Angiotensin ii type 2 receptor antagonist and use thereof for preventing or treating acute pain

Abstract

The present invention relates to an angiotensin II receptor antagonist and use thereof for preventing or treating acute pain, such as mechanical traumatic pain, in particular acute post-operative pain. Specifically, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopic label, metabolite, or prodrug thereof, and use thereof for preventing or treating acute pain, such as mechanical traumatic pain, in particular acute post-operative pain, preferably post-operative surgical incision pain.

Description

Angiotensin II type 2 receptor antagonists and their use in the prevention or treatment of acute pain.

[0001] This application claims priority to Chinese Patent Application No. 202510179989.5, filed on February 18, 2025, and Chinese Patent Application No. 202511187639.X, filed on August 22, 2025, which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to angiotensin II type 2 (AT2) receptor antagonists and their use in the prevention or treatment of acute pain, including, but not limited to, acute traumatic pain, mechanical traumatic pain, and especially postoperative pain. Background Technology

[0003] The renin-angiotensin system (RAS) plays a crucial role in neuroprotection and nerve regeneration, regulating arterial blood pressure and electrolyte homeostasis. Angiotensin II (AngII) has two major receptors: AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R). Both AT1R and AT2R are seven-transmembrane receptors with similar affinity to AngII. In the rat brain, AngII receptors are predominantly AT2R. AT2R-specific antagonists are valuable in the treatment of various cerebrovascular, cognitive, and central nervous system (CNS) diseases. Furthermore, AT2R is found in neuronal tumor cells and transformed human nerve cells. AT2R is also involved in the differentiation and regeneration of neuronal tissue and bone maintenance. AT2R expression is present in damaged nerves and invasive immune cells and is associated with pain.

[0004] Pain is an unpleasant sensory and emotional experience caused by tissue damage or potential tissue damage, or a distressing experience with sensory, emotional, cognitive, and social dimensions. Based on the healing time of the damaged tissue and the duration of the pain, pain can be classified as acute pain or chronic pain.

[0005] Acute pain is defined as pain lasting less than 3 months and with a clear history of injury or illness. According to the ICD-11 classification, acute pain includes acute traumatic pain, acute postoperative pain, etc.

[0006] Acute traumatic pain is an acute pain response caused by trauma, such as tissue damage from injury or surgery. This pain typically lasts from several hours to several days, depending on the time of the trauma. The pathophysiological mechanism of acute traumatic pain involves a series of complex neurophysiological responses caused by tissue damage, including tissue injury and inflammatory response, increased excitability of sensory nerve endings and decreased pain threshold, as well as psychological and emotional factors influencing pain perception.

[0007] Mechanical traumatic pain is acute, nociceptive pain that occurs immediately after a mechanical injury, including somatic and visceral pain. Following a mechanical injury, damaged tissue releases inflammatory substances and pain-inducing factors, such as bradykinin and prostaglandins. These substances stimulate pain receptors, thus causing pain. Local inflammation after trauma exacerbates the pain. Inflammation leads to local edema and congestion, and releases inflammatory mediators that further stimulate pain receptors, resulting in increased pain.

[0008] Acute postoperative pain (APSP), also known as postoperative pain, is an acute, nociceptive pain that occurs immediately after surgery. It includes somatic and visceral pain and typically lasts no more than 3-7 days. For highly invasive surgeries or joint replacement surgeries requiring prolonged rehabilitation, pain management may be necessary for several weeks. Surgical trauma leading to tissue damage, the release of inflammatory mediators stimulating damaged or undamaged nerves, and intraoperative ischemia-reperfusion injury are all major causes of postoperative pain.

[0009] Postoperative pain is a response of the body to surgical stimulation (tissue damage), encompassing a series of physiological, psychological, and behavioral reactions. Effective postoperative pain management not only alleviates patient suffering but also promotes disease recovery, yielding significant social and economic benefits. Statistics show that approximately 300 million surgeries are performed globally each year, with at least 50% of patients experiencing moderate to severe postoperative pain. A multicenter study of 26,193 surgical patients from 122 hospitals in China between 2019 and 2021, focusing on the epidemiology and management characteristics of acute postoperative pain, revealed that the incidence of moderate to severe pain on postoperative day 1 reached 48.7%, and pain severity was correlated with poor recovery and patient satisfaction.

[0010] Short-term adverse effects of inadequate postoperative pain management include increased oxygen consumption and significant adverse effects on cardiovascular, respiratory, gastrointestinal, urinary system, skeletal, muscular, and peripheral vascular function, as well as neuroendocrine and immune systems. Long-term effects of inadequate postoperative pain management include potential risk factors for developing chronic pain and potential psychological and mental changes. Studies have reported varying therapeutic effects of different postoperative analgesia principles and methods, including non-pharmacological therapies such as physical therapy, music therapy, and distraction. However, medication remains the primary treatment for acute postoperative pain, with the goal of achieving good pain relief with minimal side effects and high patient satisfaction. It is noteworthy that many patients can tolerate mild to moderate pain but find it difficult to tolerate moderate to severe nausea, vomiting, dizziness, and other side effects that may be related to analgesics.

[0011] Non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the production of all prostaglandins in the body. While inhibiting inflammatory prostaglandins to exert antipyretic, analgesic, and anti-inflammatory effects, they also inhibit prostaglandins that play an important protective role in physiological functions. This can lead to blood (platelet), gastrointestinal, renal, and cardiovascular side effects. Other side effects include allergic reactions and liver damage. Selective COX-2 inhibitors reduce these adverse reactions to varying degrees, but may still worsen myocardial ischemia. They should be considered relative or absolute contraindications for patients undergoing cardiac surgery and those at risk of stroke.

[0012] Therefore, there is still a need in the art for more effective drugs with fewer side effects for the prevention or treatment of acute pain, and the present invention largely addresses this need. Summary of the Invention

[0013] This invention provides the use of AT2R antagonists (or "AT2R antagonist compounds") in the prevention or treatment of acute pain.

[0014] In some implementations, the acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain.

[0015] Therefore, in one particular aspect, the present invention provides the use of AT2R antagonists in the prevention or treatment of acute traumatic pain. In a more particular aspect, the present invention provides the use of AT2R antagonists in the prevention or treatment of mechanical traumatic pain. In an even more particular aspect, the present invention provides the use of AT2R antagonists in the prevention or treatment of acute postoperative pain.

[0016] In one particular aspect, the present invention provides the use of AT2R antagonists in postoperative analgesia.

[0017] Without being limited by any theoretical framework, the mechanism of action of AT2R antagonists in this invention for the prevention or treatment of acute pain (preferably acute traumatic pain, more preferably mechanical traumatic pain, especially acute postoperative pain) or for postoperative analgesia may be as follows: the renin-angiotensin system is involved in the regulation of immune responses and T cells and macrophages, and Ang II is a pro-inflammatory factor in macrophage responses. Postoperative tissue damage leads to enhanced inflammatory responses. Ang II significantly promotes macrophage infiltration at the site of injury by activating AT2R and stimulates macrophages to produce oxidative stress products such as reactive oxygen species (ROS). These oxidative stress products not only amplify the inflammatory response but also activate neuronal ion channels (such as TRPA1 and TRPV1) at the site of injury, leading to hyperalgesia and peripheral sensitization. Furthermore, the activation of ion channels is also closely related to the occurrence of postoperative pain. AT2R antagonists can reduce macrophage recruitment at the site of pain, inhibit the high expression of AT2R within macrophages, thereby inhibiting the production of ROS and / or RNS by inhibiting AT2R, reducing inflammatory factors and hyperalgesia, and inhibiting neuronal excitability, thus inhibiting pain signal transduction. In this invention, the AT2R antagonist exerts its analgesic effect from the immune cells of the peripheral nervous system, rather than through the central nervous system, thus avoiding central side effects.

[0018] The inventors discovered that AT2R antagonists reduce the increase in ROS in mouse macrophages induced by AngII by inhibiting AT2R, and significantly reduce the calcium ion concentration in AngII-treated DRG neurons co-cultured with RAW264.7 macrophages in vitro. Furthermore, in vivo pharmacodynamic studies showed that AT2R antagonists produced good analgesic effects using the above mechanism. For example, in a mouse model of sciatic nerve branch injury, AT2R antagonists reduced AT2R expression in macrophages of the injured sciatic nerve on the side of the injury and the transient receptor site ion channel subunit (TRPA1) in the dorsal root ganglion, demonstrating significant analgesic effects; and in rat models of plantar incision pain and Bama pig models of back incision pain, they showed significant analgesic effects for acute postoperative pain.

[0019] In a preferred embodiment, the present invention provides the use of AT2R antagonistic compounds in the prevention or treatment of acute pain associated with peripheral macrophage function. The acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain. In some preferred embodiments, the acute pain is acute traumatic pain. In some more preferred embodiments, the acute pain is mechanical traumatic pain. In some more preferred embodiments, the acute pain is acute postoperative pain.

[0020] As used in this article, the term "mechanical trauma" refers to damage to the structural integrity or function of human tissues caused by mechanical factors (such as blunt instruments, sharp instruments, surgical instruments, firearms, etc.). Mechanical trauma includes closed trauma and open trauma. Based on the injuring agent, mechanical injuries can be classified as blunt force trauma, sharp force trauma, firearm trauma, and mixed injuries.

[0021] As used in this article, the term "blunt force injury" refers to an open or closed injury caused by a blunt object (such as a hammer, club, hemostat, etc.). Blunt force injuries are characterized, for example (in the case of open wounds), by irregular wound edges and may be accompanied by subcutaneous bleeding, contusions, fractures, etc.

[0022] As used in this article, the term "sharp injury" refers to an open wound caused by an object with a sharp edge or point (such as a knife, scissors, scalpel, or shard of glass), such as a cut. Sharp injuries are generally characterized by clean, sharp edges.

[0023] As used herein, the term "wound" refers to bodily injury that disrupts the integrity of normal tissue structure, including but not limited to contusions, cuts, lacerations, open wounds, non-penetrating wounds, penetrating wounds, puncture wounds, etc. In some embodiments, the term "wound" includes "surgical site." The term "surgical site" refers to a site created by any opening made within the skin or an internal organ for a specific medical purpose. A surgical site can be "open," where medical personnel have direct access to an area of ​​conventional surgical concern ("open surgery"). Alternatively, a surgical site can be "closed," where medical personnel perform the procedure using telemedicine devices (e.g., but not limited to catheters and endoscopes) ("closed surgery"). Surgical sites can include, but are not limited to, organs, muscles, tendons, ligaments, connective tissue, etc.

[0024] In some embodiments, the mechanical trauma includes open blunt force trauma. In some embodiments, the mechanical trauma includes sharp force trauma. In some embodiments, the mechanical trauma may be a mixed injury including sharp force trauma and open blunt force trauma, a mixed injury including sharp force trauma and closed blunt force trauma, or a mixed injury including sharp force trauma, open blunt force trauma, and closed blunt force trauma.

[0025] In some embodiments, the mechanical traumatic pain may be wound pain, and the wound may be a fracture site, preferably a soft tissue injury site, including but not limited to injuries to the skin, subcutaneous tissue, muscles, tendons, ligaments and / or fascia.

[0026] In some embodiments, mechanical trauma can be surgical trauma. Therefore, in some embodiments, the mechanical traumatic pain includes acute postoperative pain.

[0027] Examples of acute postoperative pain include, but are not limited to:

[0028] Postoperative abdominal pain refers to pain caused by abdominal surgery (such as laparoscopic surgery, intestinal anastomosis, etc.).

[0029] Postoperative pain after general surgery: for example, abdominal pain after appendectomy or cholecystectomy;

[0030] Postoperative pain after orthopedic surgery: For example, significant pain caused by trauma to the muscles, bones, and other tissues at the surgical site after hip replacement surgery, hallux valgus correction surgery, or lumbar discectomy; and

[0031] Postoperative pain after gynecological and obstetric surgery: For example, after a cesarean section or myomectomy, surgical trauma to the lower abdomen can cause pain.

[0032] In some embodiments, the acute postoperative pain includes surgical site pain after closed surgery, and preferably surgical site pain after open surgery. In some embodiments, the surgical site may be a fracture site, preferably a soft tissue injury site and / or incision, including but not limited to injuries and / or incisions to the skin, subcutaneous tissue, muscles, tendons, ligaments and / or fascia.

[0033] In this document, "peripheral" and "external" are used interchangeably, referring to tissues and organs outside the brain and spinal cord, including but not limited to the peripheral nervous system, skin, bones, heart, lungs, peritoneum, and abdominal cavity. 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 nerve).

[0034] As used in this article, “peripheral macrophages” and “external macrophages” are used interchangeably, referring to macrophages in tissues and organs outside the brain and spinal cord.

[0035] As used herein, “macrophage function” refers to one or more of the following: macrophage recruitment / aggregation (e.g., at peripheral nerves), expression of AT2R in macrophages (e.g., high expression), and macrophage production of inflammatory factors such as ROS and / or RNS (e.g., elevated levels of ROS and / or RNS).

[0036] Therefore, in some specific embodiments, the present invention provides the use of AT2R antagonistic compounds in the prevention or treatment of acute pain associated with one or more of the following: macrophage recruitment / aggregation, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages. The acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain. In some preferred embodiments, the acute pain is acute traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is mechanical traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is acute postoperative pain, for example, as defined above.

[0037] In a preferred embodiment, the acute postoperative pain is postoperative surgical incision pain.

[0038] Therefore, in some embodiments, the present invention provides the use of AT2R antagonistic compounds in the prevention or treatment of postoperative surgical incision pain.

[0039] In some embodiments, the present invention provides the use of AT2R antagonistic compounds in the prevention or treatment of postoperative surgical incision pain associated with peripheral macrophage function.

[0040] In particular, the present invention provides the use of AT2R antagonistic compounds in the prevention or treatment of postoperative surgical incision pain associated with one or more of the following: macrophage recruitment / aggregation, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0041] In another aspect, the present invention provides AT2R antagonistic compounds for the prevention or treatment of acute pain.

[0042] In some implementations, the acute pain is acute pain related to the function of peripheral macrophages.

[0043] In some embodiments, the acute pain is acute pain associated with one or more of the following: macrophage recruitment / aggregation, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0044] The acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain. In some preferred embodiments, the acute pain is acute traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is mechanical traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is acute postoperative pain, for example, as defined above.

[0045] In some embodiments, the mechanical trauma is selected from: open blunt force trauma, sharp force trauma, mixed injuries including sharp force trauma and open blunt force trauma, mixed injuries including sharp force trauma and closed blunt force trauma, and mixed injuries including sharp force trauma, open blunt force trauma, and closed blunt force trauma. In some embodiments, the mechanical traumatic pain may be wound pain, and the wound may be a fracture site, preferably a soft tissue injury site, including but not limited to injuries to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia.

[0046] In some preferred embodiments, the mechanical traumatic pain is acute postoperative pain. In some embodiments, the acute postoperative pain includes surgical site pain after closed surgery, and preferably surgical site pain after open surgery. In some embodiments, the surgical site may be a fracture site, preferably a soft tissue injury site and / or incision, including but not limited to injuries and / or incisions to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia. In some more preferred embodiments, the acute postoperative pain is postoperative surgical incision pain.

[0047] In another aspect, the present invention provides a method for preventing or treating acute pain, comprising administering to an individual in need a preventive or therapeutically effective amount of an AT2R antagonist compound.

[0048] In some implementations, the acute pain is acute pain related to the function of peripheral macrophages.

[0049] In some embodiments, the acute pain is acute pain associated with one or more of the following: macrophage recruitment / aggregation, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0050] The acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain. In some preferred embodiments, the acute pain is acute traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is mechanical traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is acute postoperative pain, for example, as defined above.

[0051] In some embodiments, the mechanical trauma is selected from: open blunt force trauma, sharp force trauma, mixed injuries including sharp force trauma and open blunt force trauma, mixed injuries including sharp force trauma and closed blunt force trauma, and mixed injuries including sharp force trauma, open blunt force trauma, and closed blunt force trauma. In some embodiments, the mechanical traumatic pain may be wound pain, and the wound may be a fracture site, preferably a soft tissue injury site, including but not limited to injuries to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia.

[0052] In some preferred embodiments, the mechanical traumatic pain is acute postoperative pain. In some embodiments, the acute postoperative pain includes surgical site pain after closed surgery, and preferably surgical site pain after open surgery. In some embodiments, the surgical site may be a fracture site, preferably a soft tissue injury site and / or incision, including but not limited to injuries and / or incisions to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia. In some more preferred embodiments, the acute postoperative pain is postoperative surgical incision pain.

[0053] In another aspect, the present invention provides the use of AT2R antagonistic compounds in the preparation of pharmaceutical compositions for the prevention or treatment of acute pain.

[0054] In some implementations, the acute pain is acute pain related to the function of peripheral macrophages.

[0055] In some embodiments, the acute pain is acute pain associated with one or more of the following: macrophage recruitment / aggregation, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

[0056] The acute pain includes, but is not limited to, acute traumatic pain, mechanical traumatic pain, and acute postoperative pain. In some preferred embodiments, the acute pain is acute traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is mechanical traumatic pain, for example, as defined above. In some more preferred embodiments, the acute pain is acute postoperative pain, for example, as defined above.

[0057] In some embodiments, the mechanical trauma is selected from: open blunt force trauma, sharp force trauma, mixed injuries including sharp force trauma and open blunt force trauma, mixed injuries including sharp force trauma and closed blunt force trauma, and mixed injuries including sharp force trauma, open blunt force trauma, and closed blunt force trauma. In some embodiments, the mechanical traumatic pain may be wound pain, and the wound may be a fracture site, preferably a soft tissue injury site, including but not limited to injuries to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia.

[0058] In some preferred embodiments, the mechanical traumatic pain is acute postoperative pain. In some embodiments, the acute postoperative pain includes surgical site pain after closed surgery, and preferably surgical site pain after open surgery. In some embodiments, the surgical site may be a fracture site, preferably a soft tissue injury site and / or incision, including but not limited to injuries and / or incisions to the skin, subcutaneous tissue, muscles, tendons, ligaments, and / or fascia. In some more preferred embodiments, the acute postoperative pain is postoperative surgical incision pain.

[0059] As used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms thereof to which such term is applied, or to prevent such disease or condition or one or more symptoms thereof.

[0060] As used herein, the term "individual" includes humans or non-human mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Preferably, the individual is a human.

[0061] In any aspect described herein and in embodiments thereof, the AT2R antagonist compound is a compound having the structure of formula (IV) as described in the “AT2R Antagonist Compounds” section below, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof.

[0062] AT2R antagonist compounds

[0063] This application provides embodiments of the following AT2R antagonist compounds:

[0064] 1. A compound or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein said compound has the structure of formula (IV):

[0065] in:

[0066] U is C 1-3 Alkylene;

[0067] R 1a Selected from: C 2-8 alkenyl and C 2-8 alkynyl group, wherein the C 2-8 alkenyl and C 2-8 Each of the alkynyl groups is separated by one carbon. 6-10 Aryl or 5-14 heteroaryl substitutions; C6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group; -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);

[0068] R 1b It does not exist, or is selected from: H; optionally by 1, 2, 3 or more R. 13 Replacement C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups; and -C 1-6 Alkylene-C 6-10 Aryl;

[0069] X 1 Does not exist or is CR 10 Or N;

[0070] X 4 Selected from: C (=O); and -OC (=O)- and -SC (=O)-, where O and S are related to X. 1 connect;

[0071] R 2a C 6-10 Aryl;

[0072] R 2b C 6-10 Aryl;

[0073] X 2 For CR 10 Or N;

[0074] R 3 -C(=O)OR 11 ;

[0075] R 4 For H;

[0076] R 10 Selected from H or -OR each time it appears 11 -SR 11 and C 1-6 alkyl;

[0077] R 11 and R 12 Each occurrence is independently either H or C.1-6 alkyl;

[0078] h and k are each 1 independently;

[0079] The aforementioned alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by 1, 2, 3, or more R groups each time they appear. 13 replace;

[0080] The R 13 Each time it appears, it is independently selected from: halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon group, C 6-10 Aryl, 5-14 heteroaryl, -OR 11 -SR 11 -P(O)R 11 R 12 and -NR 11 R 12 And regarding the substituent R 13 The alkyl, alkylene, aryl, and heteroaryl groups are optionally further selected by one, two, three, or more independently from halogens and C. 1-6 Alkyl substituents.

[0081] 2. The compound of implementation scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0082] R 13 Each time it appears, it is independently selected from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-7 Cyclic hydrocarbon group, C 6-10 Aryl, 5-14 heteroaryl, -OR 11 -SR 11 and -NR 11 R 12 And regarding the substituent R 13 The alkyl, aryl, and heteroaryl groups are optionally further selected by one, two, three, or more independently from halogens and C. 1-6 Alkyl substituents.

[0083] 3. The compound of implementation scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, wherein U is methylene or ethylene.

[0084] 4. The compound of implementation scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 3 It is -COOH.

[0085] 5. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 10 Each time it appears, it is independently: H, C 1-4 Alkyl, OH, or SH.

[0086] 6. The compound of Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 11 and R 12 Each time it appears, it is independently selected from H and C. 1-4 alkyl.

[0087] 7. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Each time it appears, it is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C is optionally substituted by 1, 2, 3 or more substituents independently selected from halogens. 1-4 Alkyl; C 5-7 Cyclic hydrocarbon groups; each optionally surrounded by 1, 2, 3 or more independently selected from halogen, OH, amino, cyano and C. 1-4 Alkyl substituents, substituted phenyl groups, 5-6-membered heteroaryl groups, and 9-10-membered heteroaryl groups; wherein R 11 C is optionally replaced by 1, 2, 3 or more halogens 1-6 Alkyl-OR 11 ;where R 11 C is optionally replaced by 1, 2, 3 or more halogens 1-6 Alkyl-SR 11 ; and R in it 11 and R 12 Each time it appears, it is independently C, which is optionally replaced by 1, 2, 3 or more halogens. 1-6 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 .

[0088] 8. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Each time it appears, it is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C optionally substituted with 1, 2, or 3 F or Cl groups. 1-4 Alkyl; wherein R 11 C that is optionally replaced by 1, 2, or 3 F or Cl atoms 1-3 Alkyl-OR 11 ;where R 11 C that is optionally replaced by 1, 2, or 3 F or Cl atoms 1-3 Alkyl-SR 11 ;where R 11 and R 12 It is C independently each time it appears. 1-3 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 ; each of which is optionally substituted with 1, 2, 3 or more independent substituents selected from F, Cl, Br, I and methyl, a phenyl, 5-6 membered heteroaryl or a 9-10 membered heteroaryl.

[0089] 9. The compound of embodiment 8 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the C 1-3 The alkyl group is methyl, ethyl, propyl or isopropyl.

[0090] 10. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0091] R 1a Selected from: C 2-6 alkenyl and C 2-6 alkynyl group, wherein the C 2-6 alkenyl and C 2-6 Each alkynyl group is replaced by one phenyl or 5-10 heteroaryl group; phenyl; -C 1-3 Alkylene-C 3-7 Cyclic hydrocarbon group; -C 1-3 Alkylene (5-7 membered monocyclic heterocyclic group); -C 1-3 alkylene-(8-10 benzofused heterocyclic group); -C 1-3 alkylene-phenyl; and -C 1-3 alkylene-(5-10-membered heteroaryl);

[0092] R1b Does not exist, or is selected from: H; C 1-6 Alkyl; C 3-7 Cyclic hydrocarbon group; phenyl; -C 1-3 Alkylene-C 3-7 Cyclic hydrocarbon groups; and -C 1-3 alkylene-phenyl; and

[0093] The aforementioned alkyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally represented by 1, 2, 3, or more R groups as defined in Embodiment 1, each when appearing in each instance. 13 replace.

[0094] 11. The compound of embodiment 10 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1a Selected from phenyl, -C 1-3 Alkylene-C 3-7 Cyclic hydrocarbon group, -C 1-3 alkylene-phenyl, -C 1-3 Alkylene-(5-7 membered monocyclic heterocyclic group), -C 1-3 alkylene-(9-10 benzofused heterocyclic group), -C 1-3 alkylene-(5-6-membered heteroaryl) and -C 1-3 Alkylene-(9-10-membered heteroaryl), each of which is optionally surrounded by 1, 2, 3 or more R 13 replace.

[0095] 12. The compound of embodiment 11 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from C 1-4 Alkyl-O-; halogen; and C- groups optionally substituted with one, two, or three independent substituents selected from halogens. 1-4 alkyl.

[0096] 13. The compound of embodiment 11 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein X 4 It is C (=O).

[0097] 14. The compound of embodiment 10 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0098] R 1a Selected from:

[0099] C2-6 alkenyl and C 2-6 alkynyl group, the C 2-6 alkenyl and C 2-6 Each alkynyl group is substituted by one phenyl, 5-6 heteroaryl, or 9-10 heteroaryl group, wherein each of the phenyl, 5-6 heteroaryl, and 9-10 heteroaryl groups is optionally replaced by one, two, or three independently selected from F, Cl, Br, I, and C. 1-4 Alkyl substituents;

[0100] The elements are selected independently from F, Cl, Br, I, and C, one, two, or three at a time. 1-4 Alkyl substituents of phenyl groups; and

[0101] -C 1-3 alkylene-phenyl, -C 1-3 alkylene-(5 to 6-membered heteroaryl) and -C 1-3 Alkylene (9 to 10-membered heteroaryl), wherein the alkylene is optionally preceded by a -NR each time it appears. 11 R 12 The phenyl group, the 5- to 6-membered heteroaryl group, and the 9- to 10-membered heteroaryl group are each optionally replaced by one, two, or three independently selected from F, Cl, Br, I, and C. 1-4 Alkyl substituents;

[0102] R 1b It does not exist;

[0103] X 1 It does not exist; and

[0104] X 4 It is C (=O) or -OC (=O)-.

[0105] 15. The compound of embodiment 10 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, or tert-butyl.

[0106] 16. The compound of embodiment 14 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the C 2-6 The alkenyl group is vinyl, 1-propenyl, or 2-propenyl.

[0107] 17. The compound of embodiment 14 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the C 2-6 The alkynyl group is vinyl, 1-propynyl, or 2-propynyl.

[0108] 18. The compound of embodiment 14 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 It is phenyl, pyridyl, indolyl, or furanyl, wherein the phenyl, pyridyl, indolyl, or furanyl is optionally substituted by one, two, or three independent substituents selected from F, Cl, Br, and methyl.

[0109] 19. The compound of embodiment 18 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1a Selected from:

[0110] 20. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0111] R 1a The radical is selected from the following groups: optionally substituted phenyl, -optionally substituted C 1-3 Alkylene-(optionally substituted C) 3-7 Cycloalkyl group), -optionally substituted C 1-3 Alkylene group - (optionally substituted 5-7 membered monocyclic heterocyclic group), -optionally substituted C 1-3 alkylene-(optionally substituted 8-10 benzofused heterocyclic group), -optionally substituted C 1-3 Alkylene-optionally substituted phenyl, and -optionally substituted C 1-3 Alkylene (optionally substituted 5-10-membered heteroaryl);

[0112] R 1b Selected from H, arbitrarily by 1, 2, 3 or more R 13 Replacement C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups; and -C 1-6 Alkylene-C 6-10 Aryl;

[0113] X 1 It is CR 10 Or N;

[0114] X 4 It is C (=O);

[0115] The term "optionally replaced" refers to being replaced by 1, 2, 3 or more Rs. 13 Replace; and

[0116] R 13 As defined in Implementation Scheme 1.

[0117] 21. The compound of embodiment 20 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1b The radical is selected from the following groups: H, optionally substituted C. 1-4 Alkyl, optionally substituted C 3-7 Cycloalkyl group, optionally substituted phenyl group, -optionally substituted C 1-3 Alkylene-(optionally substituted C) 3-7 (cyclic hydrocarbon group), and -optionally substituted C 1-3 Alkylene-optionally substituted phenyl;

[0118] The term "optionally replaced" refers to being replaced by 1, 2, 3 or more Rs. 13 replace.

[0119] 22. The compound of implementation scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0120] R 2a It is an optionally substituted phenyl; and / or

[0121] R 2b It is an optionally substituted phenyl group;

[0122] The term "optionally replaced" refers to being replaced by 1, 2, 3 or more Rs. 13 replace.

[0123] 23. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the compound has the structure of formula (II):

[0124] 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 Implementation Scheme 1.

[0125] 24. The compound of Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein... for:

[0126] 25. The compound of Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein... for:

[0127] 26. The compound of Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 10 It is H or methyl.

[0128] 27. The compound of embodiment 20 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1a Selected from arbitrarily substituted phenyl, -C 1-3 Alkylene-(optionally substituted C) 3-7 cyclic hydrocarbon group), -C 1-3 Alkylene (optionally substituted 5- to 7-membered monocyclic heterocyclic group), -C 1-3 alkylene-(optionally substituted 8- to 10-membered benzofused heterocyclic groups), -C 1-3 Alkylene-optionally substituted phenyl, and -C 1-3 Alkylene (optionally substituted 5 to 10 heteroaryl groups).

[0129] 28. The compound of embodiment 20 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1a It is selected from:

[0130] Optionally substituted phenyl groups;

[0131] -C 1-3 Alkylene-(optionally substituted C) 3-7 (cyclic hydrocarbon group), wherein the cyclic hydrocarbon group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0132] -C 1-3 alkylene-(optionally substituted 8-10-membered benzofused heterocyclic group), wherein the heterocyclic group is

[0133] -C 1-3 Alkylene (optionally substituted 5-10-membered heteroaryl), wherein the heteroaryl group is

[0134] 29. The compound according to embodiment 20, or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from: halogens; where R 11 C is a carbon that is optionally replaced by 1, 2, 3 or more halogens. 1-6 Alkyl-OR 11 ; cyano; C 3-7 Cyclic hydrocarbon group; C group optionally substituted with 1, 2, 3 or more halogens 1-4 Alkyl, C 2-4 alkenyl and C 2-4 alkynyl group; wherein R 11 and R 12 Each is independently selected from H and C. 1-4 Alkyl-NR 11 R 12 ; and R in it 11 and R 12 Each is independently a C that is optionally replaced by one, two, three or more halogens. 1-6 Alkyl-P(O)R 11 R 12 .

[0135] 30. The compound according to embodiment 20, or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from: halogens; where R 11 C is a carbon that can be substituted by 1, 2, or 3 F or Cl atoms. 1-3 Alkyl-OR 11 ; cyano; C 3-7 Cyclic hydrocarbon group; C14 groups optionally substituted with 1, 2, 3 or more halogens 1-4 Alkyl, C 2-4 alkenyl and C 2-4 alkynyl group; wherein R 11 and R 12 -NR, each independently selected from H and methyl groups 11 R 12 ; and R in it 11 and R 12 Each is independently a C that is optionally replaced by 1, 2, or 3 F or Cl atoms. 1-3 Alkyl-P(O)R 11 R12 .

[0136] 31. The compound according to embodiment 20, or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from: F, Cl, Br, OH, -OC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, cyano, C 3-7 Cyclic hydrocarbon group, C 2-4 alkenyl and C 2-4 Alkyne group; C group optionally substituted with 1, 2, 3 or more F, Cl or Br. 1-4 Alkyl; and wherein R 11 and R 12 Each of the -P(O)R groups is independently methyl, ethyl, propyl, or isopropyl. 11 R 12 .

[0137] 32. The compound according to embodiment 20, or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from: F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, and CF3; and R among them. 11 and R 12 Each is independently a methyl group -P(O)R 11 R 12 .

[0138] 33. The compound according to embodiment 20, or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1a Selected from:

[0139] (include

[0140] 34. The compound of embodiment 21 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1b Selected from: H, optional substituted C 1-4 Alkyl, optional substituted C 3-7 Cyclic hydrocarbon group, optionally substituted phenyl group, -C 1-3Alkylene-(optionally substituted C) 3-7 -cyclic hydrocarbon group) and -C 1-3 The alkylene oxide may optionally substitute for the phenyl group.

[0141] 35. The compound of embodiment 21 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1b Selected from:

[0142] H, phenyl;

[0143] Optional substitution of C 1-4 Alkyl group, wherein the alkyl group is methyl, ethyl or isopropyl;

[0144] Optional substitution of C 3-7 Cyclic hydrocarbon groups and -C 1-3 Alkylene-(C 3-7 (cyclic hydrocarbon group), wherein the cyclic hydrocarbon group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and

[0145] -C 1-3 Alkylene-phenyl.

[0146] 36. The compound of embodiment 21 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from halogens and C 1-4 alkyl.

[0147] 37. The compound of embodiment 21 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from F, Cl, Br and methyl.

[0148] 38. The compound of embodiment 21 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 1b Selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, Phenyl,

[0149] 39. The compound of embodiment 22 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from halogens and -OR 11 And R 11 Selected from C 1-4 alkyl.

[0150] 40. The compound of embodiment 22 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein R 13 Selected from F, Cl, Br and -OCH3.

[0151] 41. The compound of embodiment 22 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, wherein R 2a and R 2b Each is selected from phenyl,

[0152] 42. The compound of Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein:

[0153] U represents ethylene;

[0154] R 1a Selected from: -C 1-6 Alkylene-C 6-10 Aryl; and -C 1-6 alkylene-(5-14-membered heteroaryl);

[0155] R 1b Selected from: C 1-8 Alkyl; saturated C 3-10 Cyclic hydrocarbon groups; and -C 1-6 alkylene-saturated C 3-10 Cyclic hydrocarbon group;

[0156] X 1 For N; X 4 For C (=O); X 2 For N; R 2a and R 2b All are phenyl;

[0157] R 3 It is -C(=O)OH;

[0158] R 4 For H;

[0159] h and k are each independently 1; and

[0160] Each of the aforementioned cyclic hydrocarbon group, aryl group, and heteroaryl group is optionally prefixed with one R each time it appears. 13 Replace; the R 13 C 1-6 alkyl;

[0161] Preferably, the C 6-10The aryl group is phenyl, and the saturated C 3-10 The cyclic hydrocarbon group is cyclopropyl, and the 5-14 heteroaryl group is thienyl or benzothienyl.

[0162] 43. The compound of embodiment 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, wherein the compound is selected from the compounds listed in Table A below, preferably compounds A1 to A9:

[0163] The compounds A1 to A9 listed above correspond to the compounds in the examples listed in Table A below as follows: A1 = C112, A2 = C246, A3 = C202, A4 = C196, A5 = C154, A6 = C155, A7 = C184, A8 = C207, A9 = C159.

[0164] definition

[0165] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0166] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0167] As used herein, the term "alkylene" means 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.

[0168] 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 groups, for example, 1 to 6 carbon atoms ("C") 1-6 Alkyl group), 1 to 4 carbon atoms ("C") 1-4 Alkyl groups, more particularly having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. For example, as used herein, the term "C" refers to an alkyl group. 1-8"Alkyl" refers to a linear or branched group with 1 to 8 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.), optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "halogenated alkyl") (e.g., 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 with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0169] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing a double bond and having 2–8 carbon atoms ("C"). 2-8 "Alkenyl", for example "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 alkenyl group, the compounds may exist in pure E (iso-alkenyl), pure Z (iso-alkenyl), or any mixture thereof.

[0170] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group 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.

[0171] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “cycloalkyl ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6, such as 5 to 6 or 5 to 7) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0172] As used herein, the terms “heterocyclic group,” “sub-heterocyclic group,” and “heterocycle” refer to a monocyclic or bicyclic group having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6; or, suitably 8 to 10, more preferably 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 saturated (i.e., heterocyclic alkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or bicyclic group. For example, “3-10 membered (sub)heterocyclic group” is a saturated or partially unsaturated monocyclic or bicyclic (sub)heterocyclic group having 2 to 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 heterocyclic groups and heterocyclic groups include, but are not limited to: (ethylene oxide), (aziridinyl), (azetidinyl), (oxetanyl), (tetrahydrofuranyl), (dioxolinyl), (pyrrolylyl), (pyrrolidone), (imidazoalkyl), (pyrazolylyl), (pyrrololinyl), (pyrrololinyl), (tetrahydropyranyl), (piperidinyl), (morpholinyl), (dithianyl), (thiomorpholinyl), (piperazinyl), or (trithianyl). Other examples of monocyclic heterocyclic groups include, but are not limited to: tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl (e.g., pyrrolidine-1-yl), oxazolyl, thiazoyl, imidazoyl, 1,3-dioxazinyl, 1,3-oxazinyl, piperidinyl, piperazinyl, morpholinyl (e.g., morpholino), thiomorpholinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiaranyl, 1,3-oxazinyl, 1,3-thiazinyl The bicyclic group (ane), hexahydropyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepane, 1,4-diazepane, 1,3-oxazepane, and 1,3-thiazepane are all bicyclic groups. The sub-heterocyclic and heterocyclic groups include spirocyclic systems, fused (e.g., benzo-fused) systems, or bridged systems.Benzofused heterocyclic sub-heterocyclic groups and heterocyclic groups refer to the monocyclic heterocyclic sub-heterocyclic groups and heterocyclic groups described above fused with benzene, such as benzo derivatives having 3-6 (suitably 4-6, more preferably 5-6) ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms selected from N, O and S and the remaining ring atoms are C, and are saturated or partially unsaturated monocyclic groups (i.e., "7-10 quinone benzofused (heterocyclic) groups"), including, for example, (heterocyclic) 2,3-dihydrobenzofuranyl. (sub)1,3-dihydroisobenzofuranyl (sub)2,3-dihydrobenzo[c]thiophene (sub)1,3-dihydrobenzo[c]thiophene (sub)dihydroindolyl (a)dihydroisoindolyl (benzyl)benzo[d][1,3]dioxacyclopentenyl (benzyl)benzo[d][1,3]dithionyl ... (benzyl)benzo[d][1,3]oxothionyl ... (sub)3H-benzo[c][1,2]oxothionyl ... (sub)3H-benzo[d][1,2]oxothionyl ... (sub)2,3-dihydrobenzo[d]oxazolyl (sub)2,3-dihydrobenzo[d]thiazolyl (sub)2,3-dihydro-1H-benzo[d]imidazolyl (sub)2,3-dihydrobenzo[d]isoxazolyl (sub)2,3-dihydrobenzo[d]isothiazolyl (sub)1,3-dihydrobenzo[c]isoxazolyl (sub)1,3-dihydrobenzo[c]isothiazolyl (sub)2,3-dihydro-1H-indazole (Asian) Color Full Base (sub)2H-chromenyl (sub)4H-chromenyl (-)dihydrobenzothiamyl (sub)2H-thiochromene (sub)4H-benzothiochromene (4H-thiochromene) (sub)1,2,3,4,4a,8a-hexahydroquinolinyl (sub)1,2,4a,8a-tetrahydroquinolinyl (sub)1,4,4a,8a-tetrahydroquinolinyl (sub)1,2,3,4,4a,8a-hexahydroisoquinolinyl (sub)1,2,3,4,4a,8a-hexahydroquinoxalinyl (sub)1,4,4a,8a-tetrahydroquinoxalinyl (sub)1,2,3,4,4a,8a-hexahydroquinazolinyl (sub)2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]oxazinyl (sub)3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]oxazinyl (sub)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]oxazinyl (sub)2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]thiazinyl (sub)3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]thiazinyl (sub)3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]thiazinyl and 2,3-dihydrobenzo[b][1,4]dioxinyl The bridging system includes, for example, 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc. The heterocyclic group and heterocyclic group may optionally be substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0173] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0174] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (hybrid)thienyl, (hybrid)furanyl, (hybrid)pyrroleyl, (hybrid)oxazolyl, (hybrid)thiazolyl, (hybrid)imidazolyl, (hybrid)pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), (hybrid)isoxazolyl, (hybrid)isothiazolyl, (hybrid)oxadiazolyl, (hybrid)triazolyl, (hybrid)tetrazoleyl (e.g., 1-tetrazoleyl or 5-tetrazoleyl), (hybrid)thiadiazolyl, etc., and their benzo[derivatives]; or (hybrid)pyridinyl, (hybrid)pyridinyl, (hybrid)pyrazinyl, (hybrid)triazinyl, etc., and their benzo[derivatives]. Other examples of “(sub)heteroaryl” or “heteroary ring” include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, and purinel.

[0175] As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl-substituted alkyl 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.

[0176] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0177] 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 a ring, and optionally also comprising 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 are connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the remaining ring atoms, wherein the nitrogen-containing heterocycle is optionally benzofused, and preferably connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the carbon atoms in the fused benzene ring.

[0178] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0179] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0180] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0181] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0182] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0183] When the bond of a substituent is a bond that passes through the ring and connects two atoms, such a substituent can be bonded to any cyclic atom in the substituted ring, including atoms available on the bridge if the substituted ring is a bridged ring.

[0184] This application also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds described above, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable 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., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.)13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by replacing the previously used unlabeled reagent with a suitable isotopically labeled reagent. Pharmaceutically acceptable solvates include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0185] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may 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-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0186] Solid lines may be used in this article. solid wedge Or virtual wedge Depict the carbon-carbon bonds of the compounds described herein. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, 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, trans-blocking isomers, 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 diastereomer pairs).

[0187] This application covers all possible crystalline forms or polymorphs of the compound, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0188] It should also be understood that some of the compounds described herein may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds described herein or their metabolites or residues. Therefore, when referring to "compounds described herein," it is also intended to encompass the various derivative forms of the compounds described above.

[0189] Pharmaceutically acceptable salts of the compounds described herein include their acid addition salts and base addition salts.

[0190] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, hexafluorophosphates, hymenates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, and xinofoate.

[0191] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0192] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0193] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (compounds described herein that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds described herein may themselves be esters.

[0194] The compounds described herein may exist as solvates (preferably hydrates), wherein the compounds contain a polar solvent, particularly water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0195] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0196] This application also includes metabolites of the compounds described herein, i.e., substances formed in the body upon administration of the compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds. Therefore, this application includes metabolites of the compounds, including compounds prepared by methods that expose the compounds to mammals for a time sufficient to produce their metabolites.

[0197] This application further includes prodrugs of the compounds, which are certain derivatives of the compounds that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 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 portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0198] This application also covers compounds containing protecting groups. In any process of preparing the compounds described herein, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compound. This can be achieved with conventional protecting groups, such as those described in T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0199] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0200] As used herein, the numerical value “a±b” or “a(±b)” represents a range defined by the indicated numerical values ​​a and b, with a lower limit of ab and an upper limit of a+b, including the upper and lower limits and any value in between (including the indicated numerical value a). Further, the range includes a subrange with a lower limit of ac and an upper limit of a+c, including the upper and lower limits and any value in between (including the indicated numerical value a), where the numerical value c is greater than or equal to 0 and less than the numerical value b. In other words, the term “±b” includes “±c”. For example, “±4h” includes “±3.5h”, “±3h”, “±2.5h”, “±2h”, “±1.5h”, “±1h”, “±0.5h”, and “±0h”. Or, the term “±30min” includes “±25min”, “±20min”, “±15min”, “±10min”, “±5min”, and “±0min”.

[0201] Pharmaceutical Composition

[0202] The AT2R antagonist compounds described herein can be administered in the form of pharmaceutical compositions comprising the AT2R antagonist compound and one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can be solid, semi-solid, liquid, or gaseous formulations. In some embodiments, the pharmaceutical compositions may also contain one or more other therapeutic or prophylactic agents.

[0203] The term "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0204] Pharmaceutically acceptable carriers include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0205] The pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0206] For these routes of administration, the pharmaceutical composition can be administered in a suitable dosage form.

[0207] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0208] As used herein, the term "effective amount" refers to an amount of the AT2R antagonist compound that, when administered, prevents or delays the onset of cancer pain, preferably bone cancer pain, shortens its duration, reduces or eliminates the pain, and / or slows its progression.

[0209] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0210] The amount of AT2R antagonist compound administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. Generally, the 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 total 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, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0211] In some embodiments, the AT2R antagonist compound is administered at a dose 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 daily, for example at doses 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, approximately 200 μg / kg, approximately 225 μg / kg, approximately 250 μg / kg, approximately 275 μg / kg, approximately 300 μg / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg g, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 1 Dosage at doses of 0 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, and approximately 200 mg / kg body weight.

[0212] In some implementations, the daily dose of the AT2R antagonist compound is administered once or in two, three, or four divided doses.

[0213] 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 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

[0214] 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) treatment cycles, wherein each treatment cycle lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the interval between each two treatment cycles is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.

[0215] The AT2R antagonist compound in the pharmaceutical composition may be present in amounts from 0.005 mg / day to about 5000 mg / day, suitably from 0.01 mg to about 2000 mg / day, preferably 1-1500 mg, or 200-1500 mg / day, preferably 1-1200 mg, or 200-1200 mg / day, preferably 1-1000 mg / day, 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 / day, for example, about 0.005, 0.05, 0.5, 5, 10, 2 Dosage: 0, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0216] The AT2R antagonist compound may be present in a dose or amount of 50 mg to 1000 mg per dose, preferably 100 mg to about 1000 mg per day, preferably 200-1000 mg, 200-800 mg, 200-600 mg, or 200-400 mg per day, for example, at doses of 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg per dose.

[0217] There are no particular limitations on the method of administration of the AT2R antagonist compound or the pharmaceutical composition.

[0218] In some embodiments, the AT2R antagonist compound or the pharmaceutical composition is administered to the individual in need prior to surgery. The preoperative administration may be performed 1-4 times (e.g., once, twice, three times, or four times), preferably once or twice. The preoperative administration may include administration of the AT2R antagonist compound or the pharmaceutical composition 0-12 hours (h) before surgery (e.g., 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, or 10h), preferably 1-10h, 1-8h, 1-6h, 1-4h, or 2-4h before surgery.

[0219] In some embodiments, the AT2R antagonist compound or the pharmaceutical composition is administered to the individual in need after surgery. The postoperative administration may be performed 1-10 times (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times), preferably 1-8 times, 1-6 times, 2-6 times, 1-4 times, 3-4 times, or 2-4 times. The postoperative administration may include: a first postoperative administration of the AT2R antagonist compound or the pharmaceutical composition at 0-12 hours after surgery (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after surgery), preferably at 1-10 hours, 1-8 hours, 1-6 hours, 1-4 hours, or 2-4 hours after surgery, followed by administration every 4-16 hours (e.g., 4-12 hours, 6-12 hours, 6-14 hours, 8-12 hours, or 10-12 hours), preferably every 10-12 hours.

[0220] In some embodiments, the AT2R antagonist compound or the pharmaceutical composition is administered to the individual in need prior to surgery, as described above; and

[0221] The AT2R antagonist compound or the pharmaceutical composition may be administered to individuals in need after surgery, as described above.

[0222] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition may include:

[0223] The first administration is given to the individual in need, and the time of the first administration is recorded as the timing start point (T0);

[0224] Then, three more applications were performed at 12h (±4h), 24h (±4h), and 36h (±4h) after the first application, respectively;

[0225] It was applied a total of 4 times.

[0226] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition may include:

[0227] Administer once to the desired individual approximately 1–2.5 hours (T0) prior to surgery, at a dose of 200 mg–1200 mg, preferably 400 mg–1200 mg, based on the AT2R antagonist compound; and

[0228] The first postoperative administration was performed 12 hours (±4 hours) after the T0 administration, followed by administration every 12 hours (±4 hours) for a total of 2-6 postoperative administrations, preferably 3-4. The dose of each postoperative administration was 200 mg-600 mg, based on the AT2R antagonist compound.

[0229] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition may include:

[0230] Administer a single dose of 400 mg, calculated as the AT2R antagonist compound, to eligible individuals 2 hours ± 30 minutes (T0) prior to surgery; and

[0231] The first postoperative administration was performed 12 hours (±4 hours) after the T0 administration, followed by administration every 12 hours (±4 hours) for a total of 3 postoperative administrations. The dose of each postoperative administration was 200 mg, calculated based on the AT2R antagonist compound.

[0232] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition may include:

[0233] Administer a single dose of 800 mg, calculated as the AT2R antagonist compound, to eligible individuals 2 hours ± 30 minutes prior to surgery (T0); and

[0234] The first postoperative administration was performed 12 hours (±4 hours) after the T0 administration, followed by administration every 12 hours (±4 hours) for a total of 3 postoperative administrations. The dose of each postoperative administration was 400 mg, calculated based on the AT2R antagonist compound.

[0235] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition may include:

[0236] Administer a single dose of 1200 mg, calculated as the AT2R antagonist compound, to eligible individuals 2 hours ± 30 minutes prior to surgery (T0); and

[0237] The first postoperative administration was performed 12 hours (±4 hours) after the T0 administration, followed by administration every 12 hours (±4 hours) for a total of 3 postoperative administrations. The dose of each postoperative administration was 600 mg, calculated based on the AT2R antagonist compound.

[0238] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition to an individual in need may include:

[0239] The first administration is given to the individual within 10 minutes (T0) after the individual’s baseline resting NRS score reaches 4 or higher, at a dose of 400 mg to 1200 mg, such as 1200 mg, 1000 mg, 800 mg, 600 mg or 400 mg, based on the AT2R antagonist compound.

[0240] The application is performed once 12 hours (±4 hours) after the T0 administration, and then once every 12 hours (±4 hours), wherein the administration after the T0 administration is performed a total of 2-6 times, preferably 3-4 times, and the dose of each application is 200mg-600mg, for example 600mg, 400mg or 200mg, based on the AT2R antagonist compound.

[0241] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition to an individual in need may include:

[0242] The first administration of the AT2R antagonist compound was given to the individual within 10 minutes (T0) after the individual’s baseline resting NRS score reached 4 or higher. The dose was 1200 mg.

[0243] The drug is administered once 12 hours (±4 hours) after T0 administration, and then once every 12 hours (±4 hours), for a total of 3 administrations after T0 administration, each administration being 600 mg based on the AT2R antagonist compound.

[0244] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition to an individual in need may include:

[0245] The first administration of the AT2R antagonist compound was given to the individual within 10 minutes (T0) after the individual’s baseline resting NRS score reached 4 or higher. The dose was 800 mg.

[0246] The drug is administered once 12 hours (±4 hours) after the T0 administration, and then once every 12 hours (±4 hours), for a total of 3 administrations after the T0 administration, each administration being 400 mg based on the AT2R antagonist compound.

[0247] In a particular embodiment, administration of the AT2R antagonist compound or the pharmaceutical composition to an individual in need may include:

[0248] The first administration of the AT2R antagonist compound was given to the individual within 10 minutes (T0) after the individual’s baseline resting NRS score reached 4 or higher. The dose was 400 mg.

[0249] The drug is administered once 12 hours (±4 hours) after T0 administration, and then once every 12 hours (±4 hours), for a total of 3 administrations after T0 administration, each administration being 200 mg based on the AT2R antagonist compound.

[0250] As used herein, the term "baseline resting NRS score" refers to an individual's numerical rating scale for pain at rest, reported at baseline (i.e., before receiving any analgesic intervention or treatment), where 0 represents "no pain" and 10 represents "the most intense pain imaginable." Individuals select a number from 0 to 10 to represent their pain intensity based on their subjective pain perception. This score serves as a baseline for assessing pre-treatment pain intensity and is used to determine the timing of initial administration and evaluate the effectiveness of subsequent analgesia. The term "resting state" refers to a state in which an individual is in a supine or seated position, without engaging in active activity or receiving external interventions that may stimulate pain.

[0251] Brief description of the attached figures

[0252] Figure 1 shows the ROS fluorescence intensity of different treatment groups, which demonstrates 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.

[0253] Figure 2 shows the relative fluorescence intensity of calcium ions in DRG neurons in different treatment groups when DRG neurons and Raw264.7 cells were co-cultured. ### p<0.001, compared with the solvent group (Control); ** p<0.01, *** p<0.001, compared with the AngII (200 nM) group.

[0254] Figure 3 shows the paw retraction threshold PWT (Mean±SD, ***p<0.001, compared with the vehicle group at the corresponding time point) in the pharmacodynamic test of AT2R antagonist on mouse sciatic nerve branch injury (SNI) model.

[0255] Figure 4 shows typical images of macrophages co-stained with AT2R (AKA:AGTR2) and F4 / 80 on the sciatic nerve injury side and the non-injury side of SNI mice (Bar = 20 μm).

[0256] Figure 5 shows the fluorescence intensity of AT2R and F4 / 80 macrophages co-stained on the side of sciatic nerve injury in SNI mice. Note: ***p<0.001, compared with the vehicle group.

[0257] Figure 6 shows the fluorescence intensity of AT2R and F4 / 80 co-stained macrophages on the non-injured side of the sciatic nerve in SNI model mice. Note: ***p<0.001, compared with the vehicle group.

[0258] Figure 7 shows a typical TRPA1 immunofluorescence staining pattern of the DRG on the injured side of SNI mice (Bar = 20 μm).

[0259] Figure 8 shows the mean TRPA1 fluorescence intensity of DRG neurons on the injured side in SNI mice (***p<0.001, compared with the vehicle group).

[0260] Figure 9 shows the changes in 50% PWT at different time points after administration of AT2R antagonists in different treatment groups of the SD rat plantar incision pain model.

[0261] Figure 10 shows the changes in mechanical pain threshold at different time points after administration of AT2R antagonists in different treatment groups of the Bama miniature pig back incision pain model.

[0262] Figure 11 shows the trial results of different doses of AT2R antagonists in human unilateral hip replacement surgery. Detailed Implementation

[0263] Compound Examples

[0264] This application provides the compounds listed in Table A below, the preparation and identification of which are disclosed in the Examples section of WO2019179515A1. The entire contents of the Examples section of WO2019179515A1 are incorporated herein by reference.

[0265] Table A

[0266] Biological Examples

[0267] In the following biological tests, compound A1 corresponds to compound C112 shown in Table A above. It should be noted that compound A1 is used as an exemplary compound in the following tests and does not imply that the invention is limited to compound A1.

[0268] Experimental Example 1: Effects of AT2R antagonists on AngII-induced reactive oxygen species (ROS) generation in mouse peritoneal macrophages

[0269] 1.1 Experimental Objective

[0270] Mouse peritoneal macrophages express AT2R, and AngII, as a ligand of AT2R, can induce an increase in ROS production in mouse peritoneal macrophages by binding to the AT2R receptor. This experiment evaluated how AT2R antagonists inhibit AngII-induced ROS production in mouse peritoneal macrophages by inhibiting the AT2R receptor.

[0271] 1.2 Instruments and Equipment

[0272] 1.3 Test Methods

[0273] Six-week-old male C57BL / 6 mice were euthanized, and primary peritoneal macrophages were obtained by intraperitoneal injection of phenol red-free medium. After centrifugation, the macrophages were resuspended in RPMI 1640 + 5% FBS (containing 50 ng / μl GM-CSF) medium and cultured at 37°C in a 5% CO2 incubator for 2 days. The macrophages were then seeded in 96-well plates. After 24 hours of adhesion, the macrophages were stained with the ROS indicator DCFH-DA and then treated as follows: 1) blank solvent group (Control); 2) AngII alone (0.2 μM) treatment group; 3) PD123319 combined with AngII group (PD (1 μM) + AngII (0.2 μM)): P D123319 was co-treated with AngII for 0.5 hours; 4) A1 combined with AngII group (A1(0.5μM) + AngII(0.2μM)): A1(0.5μM) was co-treated with AngII for 0.5 hours; 5) A1 combined with AngII group (A1(5μM) + AngII(0.2μM)): A1(5μM) was co-treated with AngII for 0.5 hours. The ROS production level of macrophages in each group was measured by real-time fluorescence scanning.

[0274] PD123319 di-trifluoroacetate (purchased from MCE, lot number: 14354)

[0275] 1.4 Data Statistics

[0276] Data were collected using Excel software. Prism 6.01 (Graph pad software, Inc.) software was used to analyze the data (one-way ANOVA). Statistical analysis was performed on the results of each group to compare whether there were statistically significant differences between groups; p < 0.05 was considered statistically significant.

[0277] 1.5 Experimental Results

[0278] Figure 1 shows the ROS fluorescence intensity of different treatment groups. ### p < 0.001 indicates a comparison with the blank solvent group. *** p<0.001 indicates a comparison with the AngII (0.2 μM) group. Compared with the blank solvent group, the level of reactive oxygen species (ROS) produced by macrophages was significantly increased after AngII treatment (p<0.05). Compared with the AngII treatment group, the A1 (0.5 μM) combined with AngII (0.2 μM) group and the A1 (5 μM) combined with AngII (0.2 μM) group significantly reduced the AngII-induced increase in ROS (p<0.05). Therefore, both 0.5 μM and 5 μM concentrations of A1 can inhibit the AngII-induced increase in ROS.

[0279] Experimental Example 2: Effects of AT2R antagonists on neuronal excitability after co-culture of DRG neurons and Raw264.7 cells

[0280] 2.1 Test Equipment

[0281] ELISA reader (Promega, Discover System 4.92.0

[0282] 2.2 Cell source and culture conditions

[0283] DRG neurons (Catalog No.: BNCC360471, Batch No.: 23072601) and RAW264.7 cells (Catalog No.: BNCC354753, Batch No.: 23072601) were purchased from Beina Biotechnology. The culture conditions were DMEM (high glucose medium) + 10% FBS + penicillin-streptomycin (S / P) double antibody. The DMEM high glucose medium was purchased from Kaiji Biotechnology (Batch No.: 20230629), the FBS was purchased from Eva Biomedical Technology Co., Ltd. (Batch No.: 22EG01105), the S / P double antibody was purchased from Nanjing Shenghang Biotechnology Co., Ltd. (Batch No.: BC20221202), and the trypsin was purchased from Suzhou Xinsaimei Biotechnology Co., Ltd. (Batch No.: 20230607).

[0284] 2.3 Experimental Procedure

[0285] (1) DRG neurons and Raw264.7 were cultured separately in separate cell culture flasks until they reached a certain density (>1×10⁻⁶). 6 After adjusting the cell density to 3×10⁹ / ml, the cell density was then further adjusted. 5 / ml (Raw 264.7) and 1×10 5 / ml (DRG neurons);

[0286] (2) DRG neurons were co-cultured with RAW264.7 (1×10⁻⁶) 4 3×10 4 ), DRG neurons (1×10) 4 R264.7 cells (3×10⁻⁶) were cultured alone. 4 Individual culture: Seed in 96-well plates (n=8 for each case), and culture overnight until cells adhere;

[0287] (3) After the cells adhered, the culture medium was discarded, and the 96-well plate was washed three times with 1×HHBS buffer (containing 20mM Hepes). 5μM Fluo-8 AM dye was added and the plate was incubated at 37℃ for 30min. The 96-well plate was then washed three times with 1×HHBS buffer (containing 20mM Hepes).

[0288] (4) Different cells were administered the drug according to the following groups: PBS blank control group (Control), Ang II (200 nM), Ang II (200 nM) + PD123319 (1 μM), Ang II (200 nM) + A1 (0.1 μM), Ang II (200 nM) + A1 (1 μM), Ang II (200 nM) + A1 (10 μM), n=8 in each group, and the treatment time was 30 minutes;

[0289] (5) Record the fluorescence intensity at 475 / 500-550 nm using an ELISA reader.

[0290] 2.4 Data Statistics

[0291] Experimental results are expressed as mean ± standard deviation. Data were analyzed using GraphPad Prism 8.0 software and one-way ANOVA was used to compare whether there were statistical differences between groups. A p-value < 0.05 was considered statistically significant.

[0292] 2.5 Experimental Results

[0293] When DRG neurons and macrophages were co-cultured in Raw264.7 cells, treatment with AngII (200 nM) for 30 min significantly increased the calcium ion concentration in DRG neurons (approximately 135.8%, p < 0.001) compared to the PBS blank control group. Compared with the AngII (200 nM) group, A1 (0.1 μM), A1 (1 μM), A1 (10 μM), and PD123319 (1 μM) reduced calcium ion 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 with the AngII (200 nM) treatment group, A1 at both 1 μM and 10 μM concentrations significantly inhibited the increase in intracellular calcium ion concentration in DRG neurons induced by AngII (200 nM). The results are shown in Table 1 and Figure 2.

[0294] Table 1. Relative fluorescence intensity of intracellular calcium ions in DRG neurons in different treatment groups Note: ### p<0.001, compared with the solvent group; ** p<0.01, *** p<0.001, compared with the AngII (200 nM) group.

[0295] Experimental Example 3: Pharmacodynamic Test of AT2R Antagonists in a Mouse Model of Sciatic Nerve Branch Injury

[0296] 3.1 Experimental Objective:

[0297] The analgesic effect of AT2R antagonists on a mouse sciatic nerve branch injury (SNI) model was evaluated using the Von Frey electronic analgesia system. The effects of AT2R antagonists on AT2R receptors and F4 / 80 co-staining on macrophages in mouse SNI models were investigated, as well as their effect on the expression of transient receptor potential ion channel subunit 1 (TRPA1) in dorsal root ganglion (DRG) neurons.

[0298] 3.2 Test Instruments

[0299] Electronic analgesia device (IITC, 2392), small animal anesthesia machine (R510-29), laser confocal microscope (Zeiss, LSM710), cryostat (ThermoFisher, NX70).

[0300] 3.3 Experimental Animals

[0301] Male C57BL / 6 mice aged 4-6 weeks and weighing 14-20 grams were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.

[0302] 3.4 In vivo test procedure

[0303] 1) Mice were completely anesthetized by inhalation of isoflurane, fixed in a prone position on the operating table to fully expose the lateral gluteal region, and the hair on the left posterior branch was shaved and disinfected with alcohol. Aseptic procedures were performed during the operation. SNI surgery group: The mouse skin was cut along the femur parallel to the direction of the sciatic nerve to expose the sciatic nerve trunk until the tibial nerve, common peroneal nerve, and sural nerve were exposed. The tibial nerve and common peroneal nerve were tightly ligated with medical absorbable sutures (8-0). Then, a section of the nerve (about 2-4 mm) was cut from the ligation site to the distal nerve, ensuring the integrity of the sural nerve. The muscles and epidermis were sutured layer by layer to complete the mouse SNI model.

[0304] 2) On the 9th day after surgery, the animals were placed in the experimental environment to adapt for 15 minutes per day for 3 consecutive days.

[0305] 3) On the 11th day after surgery, PWT was measured. Animals with abnormal PWT (mean PWT >4g or <1g) were excluded. The mice were randomly divided into 5 groups (SNI model group) according to their body weight and PWT value: solvent control group (sterile water for injection), Gabapetin 50mg / kg, A1 50mg / kg, A1 100mg / kg, A1 200mg / kg, 12 mice / group, administered by gavage at 10mL / kg.

[0306] 4) On the 12th day post-surgery, the withdrawal threshold was tested using a Von Frey electronic anesthesiometer 0 h before and 2 and 4 h after drug administration. Animals were placed in a specially designed multi-unit metal mesh cage for pain detection and allowed 30 minutes to acclimatize. After acclimatization, the hind paw of the mouse on the surgical side was stimulated with an electronic anesthesiometer (IITC Life Science Inc.), with pressure continuously increased until a clear withdrawal response was observed. The reading recorded by the electronic anesthesiometer was the threshold for mechanical pain response, expressed in grams (g). This test was repeated 6 times. The average value was then used as the final test indicator.

[0307] 3.5 Tissue sampling and immunofluorescence staining process

[0308] 1) After the pain test was completed, the first 6 mice in the Vehicle group, A1 50mg / kg, A1 100mg / kg and A1 200mg / kg were anesthetized with isoflurane by inhalation and euthanized with cervical dislocation. The sciatic nerve on the injured side and the non-injured side, and the DRG on the injured side were fixed in 4% paraformaldehyde solution.

[0309] 2) The fixed sciatic nerve on the injured side, the sciatic nerve on the uninjured side, and the dorsal root ganglion on the injured side were dehydrated, frozen and embedded, and sectioned for later use.

[0310] 3) The immunofluorescence staining process is as follows:

[0311] 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 at room temperature for 1 h.

[0312] The primary antibodies (AT2R: Rabbit, (LSBio, LS-A1322); TRPA1: Rabbit, (Invitrogen, PA1-46159); F4 / 80: Rat, (abcam, ab6640)) were then diluted 1:200 with antibody dilution buffer (NewSemi Biotech, Lot: 20220824) and incubated overnight at 4°C; then washed three times with PBS for 5 min each time.

[0313] 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 1:2000 with antibody dilution buffer (NewSemi Bio, Lot: 20220824) and incubated at room temperature for 30 min; then washed 3 times with PBS for 5 min each time.

[0314] Mount the slides using a mounting solution containing DAPI, take pictures with a confocal microscope (Leica microscopy system, DCM8), count the number of macrophages co-stained with AT2R and F4 / 80 in the sciatic nerve tissue using the Find Maxima function of ImageJ, and count the TRPA1 fluorescence intensity of DRG neurons using ImageJ.

[0315] 3.6 Data Statistics

[0316] Experimental results are expressed as mean ± standard deviation. Data from each group were analyzed using GraphPad Prism 8.0 software. One-way ANOVA or two-way ANOVA was used to compare whether there were statistical differences between the groups, and p < 0.05 was considered statistically significant.

[0317] 3.7 Results of in vivo experiments

[0318] In mouse SNI models, 2 and 4 hours after gavage administration, compared with the model control group, A1 (50 mg / kg) administration at 4 hours, A1 (100 mg / kg) administration at 2 and 4 hours, and A1 (200 mg / kg) administration at 2 and 4 hours significantly inhibited sciatic nerve injury-induced mechanorepain hypersensitivity in mice (p<0.001). Gabapentin (50 mg / kg) administration at 2 and 4 hours significantly inhibited sciatic nerve injury-induced mechanorepain hypersensitivity in mice (p<0.001). Figure 3 shows the paw retraction threshold PWT (Mean±SD, ***p<0.001, compared with the corresponding time point of the Vehicle group) in each group of SNI mice.

[0319] 3.8 Results of Immunofluorescence Staining Experiment

[0320] Figure 4 shows typical images of macrophages co-stained with AT2R (AKA:AGTR2) and F4 / 80 on the sciatic nerve injury side and the non-injury side in SNI mice (Bar = 20 μm).

[0321] Figure 5 shows the fluorescence intensity of AT2R and F4 / 80 co-stained macrophages on the sciatic nerve injury side of SNI mice. The results indicate that, compared with the control group, both A1 (100 mg / kg) and A1 (200 mg / kg) significantly reduced the number of AT2R and F4 / 80 co-stained macrophages at the sciatic nerve injury site on the injury side. Figure 6 shows the fluorescence intensity of AT2R and F4 / 80 co-stained macrophages on the non-injured side of the sciatic nerve in SNI model mice. The results indicate that the number of AT2R and F4 / 80 co-stained macrophages was low in all experimental groups on the non-injured side of the sciatic nerve, and there was no significant difference in the number of AT2R and F4 / 80 co-stained cells among the groups. These results suggest that the sciatic nerve injury side recruits more peripheral macrophages than the non-injured side, and that gavage administration of the AT2R antagonist A1 at 100 mg / kg and 200 mg / kg significantly reduced the number of peripheral macrophages and the expression level of AT2R.

[0322] Figure 7 shows a typical immunofluorescence staining pattern of TRPA1 in the DRG of the injured side of SNI mice (Bar = 20 μm). Figure 8 shows the average fluorescence intensity of TRPA1 in the DRG neurons of the injured side of SNI mice. The results suggest that, compared with the control group, A1 (100 mg / kg) and A1 (200 mg / kg) can significantly reduce the expression of TRPA1 in DRG neurons.

[0323] Example 4: Pharmacodynamic test of AT2R antagonists in a rat model of plantar incision pain

[0324] 4.1 Experimental Objective

[0325] This experiment established a rat model of plantar incision pain to evaluate the analgesic effect of A1 on plantar incision pain in rats.

[0326] 4.2 Experimental Equipment and Main Reagents

[0327] 4.3 Experimental Animals

[0328] Male SD rats (SPF grade) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0329] 4.4 Test Methods

[0330] Eighty-five male SD rats were selected based on the 50% Paw Withdrawal Threshold (50% PWT), and 72 qualified rats were randomly divided into 6 groups: model group, dezocine group (dose 0.5 mg / kg), flurbiprofen ester group (dose 5 mg / kg), and low, medium and high dose A1 groups (dose 50, 100 and 300 mg / kg, respectively), with 12 rats in each group.

[0331] Establishment of a plantar incision pain model in SD rats:

[0332] After induction and maintenance anesthesia with isoflurane, the animal was fixed on the operating table. The metatarsal area of ​​the left hind paw was disinfected with povidone-iodine, deiodized with alcohol, and then the hind paw was fixed with tape. The hind paw was stabilized with forceps, and a longitudinal strip incision of about 1 cm was made from the proximal end of the foot towards the toes. After incising the skin and fascia of the foot, the foot muscles were lifted with ophthalmic forceps and bluntly dissected longitudinally, keeping their origin and insertion points intact. The muscle belly was longitudinally incised with a scalpel blade, keeping the muscle attachment points intact. Hemostasis was achieved at the incision site, the skin was sutured with 5-0 sutures, and erythromycin ointment was applied. 80,000 units of penicillin were injected subcutaneously for two consecutive days postoperatively to prevent infection.

[0333] The dezocine group and flurbiprofen ester group were administered dezocine injection or flurbiprofen ester injection at 5 mL / kg via tail vein injection, once a day on the test day. The model group, low-, medium-, and high-dose A1 groups were administered control (sterile water for injection) or the corresponding concentration of A1 preparation orally by gavage at 5 mL / kg, once a day for 3 days, at the following times: one day before surgery (morning), on the day of surgery (approximately 1 hour before surgery), and the second day after surgery (before the test). On the second day after surgery, all animals underwent Von Frey tests before administration and at 1, 3, and 6 hours after administration. Efficacy was evaluated based on the change in 50% PWT in rats.

[0334] 50% PWT value, the formula is: 50% g threshold = (10 [Xf+kδ] ) / 10000

[0335] Where X f= The final Von Frey nylon filament Log value used in the test; k = positive / negative response mode value; δ = the average difference Log value between nylon filament stimuli, which is a constant of 0.224 here.

[0336] 4.5 Statistical Analysis

[0337] The experimental data were statistically analyzed using EXCEL and Graph Pad Prism 8.

[0338] Experimental data are expressed as mean ± standard error (Mean ± SEM). Graph Pad Prism 8 software was used to plot the parameters of different groups of animals before and after drug administration. Two-way ANOVA was used to analyze and compare the differences in 50% PWT values ​​at different pain measurement time points between different drug administration groups and within the same group.

[0339] 4.6 Experimental Results

[0340] Compared with the baseline 50% PWT (16.07±0.35g) before modeling, the mean 50% PWT of each group after modeling (4.99±0.18g) was significantly reduced (p≤0.001), indicating that the SD rat incision pain model was successfully established.

[0341] Compared with the model group, the 50% PWT of rats in the dezocine, flurbiprofen ester, and A1 (50, 100, 300 mg / kg) groups increased significantly 1 h after administration (p≤0.01), reaching the peak efficacy. 3 h after administration, the 50% PWT of rats in all groups decreased, while the 50% PWT of rats in the flurbiprofen ester, A1 (100 mg / kg), and A1 (300 mg / kg) groups remained significantly higher than that in the model group (p≤0.01). 6 h after administration, there was no significant change in the 50% PWT of rats in all groups compared with the model group.

[0342] Conclusion: Under the conditions of this experiment, oral administration of A1 (50, 100, 300 mg / kg) to SD rats exerted a dose-dependent analgesic effect. The 50 mg / kg dose group showed good analgesic effects 1 h after administration, and the 100 and 300 mg / kg dose groups showed good analgesic effects 1 h and 3 h after administration. The analgesic threshold of A1 (100 and 300 mg / kg) at peak efficacy was higher than that of dezocine injection and flurbiprofen ester injection.

[0343] Example 5: Efficacy test of AT2R antagonist in Bama pig back incision pain model

[0344] 5.1 The purpose of this study was to evaluate the analgesic effect of AT2R antagonists on acute postoperative pain in a miniature pig back incision pain model.

[0345] 5.2 Test Equipment and Reagents

[0346] 5.3 Experimental Animals

[0347] Male Bama miniature pigs (standard grade), purchased from Jiangsu Laika Biotechnology Co., Ltd.

[0348] 5.4 Experimental Procedure

[0349] Thirty-six male Bama miniature pigs were randomly divided into six groups: model control group, flurbiprofen ester group (iv, 1 mg / kg), dezocine group (iv, 0.15 mg / kg), and A1 group (80, 120, 180 mg / kg), with six pigs per group.

[0350] Incision pain model establishment:

[0351] After induction of anesthesia with isoflurane, the Bama pigs were placed in a prone position. The skin was prepared 3 cm from the midline of the back on the right posterior side. After disinfection with iodine, a 5 cm incision was made parallel to the midline of the back. The incision was made by cutting the skin and then using forceps to separate the fascia downwards and bluntly dissecting the muscle to a depth of 0.5 cm.

[0352] The mechanical pain threshold of animals was measured using a Von Frey electronic analgesia meter before surgery, before administration of medication after surgery, and at 0.5h, 1h, 2h, 4h, 6h, and 8h after administration. The postoperative analgesic effect of test product A1 was evaluated based on the results of the mechanical pain threshold around the incision in the animals.

[0353] 5.5 Statistical Analysis

[0354] Data were collected using Excel software. Experimental data are expressed as mean ± standard error (Mean ± SEM) and analyzed using Prism (Graph pad software, Inc.) software (Two-way ANOVA). p < 0.05 was considered statistically significant.

[0355] 5.6 Test Results

[0356] On the second day after surgery, the mechanical pain threshold of animals in the model group and the drug treatment group was significantly reduced, indicating that the model was successful.

[0357] As shown in Figure 10, the positive control drugs flurbiprofen ester (iv, 1 mg / kg) and dezocine (iv, 0.15 mg / kg) all showed significant analgesic effects at 0.5, 1, and 2 hours after administration (p≤0.0001). A1 (PO, 80 mg / kg) showed significant analgesic effects at 0.5, 1, and 2 hours after administration, and A1 (PO, 120 mg / kg) and A1 (PO, 180 mg / kg) showed significant analgesic effects at 0.5, 1, 2, and 4 hours after administration (p≤0.0001), with the analgesic intensity increasing with increasing dose. The duration of analgesia for A1 (PO, 120 mg / kg) and A1 (PO, 180 mg / kg) was 4 hours, which was longer than that of the positive control drugs flurbiprofen ester and dezocine.

[0358] Conclusion: A1 showed dose-dependent analgesic effects at dose levels of 80 mg / kg, 120 mg / kg and 180 mg / kg. The analgesic intensity and duration of A1 at 180 mg / kg were superior to those of the positive control drug dezocine, and the analgesic intensity and duration of A1 at 120 and 180 mg / kg were superior to those of the positive control drug flurbiprofen ester.

[0359] Example 6: Clinical study evaluating the safety, efficacy, and pharmacokinetic characteristics of compound A1 for analgesia after unilateral hip replacement surgery.

[0360] This study is a randomized, double-blind, placebo-controlled parallel trial. It plans to enroll 40 participants undergoing elective unilateral total hip arthroplasty under general anesthesia, who will be randomly assigned in a 1:1:1:1 ratio to the low-dose, medium-dose, high-dose, and placebo groups of compound A1.

[0361] The study included a screening period (from the signing of the informed consent form (ICF) to successful randomization, not exceeding 7 days) and a treatment period (from successful randomization to 48 hours after the end of the surgery).

[0362] After successful screening, participants can be randomly assigned to low-dose, medium-dose, high-dose, or placebo groups of compound A1 on day D-1 or day D1 (the day of the first dose is designated as D1) in a 1:1:1:1 ratio. Successfully randomized participants will receive the medication as directed in the protocol, with the day of the first dose designated as D1.

[0363] Dosage of investigational drug:

[0364] The low-dose group (400 mg initial dose, followed by 200 mg each time), the medium-dose group (800 mg initial dose, followed by 400 mg each time), the high-dose group (1200 mg initial dose, followed by 600 mg each time), and the placebo group were all administered orally for a total of 4 doses. The dosing times are shown in the table below:

[0365] Participants who were successfully randomized received their first dose of the investigational drug 2 hours before the scheduled surgery on day 1, and then underwent unilateral total hip replacement surgery under general anesthesia. The actual surgery start time (start of skin incision) and surgery end time (end of last suture, recorded as 0h) were recorded.

[0366] Anesthesia method:

[0367] Total intravenous or combined intravenous-inhalation anesthesia can be used, but other anesthetic methods (such as spinal block anesthesia, nerve block anesthesia, local infiltration anesthesia, etc.) should not be used in combination.

[0368] Anesthesia recovery assessment:

[0369] The first MOAA / S score should be performed within 5 minutes after endotracheal tube removal, and then the MOAA / S score should be performed every 5 minutes or less until three consecutive MOAA / S scores reach 5.

[0370] Within 10 minutes of the initial resting NRS score, the patient-controlled intravenous analgesia (PCIA) device was activated. The analgesia device formulation was: morphine hydrochloride injection diluted to 0.5 mg / mL with 0.9% sodium chloride injection. The researchers stopped the PCIA device at 12 h (±5 min), 24 h (±5 min), 36 h (±5 min), and 48 h (±5 min) after the operation, and read and recorded the morphine dosage.

[0371] NRS pain score:

[0372] Resting NRS score (15 time points): The first resting NRS score was within 15 minutes (+15 min) after three consecutive MOAA / S scores of 5; the resting NRS scores were given at 2 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 12 h (±10 min), 16 h (±15 min), 20 h (±15 min), 24 h (±15 min), 28 h (±15 min), 32 h (±15 min), 36 h (±15 min), 40 h (±15 min), and 48 h (±15 min) after surgery.

[0373] Pain relief:

[0374] If participants require pain management beyond PCIA pump analgesia within 48 hours post-surgery: If a participant complains of unbearable pain and has a resting NRS score ≥4, rescue analgesia may be administered after investigator evaluation. The NRS pain score must be assessed within 5 minutes prior to each rescue analgesia session. The rescue analgesic is morphine hydrochloride injection (intravenous, 2 mg / dose), and it is recommended that there be at least a 30-minute interval between two rescue analgesia treatments. The morphine dose administered during rescue analgesia is included in the total morphine dose, and the cumulative morphine dose in 24 hours should not exceed 60 mg.

[0375] Primary efficacy endpoint: Morphine (mg) administered 0-48 hours after surgery.

[0376] As shown in Figure 11, in a clinical trial of unilateral hip replacement in humans, the medium- and high-dose groups of compound A1 reduced opioid use by 31%-35%.

[0377] In addition to the embodiments described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. Use of an angiotensin II type 2 receptor (AT2R) antagonizing compound in the manufacture of a pharmaceutical composition for the prevention or treatment of acute pain.

2. The use of claim 1, wherein the acute pain is acute pain associated with peripheral macrophage function.

3. The use of claim 1 or 2, wherein the acute pain is acute pain associated with one or more of 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.

4. The use of any one of claims 1-3, wherein: the acute pain is selected from the group consisting of acute traumatic pain, mechanical traumatic pain, and acute postoperative pain; preferably, wherein the acute pain is acute traumatic pain; more preferably, wherein the acute pain is mechanical traumatic pain, preferably wherein the mechanical trauma is selected from the group consisting of open blunt force trauma, sharp force trauma, mixed trauma comprising sharp force trauma and open blunt force trauma, mixed trauma comprising sharp force trauma and closed blunt force trauma, and mixed trauma comprising sharp force trauma, open blunt force trauma, and closed blunt force trauma.

5. The use of claim 4, wherein the mechanical traumatic pain is acute postoperative pain, preferably postoperative surgical incision pain.

6. An AT2R antagonizing compound for use in the prevention or treatment of acute pain.

7. The AT2R antagonizing compound for use of claim 6, wherein the acute pain is acute pain associated with peripheral macrophage function.

8. The AT2R antagonizing compound for use of claim 6 or 7, wherein the acute pain is acute pain associated with one or more of recruitment / aggregation of macro phages, high expression of AT2R in macrophages, and elevated levels of ROS and / or RNS produced by macrophages.

9. The AT2R antagonizing compound for use of any one of claims 6-8, wherein: the acute pain is selected from the group consisting of acute traumatic pain, mechanical traumatic paint, and acute postoperative pain; preferably, wherein the acute pain is acute traumatic pain; more prefera bly, wherein the acute pain is mechanical traumatic pain, preferably wherein the mechanical trauma is selected from the goup consisting of open blunt force trauma, sharp force trauma, mixed trauma comprising sharp force trauma and open blun force trauma, mixed trauma comprising sharp force trauma and closed blunt force trauma, and mixed trauma comprising shar force trauma, open blunt force trauma, and closed blunt force trauma.

10. The AT2R antagonizing compound for use of claim 9, wherein the mechanical traumatic pain is acute postoperative pain, preferably postoperative surgical incision pain. 1 11. A method for the prevention or treatment of acute pain, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of an AT2R antagonizing compound; preferably, wherein the AT2R antagonizing compound is administered in the form of a pharmaceutical composition.

12. The method of claim 11, wherein the acute pain is acute pain associated with peripheral macrophage function. ​ ​ ​ ​ ​ ​ ​ 13. The method of claim 11 or 12, wherein the acute pain is acute pain associated with one or more of 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.

14. The method of any one of claims 11-13, wherein: the acute pain is selected from the group consisting of acute traumatic pain, mechanical traumatic pain, and acute post-surgical pain; preferably, wherein the acute pain is acute traumatic pain; more preferably, wherein the acute pain is mechanical traumatic pain, preferably wherein the mechanical trauma is selected from the group consisting of open blunt force trauma, sharp force trauma, mixed trauma comprising sharp force trauma and open blunt force trauma, mixed trauma comprising sharp force trauma and closed blunt force trauma, and mixed trauma comprising sharp force trauma, open blunt force trauma, and closed blunt force trauma.

15. The method of claim 14, wherein the mechanical traumatic pain is acute post-surgical pain, preferably post-surgical incision pain; preferably, wherein: the AT2R antagonist compound or the pharmaceutical composition is administered pre-operatively, or the AT2R antagonist compound or the pharmaceutical composition is administered post-operatively; or the AT2R antagonist compound or the pharmaceutical composition is administered pre-operatively and further administered post-operatively; more preferably, wherein: the pre-operative administration is performed 1-4 times, 1-2 times, 1 time, 2 times, 3 times, or 4 times, preferably, the pre-operative administration comprises dosing the AT2R antagonist compound or the pharmaceutical composition 0-12 h, 1-10 h, 1-8 h, 1-6 h, 1-4 h, 2-4 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, or 10 h prior to the surgery; and / or the post-operative administration is performed 1-10 times, 1-8 times, 1-6 times, 2-6 times, 1-4 times, 3-4 times, 2-4 times, 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times, preferably, the first post-operative administration of the AT2R antagonist compound or the pharmaceutical composition is performed 0-12 h, 1-10 h, 1-8 h, 2-6 h, 1-4 h, 2-4 h, 1 h 2 h, 3 h, 4 h, 5 h, 6 h 7 h, 8 h, 9 h, 10 h, 11 h, or 12 h after the surgery, and then once every 4-16 h, 4-12 h, 6-12 h, 6-14 h, 8-12 h, or 10-12 h; or, preferably, wherein: the administration of the AT2R antagonist compound or the pharmaceutical composition comprises: a first administration to the individual is performed and the time of this first administration is noted as the start of the clock (TO); then, three administrations are performed 12 h (± 4 h), 24 h (± 4 h), and 36 h (± 4 h) after the first administration, respectively; a total of four administrations are performed; or, the administration of the AT2R antagonist compound or the pharmaceutical composition can comprise: a first administration to the individual is performed and the time of this first administration is noted as a start of the clock (TO); then, three administrations are performed 12 h (± 2 h), 24 h (± 2 h), and 36 h (± 2 h) after the first administration, respectively; a total of four administrations are performed. administering once to the individual about 1-2.5 h (TO) prior to the surgery, in a dose of 200-1200 mg or 400-1200 mg of the AT2R antagonist compound; and administering a first post-surgery administration 12 h (±4 h) after the TO administration, and then administering once every 12 h (±4 h), for a total of 2-6, preferably 3-4, post-surgery administrations, each in a dose of 200-600 mg of the AT2R antagonist compound; or, the administration of the AT2R antagonist compound or the pharmaceutical composition can comprise: administering once to the individual 2 h ± 30 min (TO) prior to the surgery, in a dose of 400 mg of the AT2R antagonist compound; and administering a first post-surgery administration 12 h (±4 h) after the TO administration, and then administering once every 12 h (±4 h), for a total of 3 post-surgery administrations, each in a dose of 200 mg of the AT2R antagonist compound; or, the administration of the AT2R antagonist compound or the pharmaceutical composition can comprise: administering once to the individual 2 h ± 30 min (TO) prior to the surgery, in a dose of 800 mg of the AT2R antagonist compound; and administering a first post-surgery administration 12 h (±4 h) after the TO administration, and then administering once every 12 h (±4 h), for a total of 3 post-surgery administrations, each in a dose of 400 mg of the AT2R antagonist compound; or, the administration of the AT2R antagonist compound or the pharmaceutical composition can comprise: administering once to the individual 2 h ± 30 min (TO) prior to the surgery, in a dose of 1200 mg of the AT2R antagonist compound; and administering a first post-surgery administration 12 h (±4 h) after the TO administration, and then administering once every 12 h (±4 h), for a total of 3 post-surgery administrations, each in a dose of 600 mg of the AT2R antagonist compound; or, the administration of the AT2R antagonist compound or the pharmaceutical composition to the individual can comprise: administering a first administration to the individual within 10 minutes (TO) after the individual’s baseline resting NRS score reaches 4 or higher post-surgery, in a dose of 400-1200 mg, 1200 mg, 1000 mg, 800 mg, 600 mg, or 400 mg of the AT2R antagonist compound; administering once 12 h (±4 h) after the TO administration, and then administering once every 12 h (±4 h) thereafter, for a total of 2-6, or 3-4, administrations after the TO administration, each in a dose of 200-600 mg, 600 mg, 400 mg, or 200 mg of the AT2R antagonist compound; preferably, the administration of the AT2R antagonist compound or the pharmaceutical composition to the individual can comprise: a first administration to the individual within 10 minutes (TO) of the individual's baseline resting NRS score reaching 4 or higher after surgery, at a dose of 1200 mg, calculated as the AT2R antagonist compound; one administration 12 h (+ 4 h) after the TO administration, and then one administration every 12 h (+ 4 h) thereafter, wherein the administrations after the TO administration are a total of 3, at a dose of 600 mg, calculated as the AT2R antagonist compound, per administration; or, the administration of the AT2R antagonist compound or the pharmaceutical composition to the individual can comprise: a first administration to the individual within 10 minutes (TO) of the individual's baseline resting NRS score reaching 4 or higher after surgery, at a dose of 800 mg, calculated as the AT2R antagonist compound; one administration 12 h (+ 4 h) after the TO administration, and then one administration every 12 h (+ 4 h) thereafter, wherein the administrations after the TO administration are a total of 3, at a dose of 400 mg, calculated as the AT2R antagonist compound, per administration; or, the administration of the AT2R antagonist compound or the pharmaceutical composition to the individual can comprise: a first administration to the individual within 10 minutes (TO) of the individual's baseline resting NRS score reaching 4 or higher after surgery, at a dose of 400 mg, calculated as the AT2R antagonist compound; one administration 12 h (+ 4 h) after the TO administration, and then one administration every 12 h (+ 4 h) thereafter, wherein the administrations after the TO administration are a total of 3, at a dose of 200 mg, calculated as the AT2R antagonist compound, per administration.

16. The use of any one of claims 1-5, the AT2R antagonist compound of any one of claims 6-10, or the method of any one of claims 11-15, wherein the AT2R antagonist compound is a compound of the structure of Formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite, or prodrug thereof: wherein: 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 are each substituted by 1 C 6-10 aryl or 5-14 membered heteroaryl; C 6-10 aryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 membered heterocyclyl; -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl); R 1b H; optionally substituted with 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 absent or CR 10 or N; X 4 is selected from: C(=0); and -0-C(=0)- and -S-C(=0)-, wherein O and S are attached to X 1 is connected; R 2a is C 6-10 aryl; R 2b is C 6-10 aryl; X 2 CR 10 or N; R 3 -C(=O)OR 11 ; R 4 is H; R 10 at each occurrence is selected from the group consisting of H, -OR 11 , -SR 11 , and C 1-6 1-6alkyl; R 11 and R 12 each independently at each occurrence is H or C 1-6 alkyl; h and k are each independently 1 ; each occurrence of the above alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or more R 13 substituted; said R 13 is independently at each occurrence selected from: halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -OR 11 , -SR 11 , -P(O)R 11 R 12 and -NR 11 R 12 , and wherein the alkyl, alkylene, aryl and heteroaryl groups referred to in respect of substituent R 13 are optionally further substituted by 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.

17. The use, compound, or method of claim 16, wherein: R 13 independently at each occurrence selected from: halogen, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -OR 11 , -SR 11 , and -NR 11 R 12 , and wherein the alkyl, aryl and heteroaryl groups described in connection with substituent R 13 are optionally further substituted by 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.

18. The use, compound, or method of claim 16, wherein U is methylene or ethylene.

19. The use, compound, or method of claim 16, wherein R 3 is -COOH.

20. The use, compound, or method of claim 16, wherein R 10 independently at each occurrence is: H, C 1-4 alkyl, OH, or SH.

21. The use, compound, or method of claim 16, wherein R 11 and R 12 are each independently selected at each occurrence from H and C 1-4 alkyl.

22. The use, compound, or method according to claim 16, wherein R 13 Each time it appears, it is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C is optionally substituted by 1, 2, 3 or more substituents independently selected from halogens. 1-4 Alkyl; C 5-7 Cyclic hydrocarbon groups; each optionally surrounded by 1, 2, 3 or more independently selected from halogen, OH, amino, cyano and C. 1-4 Alkyl substituents, substituted phenyl groups, 5-6-membered heteroaryl groups, and 9-10-membered heteroaryl groups; wherein R 11 C is optionally replaced by 1, 2, 3 or more halogens 1-6 Alkyl-OR 11 ;where R 11 C is optionally replaced by 1, 2, 3 or more halogens 1-6 Alkyl-SR 11 ; and R in it 11 and R 12 Each time it appears, it is independently C, which is optionally replaced by 1, 2, 3 or more halogens. 1-6 Alkyl-NR 11 R 12 or -P(O)R 11 R 12 .

23. The use, compound, or method of claim 16, wherein R 13 independently at each occurrence is selected from: F, Cl, Br, I, amino, cyano, nitro; C 1-4 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 is -OR 1-3 of C 11 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 is -SR 1-3 of C 11 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 and R 12 independently at each occurrence is C 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 with 1, 2, 3, or more substituents independently selected from F, Cl, Br, I, and methyl.

24. The use, compound, or method of claim 23, wherein the C 1-3 alkyl is methyl, ethyl, propyl, or isopropyl.

25. The use, compound, or method of claim 16, wherein: R 1a selected from: C 2-6 alkenyl and C 2-6 alkynyl, wherein said C 2-6 alkenyl and C 2-6 alkynyl are each substituted with 1 phenyl or 5-10 membered heteroaryl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; -C 1-3 alkylene-(5-7 membered monocyclic heterocyclyl); -C 1-3 alkylene-(8-10 membered benzo-fused heterocyclyl); -C 1-3 alkylene-phenyl; and -C 1-3 alkylene-(5-10 membered heteroaryl); R 1b is absent, or is selected from: H; C 1-6 alkyl; C 3-7 cycloalkyl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; and -C 1-3 alkylene-phenyl; and each occurrence of the above alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or more R 13 substituted.

26. The use, compound, or method of claim 25, wherein R 1a is selected from phenyl, -C 1-3 alkylene-C 3-7 cycloalkyl, -C 1-3 alkylene-phenyl, -C 1-3 alkylene-(5-7 membered monocyclic heterocyclyl), -C 1-3 alkylene-(9-10 membered benzo-fused heterocyclyl), -C 1-3 alkylene-(5-6 membered heteroaryl), and -C 1-3 alkylene-(9-10 membered heteroaryl), each of which is optionally substituted with 1, 2, 3, or more R 13 substituents.

27. The use, compound, or method of claim 26, wherein R 13 selected from C 1-4 alkyl-O-; halo; and C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo.

28. The use, compound, or method of claim 26, wherein X is C(=O). 4 is C(=O).

29. The use, compound, or method of claim 25, wherein: R 1a selected from the group consisting of: C 2-6 alkenyl and C 2-6 alkynyl, said C 2-6 alkenyl and C 2-6 alkynyl are each substituted with 1 phenyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, and C 1-4 alkyl; optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, and C 1-4 phenyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, and C -C 1-3 alkylene-phenyl, -C 1-3 alkylene-(5- to 6-membered heteroaryl), and -C 1-3 alkylene-(9- to 10-membered heteroaryl), wherein the alkylene is optionally substituted 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 with 1, 2, or 3 substituents independently selected from F, Cl, Br, I, and C 1-4 alkyl; R 1b absent; X 1 absent; and X 4 is C(=O) or -O-C(=O)-.

30. The use, compound, or method of claim 25, wherein the C 1-6 Alkyl is methyl, ethyl, propyl, isopropyl, or tert-butyl.

31. The use, compound, or method of claim 29, wherein the C 2-6 Alkenyl is ethenyl, 1 -propenyl, or 2-propenyl.

32. The use, compound, or method of claim 29, wherein the C 2-6 Alkynyl is ethynyl, 1-propynyl, or 2-propynyl.

33. The use, compound, or method of claim 29, wherein R 13 is phenyl, pyridyl, indolyl, or furanyl, optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, and methyl.

34. The use, compound, or method of claim 33, wherein R 1a is selected from:

35. The use, compound, or method of claim 16, wherein: R 1a is a group selected from the group consisting of optionally substituted phenyl, - optionally substituted C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), - optionally substituted C 1-3 alkylene-(optionally substituted 5-7 membered monocyclic heterocyclyl), - optionally substituted C 1-3 alkylene-(optionally substituted 8-10 membered benzo-fused heterocyclyl), - optionally substituted C 1-3 alkylene-optionally substituted phenyl, and - optionally substituted C 1-3 alkylene-(optionally substituted 5-10 membered heteroaryl); R 1b Selected from H, arbitrarily by 1, 2, 3 or more R 13 Replacement C 1-8 Alkyl; saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group; C 6-10 Aryl; -C 1-6 Alkylene-saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups; and -C 1-6 Alkylene-C 6-10 Aryl; X 1 is CR 10 or N; X 4 is C(=O); wherein said "optionally substituted" means substituted with 1, 2, 3, or more R 13 substituents; and R 13 As defined in claim 16.

36. The use, compound, or method of claim 35, wherein R 1b is a member 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 said "optionally substituted" means substituted with 1, 2, 3, or more R 13 substituted.

37. The use, compound, or method of claim 16, wherein: R 2a is optionally substituted phenyl; and / or R 2b is optionally substituted phenyl; wherein said "optionally substituted" means substituted with 1, 2, 3, or more R 13 substituted.

38. The use, compound, or method of claim 16, wherein the compound has the structure of formula (II): wherein R 1a , R 1b , X 1 , X 4 , R 2a , R 2b , X 2 , R 3 , R 4 , h and k are as defined in claim 16.

39. The use, compound, or method of claim 16, wherein is:

40. The use, compound, or method of claim 16, wherein is:

41. The use, compound, or method of claim 16, wherein R 10 is H or methyl.

42. The use, compound, or method of claim 35, wherein R 1a is selected from optionally substituted phenyl, -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), -C 1-3 alkylene-(optionally substituted 5- to 7-membered monocyclic heterocyclyl), -C 1-3 alkylene-(optionally substituted 8 to 10 membered benzo-fused heterocyclyl), -C 1-3 alkylene-optionally substituted phenyl, and -C 1-3 alkylene-(optionally substituted 5 to 10 membered heteroaryl).

43. The use, compound, or method of claim 35, wherein R 1a is selected from: optionally substituted phenyl; -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; -C 1-3 alkylene-(optionally substituted 8-10 membered benzo-fused heterocyclyl), wherein the heterocyclyl is -C 1-3 alkylene-(optionally substituted 5-10 membered heteroaryl), wherein the heteroaryl is 44. The use, compound, or method according to claim 35, wherein R 13 Selected from: halogens; where R 11 C is a carbon that is optionally replaced by 1, 2, 3 or more halogens. 1-6 Alkyl-OR 11 ; cyano; C 3-7 Cyclic hydrocarbon group; C group optionally substituted with 1, 2, 3 or more halogens 1-4 Alkyl, C 2-4 alkenyl and C 2-4 alkynyl group; wherein R 11 and R 12 Each is independently selected from H and C. 1-4 Alkyl-NR 11 R 12 ; and R in it 11 and R 12 Each is independently a C that is optionally replaced by one, two, three or more halogens. 1-6 Alkyl-P(O)R 11 R 12 .

45. The use, compound, or method of claim 35, wherein R 13 is selected from: halo; -OR 11 wherein R 1-3 is C 11 alkyl optionally substituted with 1, 2, or 3 F or CI; cyano; C 3-7 ycloalkyl; C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl; wherein R 11 and R 12 are each independently selected from H and methyl; -NR 11 R 12 ; and wherein R 11 and R 12 are each independently C 1-3 alkyl optionally substituted with 1, 2, or 3 F or CI; -P(O)R 11 R 12 .

46. The use, compound, or method of claim 35, wherein R 13 is selected from the group consisting of: F, CI, Br, OH, -OC 1-4 alkyl, -N(C 1-4 alkyl)2, cyano, C 3-7 ycloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl; C 1-4 alkyl optionally substituted with 1, 2, 3, or more F, CI, or Br; and wherein R 11 and R 12 each independently is methyl, ethyl, propyl, or isopropyl. 11 R 12 .

47. The use, compound, or method of claim 35, wherein R 13 is selected from the group consisting of F, Cl, Br, -OCH3, -N(CH3)2, cyano, cyclopropyl, ethenyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, and CF3; and wherein R 11 and R 12 each independently is -P(O)R 11 R 12 .

48. The use, compound, or method of claim 35, wherein R 1a selected from the group consisting of: (including 49. The use, compound, or method of claim 36, wherein R 1b is selected from the group consisting of H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, -C 1-3 alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 alkylene optionally substituted phenyl.

50. The use, compound, or method of claim 36, wherein R 1b is selected from the group consisting of: 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.

51. The use, compound, or method of claim 36, wherein R 13 selected from halo and C 1-4 alkyl.

52. The use, compound, or method of claim 36, wherein R 13 is selected from F, CI, Br, and methyl.

53. The use, compound, or method of claim 36, wherein R 1b is selected from H, methyl, ethyl, isopropyl, CF3CH2, cyclopropyl, phenyl, 54. The use, compound, or method of claim 37, wherein R 13 is selected from the group consisting of halogen and -OR 11 and wherein R 11 is selected from the group consisting of C 1-4 alkyl.

55. The use, compound, or method of claim 37, wherein R 13 is selected from F, CI, Br, and -OCH3.

56. The use, compound, or method of claim 37, wherein R 2a and R 2b are each selected from phenyl, 57. The use, compound, or method of claim 16, 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 is N; X 4 is C(=O); X 2 is N; R 2a and R 2b are each phenyl; R 3 -C(=O)OH; R 4 is H; h and k are each independently 1 ; and h and k are each independently 1 ; and each occurrence of the above cycloalkyl, aryl, and heteroaryl groups is optionally substituted with 1 R 13 ; the R 13 group is C 1-6 alkyl; Preferably, said C 6-10 Aryl is phenyl, said saturated C 3-10 Cycloalkyl is cyclopropyl, and said 5-14 membered heteroaryl is thienyl or benzothienyl.

58. The use, compound, or method of claim 16, wherein the compound is selected from:

Images