is optionally substituted at each occurrence with one -NR 11 R 12 substituted, and the phenyl, 5- to 6-membered heteroaryl and 9- to 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 independently selected from F, Cl, Br, I and C 1-4 Substitution of alkyl groups; R 1b does not exist; X 1 does not exist; and X 4 is C(=O) or -OC(=O)-. The use, compound, or method of claim 15, wherein the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl or tert-butyl. The use, compound, or method of claim 18, wherein the C 2-6 Alkenyl is ethenyl, 1-propenyl or 2-propenyl; and / or wherein the C 2-6 Alkynyl is vinyl, 1-propynyl or 2-propynyl. The use, compound, or method of claim 15 or 18, wherein R 13 is phenyl, pyridyl, indolyl or furanyl, said phenyl, pyridyl, indolyl or furanyl being optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and methyl. The use, compound, or method of claim 21, wherein R 1a Selected from: The use, compound, or method of claim 11, 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 heterocyclic group), -optionally substituted C 1-3 Alkylene-optionally substituted phenyl, and -optionally substituted C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl); R 1b selected from H, optionally 1, 2, 3 or more R 13 Substituted C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cycloalkyl; 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 It's CR 10 or N; X 4 is C(=O); wherein the "optionally substituted" refers to 1, 2, 3 or more R 13 Replacement; and R 13 As defined in claim 11; Preferably, 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; wherein the "optionally substituted" refers to 1, 2, 3 or more R 13 replace. The use, compound, or method of claim 11, wherein: R 2a is optionally substituted phenyl; and / or R 2b is optionally substituted phenyl; wherein the "optionally substituted" refers to 1, 2, 3 or more R 13 replace. The use, compound, or method of claim 11, wherein the compound has the structure of formula (II): where R 1a 、R 1b 、X 1 、X 4 、R 2a 、R 2b 、X 2 、R 3 、R 4 , h and k are as defined in claim 11. The use, compound, or method of claim 11 or 25, wherein for: The use, compound, or method of claim 11 or 25, wherein for: The use, compound, or method of claim 11 or 25, wherein R 10 It is H or methyl. The use, compound, or method of claim 23, wherein R 1a is selected from optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 Cycloalkyl), -C 1-3 Alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclyl), -C 1-3 Alkylene-(optionally substituted 8- to 10-membered benzofused heterocyclic group), -C 1-3 Alkylene-optionally substituted phenyl, and -C 1-3 Alkylene-(optionally substituted 5- to 10-membered heteroaryl), Preferably, 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 benzofused heterocyclyl), wherein the heterocyclyl is -C 1-3 Alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is The use, compound, or method of claim 23, wherein R 13 Selected from: halogen; wherein R 11 is C optionally substituted by 1, 2, 3 or more halogens 1-6 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; wherein R 11 and R 12 Each independently selected from H and C 1-4 Alkyl-NR 11 R 12 ; and where R 11 and R 12 are each independently C optionally substituted by 1, 2, 3 or more halogens 1-6 Alkyl -P(O)R 11 R 12 ; Preferably, wherein R 13 Selected from: halogen; wherein R 11 is C optionally substituted with 1, 2 or 3 F or Cl 1-3 -OR of alkyl 11 ; cyano; C 3-7 Cycloalkyl; C optionally substituted by 1, 2, 3 or more halogen 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; wherein R 11 and R 12 -NR, each independently selected from H and methyl 11 R 12 ; and where R 11 and R 12 Each is independently C optionally substituted with 1, 2 or 3 F or Cl 1-3 Alkyl -P(O)R 11 R 12 . The use, compound, or method of claim 23, wherein R 13 Selected from: F, Cl, Br, OH, -OC 1-4 Alkyl, -N(C 1-4 Alkyl)2, cyano, C 3-7 Cycloalkyl, C 2-4 Alkenyl and C 2-4 Alkynyl; C optionally substituted by 1, 2, 3 or more F, Cl or Br 1-4 alkyl; and wherein R 11 and R 12 -P(O)R are each independently methyl, ethyl, propyl or isopropyl 11 R 12 ; Preferably, wherein R 13 is selected from the group consisting of: F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, and CF3; and wherein R 11 and R 12 -P(O)R, each independently methyl 11 R 12 . The use, compound, or method of claim 23, wherein R 1a Selected from: (include )、 The use, compound, or method of claim 23, wherein R 1b Selected from: H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-7 Cycloalkyl, optionally substituted phenyl, -C 1-3 Alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 an alkylene group optionally substituted with a phenyl group, Preferably, wherein R 1b 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 use, compound, or method of claim 23, wherein R 13 Selected from halogen and C 1-4 alkyl, Preferably, wherein R 13 Selected from F, Cl, Br and methyl. The use, compound, or method of claim 23, wherein R 1b Selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, Phenyl, The use, compound, or method of claim 24, wherein R 13 Selected from halogen and -OR 11 , and where R 11 Selected from C 1-4 alkyl, Preferably, wherein R 13 Selected from F, Cl, Br and -OCH3. The use, compound, or method of claim 24, wherein R 2a and R 2b Each selected from phenyl, The use, compound, or method of claim 11, wherein: U is ethylene; R 1a Selected from: -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 Alkylene-(5-14 membered heteroaryl); R 1b Selected from: C 1-8 Alkyl; saturated C 3-10 Cycloalkyl; and -C 1-6 Alkylene-saturated C 3-10 Cycloalkyl; X 1 N; X 4 is C(=O); X 2 N; R 2a and R 2b All are phenyl; R 3 is -C(=O)OH; R 4 is H; h and k are each independently 1; and The above cycloalkyl, aryl and heteroaryl groups are each optionally substituted with one R 13 Substituted; said R 13 C 1-6 alkyl; Preferably, the C 6-10 Aryl is phenyl, the saturated C 3-10 The cycloalkyl group is a cyclopropyl group, and the 5-14 membered heteroaryl group is a thienyl group or a benzothienyl group. The use, compound, or method of claim 11, wherein the compound is selected from:

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