Compounds for treatment of pain, in particular neuropathic pain, and / or other diseases or disorders that are associated with at2r and / or at2r mediated signaling

Abstract

To provide novel classes of molecules that can be used to target AT2R (angiotensin II receptor type 2) and / or to modulate the interaction(s) of AT2R with one or more of its ligands (such as Ang II) and that can be used in the prevention and / or treatment of various forms of chronic pain.SOLUTION: There is provided a compound of formula I. In the formula, [C] is a monocyclic or polycyclic (preferably monocyclic or bicyclic) aromatic ring system.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to compounds that can be used for the prevention, treatment and / or management of pain, particularly chronic pain such as neuropathic pain, and / or other diseases or disorders related to AT2R and / or or AT2R-mediated signaling (further described herein).

Background Art

[0002] Pain can occur in many forms and can have various causes and underlying pathophysiological mechanisms. Pain can be spontaneous, chronic or acute, for example, due to physical or potential injury to the body (so-called "nociceptive pain"), or due to injury and / or disease of the somatosensory nervous system (so-called "neuropathic pain"), for example, injury or disease of peripheral nerves (i.e., nerves that extend beyond the brain and spinal cord), also known as "peripheral neuropathy" or simply " neuropathy".

[0003] Pain conditions can also take the form of hypersensitivity to pain, for example, in the case of so-called "inflammatory pain", which term is generally used to describe the spontaneous hypersensitivity to pain that occurs in response to tissue injury and inflammation (e.g., postoperative pain, trauma, arthritis). Persistent pain conditions are often associated with the development of hyperalgesia (an increase in pain induced by noxious stimuli and a decrease in the pain threshold and / or allodynia (an increase in sensitivity to stimuli that were previously non-noxious), although the term hyperalgesia is also used in the literature to collectively refer to both hyperalgesia and allodynia ​​​​​and Hohmann, British Journal of Pharmaco logy (2008) 153, 319 - 334 (see reference).

[0004] The prevention, treatment and / or management of chronic and severe pain in patients is described as "clinician burden" in the description of Guindon a nd Hohmann (above).

[0005] To experimentally evaluate the pathophysiological mechanisms underlying characteristic clinical pain states induced by tissue damage, inflammation, nerve trauma, chemotherapeutic agents and metabolic problems, various animal mo dels have been developed, and this model also enables preclinical evaluation and verification of the therapeutic effects of analgesic candidates. For example, Dubner and Ren, "Assessing tra nsient and persistent pain in animals", I n: Textbook of Pain, 4 th edition (Wall and Melzack, Eds.), pp. 359 - 369, Churchill Livin gstone, 1999, 53, 319 - 334 (also cited in Guindon and Hohma nn (above)) is referred to.

[0006] In addition, various molecular targets for the prevention, treatment and / or management of pain have been suggested in the art. These include the cannabinoid CB2 receptor (e.g., see Guindon and Hohmann (above) again), the NMDA receptor (e.g., Parsons s, European Journal of Pharmacology, 429 Z 2001, 71 - 78), various ion channels (e.g., Dib-Hajj et al, see reference), et al., Brain Research Reviews, Volume 60, Issue 1, April 2009, Pages 65 - 83, and Markman and Dworkin, The Journal of Pain, Volume 7, Issue 1, Supplement, January 2006, Pages S38 - S47 (see also Welch et al., Biochemical Pharmacology, Volume 84, Issue 12, 15 December 2012, Pages 1551 - 1562 and International Publication No. WO 2020 / 112905). Issue 1, April 2009, Pages 65 - 83, and Markman a nd Dworkin, The Journal of Pain, Volume 7, Issue 1, Supplement, January 2006, Pages S3 8 - S47 (see also Welch et a l., Biochemical Pharmacology, Volume 84, Is sue 12, 15 December 2012, Pages 1551 - 1562 see also and monoacylglycerol lipase (MAGL) (see, for example, International Publication No. WO 2020 / 112905).

[0007] Neuropathic pain is a chronic secondary pain condition generally characterized by hyperalgesia and / or allodynia and caused by damage and / or disease of the somatosensory nervous system. Approximately 7 - 10% of the population suffers from neuropathic pain, which can have a significant impact on quality of life. See, for example, Szok et al., Behav. Neurol., 2019: 8685954, Colloca et al., Nat. Rev. Dis. Primers, 2017 Feb 16, 3:17002, Alles and Smith, P harmacol. Rev. 70:315 - 347, April 2018, and Cav alli et al., Int. J. Immunopathol. Pharmacol ., 2019 Jan - Dec, 33, and further references cited therein. See also and further references cited herein. ., 2019 Jan - Dec, 33, and further references cited in this regard. See also and further references cited herein.

[0008] As mentioned in these references, neuropathic pain (also abbreviated as "NP") is a disease of the somatosensory system that includes peripheral fibers (Aβ, Aδ, and C fibers) and central neurons. or disorder. Multiple causes of neuropathic pain have been described, for example, metabolic diseases such as diabetes, cancer and cancer treatment, such as chemotherapy, neurological conditions, such as those caused by autoimmune diseases (e.g., multiple sclerosis), neurodegenerative conditions such as Parkinson's disease, stroke, neuropathies caused by viral infections, such as those caused by herpes simplex virus (e.g., shingles), leprosy, Guillain -Barr syndrome, HIV infection, vascular diseases and vascular malformations, autoimmune conditions, and damage to nerves or the nervous system. Therefore, chronic neuropathic pain can originate from the peripheral part of the nervous system (e.g., in the case of trigeminal neuralgia or postherpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or radiculopathy) or can originate from or involve the central nervous system (e.g., in the case of chronic neuropathic pain resulting from spinal cord injury or brain injury, stroke, or multiple sclerosis). As mentioned, when it originates from nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy". As mentioned by Szok et al. (supra), in 2019, the International Association for the Study of Pain (IASP) published a classification of these qualitatively different pain syndromes, and the following subtypes

[0009] are recognized. are recognized. or can originate from or involve the central nervous system (e.g., in the case of chronic neuropathic pain resulting from spinal cord injury or brain injury, stroke, or multiple sclerosis). As mentioned, when it originates from nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy". spinal cord injury or brain injury, stroke, or chronic neuropathic pain that develops as a result of multiple sclerosis). As mentioned, when it originates from nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy". As mentioned, when it originates from nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy". As mentioned, when it originates from nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy".

[0010] As mentioned by Szok et al. (supra), in 2019, the International Association for the Study of Pain (IASP) published a classification of these qualitatively different pain syndromes, and the following subtypes are recognized. are recognized. - Subtypes of chronic peripheral NP: Trigeminal neuralgia (TN), chronic NP after peripheral nerve injury, painful polyneuropathy, post-herpetic neuralgia, and painful radiculopathy. - Subtypes of chronic central NP: Chronic central NP associated with spinal cord injury (SCI), brain injury-related chronic central NP, post-stroke chronic central pain, and multiple sclerosis-related chronic central NP.

[0011] As also stated by Szok et al., "Generally, the NP condition is poorly recognized, poorly diagnosed, and poorly treated."

[0012] Angiotensin II receptor type 2 (also referred to herein as "AT2R") has been proposed as a target for the treatment of neuropathic pain. For example, see Shepherd et al., PNAS, vol. 115, no. 34, E8057-E8066 and Kepp el Hesselink and Schatman, Journal of Pai n Research, 2017, 10:439-443, and Matavelli a nd Siragy, J. Cardiovasc. Pharmacol., 2015;6 5(3):226-232, and International Publication No. WO 2015 / 003223. Some of the known modulators of AT2R that have been proposed or studied for the treatment of neuropathic pain include the compounds EMA200 (also known as PD-123319), EMA300 , EMA400 (also known as PD-126055) and EMA401 / oloda nrigan (e.g., Smith et al., Pain Medicine 20 13, 14:692-705, Anand et al., Mol. Pain 2015 , 11:38, and see International Publication No. WO 2006 / 066361), the compound PD-123 177 (for example, Singh and Karnik, J. Cell. Signal., June 1, 2016, 1(111)), and the compound known as C-38 (for example, Wallinder et al., ACS Med. Chem. Lett., 2 2015, 6, 2, 178 - 182, and Isaksson et al., Chemistry Open 2019, 8(1), 114 - 125).

[0013] The mechanism underlying the analgesic properties of AT2R antagonists (such as EMA-401 mentioned below) remains to be further elucidated. Some researchers have reported from preclinical studies that there is a suggestion that the analgesic properties of AT2R antagonists may be explained by a mechanism involving the regulation of macrophage-mediated neuroimmune interactions (Shepherd et al., J. Neurosci., 2018, 38(32): 7032 - 70 57 and Shepherd et al., Proc. Natl. Acad. Sci. U SA, 2018 Aug 21; 115(34): E8057 - E8066). Another group of researchers has suggested, based on the finding that AT2R is located at the same site as TRPV1 in human dorsal root ganglia (DRG), that AT2R plays a role in nociception by capsaicin-sensitive sensory neurons and that AT2R antagonists may inhibit pain responses and neurite outgrowth in such cells (Anand et al., Eur. J. Pain, 17, (2013), 1012 - 1026).

[0014] AT2R and its ligand, angiotensin II, are well known in the art For example, Matavelli and Siragy, J.Cardiovasc .Pharmacol., 2015; 65(3): 226-232, Kaschina et al., Pharmacological Research 125(2017 ), 39-47(review), Berk, Science’s STKE, 2003 , Vol.2003, Issue 181, pp.pe16, Juillerat-Je anneret, J.Med.Chem., 2020, 63, 5, 1978-1995, Zhang et al., Nature, 2017; 544(7650): 327-3 32, Kemp et al., Circ.Res., 2014; 115(3): 388 -399, Namsolleck et al., Curr.Hypertens.Re p., (2014)16:416, Steckelings et al., Curr. Opin.Pharmacol., 2011 Apr; 11(2): 187-92, Me hta and Griendling, Am.J.Physiol.Cell Phy siol., 292:C82-C97, 2007, Carey and Padia, E ndocrine Hypertension, Volume 19, ISSUE 3, P84-87, April 01, 2008, and Singh and Karnik( supra), and see also a portion of the further references cited herein.

[0015] As described in these references, AT2R is part of the renin-angiotensin system A G protein-coupled receptor that forms part of the (RAS), and this system includes multiple enzymes, peptide hormones and receptors, and among its various biological functions, it is known to be a major regulatory element in the control of cardiovascular and renal

[0016] functions. Some of the main receptors in the RAS are the angiotensin II receptor type 1 (AT1R), the angiotensin II receptor type 2 (AT2R), the Ang IV receptor (also known as AT4R), the pro(renin) receptor, and the MAS receptor. Some of the natural peptide ligands known to be involved in the RAS are angiotensin, ligands for the pro(renin) receptor (such as renin and prorenin), and ligands

[0017] for the MAS receptor. Angiotensin includes the octapeptide Ang II and its natural degradation product Ang III (both are known to be ligands for AT1R and AT2R), the hexapeptide Ang(1-7) (known to be the endogenous ligand for the MAS receptor), Ang IV (the natural degradation product of Ang II, which is the main ligand for AT4R), and Ang I (the decapeptide precursor of Ang II, which itself does not seem to have major known

[0018] direct biological activity). Ang II has been described as a central peptide hormone of the RAS, is a potent vasopressor hormone, and is known to be the main regulator of aldosterone secretion by the adrenal cortex, which promotes sodium retention by the kidneys. Thus, it is an important It is also used as a medicament for the treatment of shock (commercially available under the trademark GIAPREZA(™)). It is used.

[0019] Ang II and its natural degradation product Ang III are known to act (mainly) via AT1R and A T2R, both of which are G protein-coupled receptors with approximately 34% sequence identity to each other. The actions of AT1R and AT2R are generally , assumed to be antagonistic to each other. Activation of AT1R induces, but is not limited to, biological effects such as dedifferentiation and proliferation of cells, vasoconstriction, antinatriuresis, aldosterone secretion, and ultimately sympathetic activation leading to hypertension. Activation of AT 2R is described as inducing, among other biological effects, cell differentiation and growth inhibition / apoptosis, vasodilation and natriuresis, potentially resulting in a hypotensive effect in kidney disease and as having a protective function with respect to various tissues and organs. AT2R is known to be highly expressed in fetal tissues, such as fetal aorta, gastrointestinal mesenchyme, connective tissue, skeletal system, brain, adrenal medulla and fetal kidney tissue. AT2R expression is generally decreased after birth and is mainly at significant levels in the myometrium of the adult uterus, with lower levels in the adrenal gland and fallopian

[0020] tubes. Otherwise, in healthy adult tissues , the expression level of AT2R is generally low, but AT2R is strongly upregulated under pathological conditions such as tissue injury and damage (including vascular injury, neuronal injury, myocardial infarction and cerebral ischemia) and is also known to mainly antagonize AT1R, thereby reducing inflammation, oxidative stress, fibrosis, cell proliferation, apoptosis, and tissue necrosis, and promoting cell survival, angiogenesis, and tissue repair, and ultimately playing a role in protecting tissues and organs from damage. In addition, AT2R is known to be strongly upregulated under pathological conditions such as tissue injury and damage (including vascular injury, neuronal injury, myocardial infarction and cerebral ischemia) and is also known to mainly antagonize AT1R, thereby reducing inflammation, oxidative stress, fibrosis, cell proliferation, apoptosis, and tissue necrosis, and promoting cell survival, angiogenesis, and tissue repair, and ultimately playing a role in protecting tissues and organs from damage. and is thought to provide endogenous protection against the apoptotic process.

[0021] In particular, as described by Anand (supra), "AngII and AT2R are co-expressed in human nociceptive sensory neurons, and the levels of AngII, a major endogenous ligand in human peripheral nerves, are preserved after injury. [...] Thus, the increase in AngII / AT2R signaling in DRG neurons following peripheral nerve injury may have an important role in chronic pain mechanisms, including neuropathic pain." Anand is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. AngII levels are preserved after injury. [...] Thus, the increase in AngII / AT2R signaling in DRG neurons following peripheral nerve injury may have an important role in chronic pain mechanisms, including neuropathic pain." Anand The increase in AngII / AT2R signaling in DRG neurons following peripheral nerve injury may have an important role in chronic pain mechanisms, including neuropathic pain. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. gII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats.

[0022] AT2R antagonists such as EMA401 have been shown to be effective in the treatment of postherpetic neuralgia in human subjects (see, e.g., Rice et al., The Lancet, Volume 383, P1637-1647, May 10, 2014), as well as in preclinical pain models of herpes zoster, is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. is also hypothesizing that the mechanism of action of the known AT2R antagonist EMA401 is "involved in the inhibition of enhanced AngII / AT2R-induced p38 and p42 / p44 MAPK activation, and thus in the inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) demonstrated that the analgesic dose of the AT2R antagonist EMA300 blocks enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibits p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats. diabetes, osteoarthritis, HIV, and chemotherapy (see, e.g., International Publication No. 2006 / 066361 and Anand et al., (supra)). Notwithstanding the foregoing, known AT2R antagonists have thus far had limited success in (further) clinical development.

[0023] In Rice et al., Pain, 2021, March, 1, the analgesic effect and safety of EMA401 in patients with postherpetic neuralgia and painful diabetic neuropathy are described in the results of two multicenter, randomized, double-blind, placebo-controlled Phase 2b trials. As noted by Rice et al., “The primary outcome in both trials was the mean weekly change in the 24-hour average pain score using the Numerical Rating Scale (NRS) from baseline to week 12. Although not observed in these trials, both trials were terminated early due to preclinical hepatic toxicity during long-term dosing.” Rice et al. further state, “[...] Due to early termination of the trials, definitive conclusions could not be drawn, but the consistent clinical improvement in pain intensity reduction in these two trials in two different populations is noteworthy.”

[0024] As is clear from the above, compounds that can be used for the prevention and / or treatment of pain, particularly chronic pain such as neuropathic pain, are always in demand in the art. In the words of Rice et al., “The effects of existing treatments for peripheral neuropathic pain (PNP) are modest and often not well tolerated, and the development of improved treatments for these common chronic pain states is recognized

[0025] as an important unmet need.” Can be used to modulate interactions with one or more and for various forms of chronic pain, such as caused by and / or associated with damage and / or disease of the somatosensory nervous system (particularly damage and / or disease of the peripheral nerves), chronic pain conditions, tissue damage and / or inflammation caused by and / or associated with hypersensitivity to pain in response to chronic pain conditions caused by and / or associated with hypersensitivity to pain caused by and / or associated with tissue damage and / or inflammation more generally, AT2R-mediated signaling, AngII-mediated activation of AT2R, and and / or chronic pain conditions associated with Ang II-mediated activation signaling pathways involving p38 MAPK and / or p44 / p42 MAPK for prevention and / or treatment of There is a need for a new class of molecules that can be used. Summary of the Invention

[0026] Description The present invention generally aims to meet this need by providing compounds that can interact with AT2R. In particular, the present invention generally aims to provide compounds that can modulate AT2R and AT2R-mediated signaling, such as AT2R-mediated signaling associated with the binding of an AT2R ligand (e.g., a natural ligand of AT2R such as Ang II) to AT2R (as defined herein).

[0027] The compounds provided by the present invention (also referred to herein as "compounds of the present invention") are as further described herein. Without being limited to any particular explanation, hypothesis or mechanism of action, the compounds of the present invention are such that the compounds of the present invention are one or more ligands of AT2R with respect to binding to AT2R (particularly, Ang as further described herein.

[0028] Without being limited to any particular explanation, hypothesis or mechanism of action, the compounds of the present invention are such that the compounds of the present invention are one or more ligands of AT2R with respect to binding to AT2R (particularly, Ang II) and the compounds of the present invention can modulate the binding of one or more ligands of AT2R to AT2R capable of competing with one or more natural ligands of AT2R, such as II, A is generally assumed to be capable of binding to T2R.

[0029] Also, in general, the compounds of the present invention have a preferred selectivity for AT2R (e.g., as compared to AT1R).

[0030] Furthermore, in general, based on their overall chemical structure, the compounds of the present invention are assumed to contain pharmacophores favorable for clinical applications and therapeutic uses in humans and other mammals. The compounds of the present invention may also have certain advantages with respect to safety and tolerability as compared to some of the known AT2R modulators described in the art.

[0031] Also, without being limited to any particular explanation, hypothesis or mechanism of action, it will be apparent from the present specification that the compounds of the present invention are generally capable of interacting with angiotensin type receptors, particularly angiotensin II receptor type 2. It will be apparent from the present specification that the compounds of the present invention are generally considered to be capable of interacting

[0032] In particular, the compounds of the present invention are capable of regulating (as defined herein), particularly specifically regulating (as defined herein), for example inhibiting, angiotensin II receptor type 2, AT2R-mediated signal transduction and / or the pathways and / or biological processes in which AT2R and / or AT2R-mediated signal transduction is involved. More specifically, as mentioned in the present specification, the compounds of the present invention are assumed to be able to compete with one or more natural ligands of AT2R for binding to AT2R. As mentioned herein, the compounds of the present invention are assumed to be able to compete with one or more natural ligands of AT2R for binding to AT2R.

[0033] ​​Accordingly, the present compound and its composition can regulate, in a subject in need thereof, the angiotensin II receptor type 2, AT2R mediated signal transduction and / or the pathways and / or biological processes involving AT2R and / or AT2R-mediated signal transduction by administering, to the subject, one or more pharmaceutically active amounts (e.g., dosages) of the compound of the present invention, in particular, according to an appropriate treatment or dosing regimen (determined by the treating physician based on the condition of the patient, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that can be appropriately considered), it is expected that it can also be used for the prevention and treatment of diseases and disorders that can be prevented or treated. Accordingly, the present compound and composition can be used for the prevention and treatment of diseases and disorders that can be prevented or treated by administering to a subject in need thereof a compound that can compete with the binding of one or more natural ligands to the angiotensin II receptor type 2. In particular, according to an appropriate treatment or dosing regimen (determined by the treating physician based on the condition of the patient,

[0034] the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that can be appropriately considered and determined by the treating physician), one or more pharmaceutically active amounts (e.g., dosages) of the compound of the present invention are administered, and it is further expected that it can be used for the prevention and treatment of diseases and disorders that can be prevented or treated. Without being limited to any specific explanation, hypothesis, or mechanism of action, generally, the administration of a compound that can compete with the binding of one or more natural ligands to the angiotensin II receptor type 2 to a subject results in a reduction in AT2R-mediated signal transduction related to the binding of the ligand to AT2R, and / or By administering, to the subject, one or more pharmaceutically active amounts (e.g., dosages) of the compound of the present invention, it is further expected that it can be used for the prevention and treatment of diseases and disorders that can be prevented or treated. Without being limited to any particular explanation, hypothesis, or mechanism of action, generally, the administration of a compound that can compete with the binding of one or more natural ligands to the angiotensin II receptor type 2 to a subject results in a reduction in AT2R-mediated signal transduction related to the binding of the ligand to AT2R, and / or It will be apparent to those skilled in the art that binding of the ligand to AT2R results in inhibition and / or antagonism of the pathways and / or biological processes induced and / or activated thereby. Of course.

[0035] Examples of such diseases and disorders related to AT2R, AT2R-mediated signal transduction, pathways and / or biological processes in which AT2R and / or AT2R-mediated signal transduction are involved, and / or binding of one or more natural ligands to AT2R are apparent to those skilled in the art (e.g., from the prior art cited herein), and include the use of known modulators (especially modulators that compete for ligand binding to AT2R) and / or the use of known inhibitors and / or antagonists of AT2R and / or AT2R-mediated signal transduction. Other diseases and disorders described in the art are included. For example, see also the list of AT2R-mediated diseases and disorders described in International Publication No. WO 2019 / 179515. Also see Bonas-Guarch et al., Nat. Commun., 2018 Jan 22;9(1):321 and Dominguez-Cruz et al., Gene, 2018 Nov 30;677:324-331, which describe the involvement of AT2R in diabetes, particularly type II diabetes, as follows: "This rare variant identified on chromosome Xq23 is located near the AGTR2 gene and increases the risk of T2D by approximately two-fold in men, which, to the best of our knowledge, represents a magnitude similar to that of the largest effect size identified to date in Europeans and other large-effect variants identified in other populations. We used binding and gene reporter assays to demonstrate the functional role of this variant and proposed a mechanism that may underlie the pathophysiology of T2D in T-risk allele carriers Thus, this rare variant may have supported the gain of function of AG TR2. Thus, AGTR2 is thought to be a potential therapeutic target, consistent with previous studies showing that blockade of the renin-angiotensin system in mice and humans prevents the development of T2D and restores normoglycemia.", " This gene encodes a receptor that binds to G proteins and helps angiotensin II (Ang II) mediate its actions (Harrison-Bernard, 20 09). Furthermore, the AGTR2 gene is a modulator of insulin sensitivity and previous studies have shown blockade of the renin-angiotensin system in mice (Fran tz et al., 2013; Leung, 2007) and in humans, prevention of the development of T2D and restoration of normoglycemia (Geng et al., 2013).」 Thus, the compounds of the present invention are expected to be useful for the prevention and treatment of diabetes, particularly type II diabetes

[0036] .

[0036] The present invention further relates to a composition, particularly a pharmaceutical composition, comprising at least one compound of the present invention . These compositions, further described herein, are also referred to as "compositions of the present invention".

[0037] The present invention particularly relates to pain, particularly chronic pain, such as neuropathic pain and / or inflammatory pain in various forms as further described herein, and AT2R and / or AT2R-mediated signaling ​The use of the compounds and compositions of the present invention in the prevention, treatment and / or management of other diseases or disorders related to endocannabinoid signaling (further described herein). / or management of the compounds and compositions of the present invention is related.

[0038] These and other features, aspects, embodiments, uses and advantages of the present invention will become apparent from the further description herein. will become apparent.

[0039] WO 2020 / 112905 describes compounds and methods for treating diseases using inhibitors of monoacylglycerol lipase (MAGL ), and the compounds have the following formula, where R1 is a -C(O)OR group (R 15 is hydrogen or C 15 ~C 1 ~C 6 alkyl) or a -C(O)NR R 10 R 11 group (R 10 and R 11 are each independently hydrogen or C 1 ~C 6 alkyl).

[0040] [Chemical formula]

[0041] Among the diseases mentioned are atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular diseases, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, childbirth, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic diseases, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, mastitis ... ... ... ... Post - hysterectomy pain syndrome, trigeminal neuralgia, postoperative pain, kidney deficiency blood stasis, rheumatoid arthritis, skeletal muscle contusion , skin diseases, sunburn, systemic lupus erythematosus, toothache, vaso - occlusive pain attacks in sickle cell disease , and visceral pain.

[0042] Among various MAGL inhibitors for which detailed chemical structures are listed, in International Publication No. WO2020 / 112905, page 53, paragraph

[0118] , a compound having the following formula is described .

[0043] [Chemical formula]

[0044] Neither the activity against AT2R is described nor suggested. Also, as can be seen from Formula B, the said MAGL inhibitor has a substituent (i.e., a CF group) at the meta - position with respect to the tetrazole group, and there are linking groups both between the piperazine ring and the tetrazole - substituted phenyl ring (i.e., a methylene linking group), 3 and between the piperazine ring and the carboxyl - substituted pyrazole group of Formula A. Also, in the compounds of Formula A and B, the substituted pyrazole group is linked to the rest of the molecule via a nitrogen atom rather than a carbon atom in the pyrazole ring. ,

[0045] In this specification and the claims, - When a term is not specifically defined in this specification, it has its ordinary meaning that would be apparent to a person skilled in the art. For example, standard reference books in the fields of organic chemistry and / or pharmaceutical chemistry, such as Karrer, Organic Chemistry, 3 rd Ed, 1947, Vogel, Practical Organic Chemistry rd Ed, 1947, Vogel, Practical Organic Chemistry ​​​​hemistry,3 rd Ed, 1964, Roberts and Caserio , Basic Principles of Organic Chemistry, 1 st Ed, 1965, Carey and Sundberg, Advanced O rganic Chemistry, 2 nd Ed, 1985, Michael B. S mith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 1 st E d, 2020, Jonathan Clayden, Nick Greeves, Stu art Warren, Organic Chemistry, 2 nd Ed, 2012 , D. Sriram, Medicinal Chemistry, 2 nd Ed, 201 0; and Camille Georges Wermuth, David Aldo us, Pierre Raboisson, The Practice of Medi cinal Chemistry, 4 th Ed, 2015, and, “Glossar y of terms used in medicinal chemistry (I UPAC Recommendations 1998)” by Wermuth et al., Pure and Applied Chemistry, 70(5):11 29 - 1143(1998). Please refer to it. - Certain embodiments are preferred (e.g., for the presence of certain parts or structural elements of the compounds of the present invention, and / or certain preferred substituents or combinations of substituents are preferred) When shown as such, such embodiments can be suitably combined with another embodiment described as being preferred (e.g., preferred with respect to the presence of another part or structural element of the compound of the invention and / or another preferred substituent or combination of substituents), and such a combination of preferred embodiments forms another preferred embodiment of the invention. The same applies, mutatis mutandis, to embodiments described herein by expressions such as "more preferred", "particularly preferred", "even more preferred", "most preferred" or similar / equivalent expressions. - When a structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can follow the further description of such compound / embodiment / implementation form herein, and in the absence of such further description, can be hydrogen or, optionally and independently appropriately selected from appropriate substituents (defined herein), but are usually understood to be hydrogen atoms. - When referring to "appropriate substituents" or stating that an atom or position in a compound of the invention can be "appropriately substituted", each of these substituents (and combinations thereof) can be suitably selected by a person skilled in the art, optionally after some trial and error. Appropriate substituents are apparent to a person skilled in the art based on the disclosure herein (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the invention described herein and / or shown in the experimental section below. - If the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can conform to the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can comply with the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. It should also be understood. - If the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can follow the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can comply with the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. - When the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can conform to the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When the structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula shows atoms where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not shown can comply with the further description of such compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen or, optionally and independently, can be appropriately selected from appropriate substituents (defined in this specification), but are usually understood to be hydrogen atoms. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. - When referring to "suitable substituents" or stating that an atom or position in a compound of the present invention can be "suitably substituted", each of these substituents (and their combinations) can be preferably selected by a person skilled in the art after some trial and error. Suitable substituents are apparent to a person skilled in the art based on the disclosure in this specification (optionally after some trial and error), and are, for example, substituents or combinations of substituents present in the compounds of the present invention described in this specification and / or shown in the following experimental section. including a wase (see Compounds A-01 to A-251 in Table 1). Other suitable substituents will be apparent to those skilled in the art based on the disclosure herein and, for example, halogen (i.e., F, Cl, Br and I), C 1 ~C 8 alkyl (especially C 1 ~C 4 alkyl), C 1 ~C 8 alkoxy (especially C 1 ~C 4 alkoxy), C 1 ~C 8 amine (especially C 1 ~C 4 amine), cyclo propyl, cyclobutyl, trifluoromethyl (CF 3 3), and cyano, and, for example, acid groups (i.e., to form a carbonyl group) are included (but not limited to ), and, for example, one or more substituents present in the compounds of the present invention exemplified in the following experimental section may be included (see the relevant substituents or combinations of substituents present in Compounds A-01 to A-251 in Table 1). - When a particular position in a compound of the present invention (especially a carbon atom or nitrogen atom present at that position) is said to be "optionally substituted", the atom at that position is unsubstituted or, appropriately and independently of each other, one or more suitable substituents (as defined herein ) selected from 1, 2, and up to 3 (in the case of a carbon atom) or 1 or 2 substituents (in the case of a nitrogen atom) may be appropriately substituted. The maximum number of such suitable substituents that may be present at a particular position in a compound of the present invention is the number of hydrogens carried by the atom present at that position and that can be appropriately substituted by a suitable substituent (as defined herein) and is carried by the atom that can be appropriately substituted by a suitable substituent (as defined herein) present at that position. Factors such as other atoms in the compounds of the present invention to which the atom at the position is bonded, depending on the number of elemental atoms, are also taken into account. Also, as will be apparent, the total number of substituents that may be present in or on the compounds (or any structural moiety thereof) of the present invention generally depends on the number of atoms in such compounds that are (suitably) available for such substitution (e.g., carrying hydrogen atoms that can be suitably substituted by such substituents). - Each compound of the present invention may, if desired, be in the form of a suitable salt or ester (further described herein), in particular, in the form of a pharmaceutically acceptable salt or ester (also further described herein). Examples of suitable salts will be apparent to those skilled in the art and include, but are not limited to, those mentioned in further description herein. - The compounds of the present invention (including any salts or esters thereof) may generally be in any suitable or desired physical form, e.g., a suitable crystalline form (including co-crystalline or co-crystalline salt forms), a suitable amorphous form, and / or an anhydrous or suitable hydrate or solvate (including, but not limited to, hydrates or hemihydrates). - The compounds of the present invention (or salts or esters thereof) may generally also be present in solution, e.g., in a suitable solvent or mixture of solvents such as a suitable aqueous solvent or buffer. For pharmaceutical uses, the compounds of the present invention may in particular be present in a pharmaceutically acceptable solution, which is usually (sterile) water or a pharmaceutically acceptable aqueous buffer or solution. Suitable examples of such pharmaceutically acceptable aqueous buffers or solutions will be apparent to those skilled in the art and include, but are not limited to, those mentioned in further description herein. ​​​​​​​​​​​​​​​​- The compound (or its salt or ester) of the present invention is generally in a pure or substantially pure form, isolated or substantially isolated form, or a suitable mixture with one or more other compounds. - When the compound of the present invention contains one or more chiral atoms or centers, it can be in the form of one or more different optical forms, for example, in the form of different enantiomers or different stereoisomers (e.g., in the form of two or more enantiomers or two or more diastereomers), and the terms "diastereomer" or "diastereoisomer" are generally used herein to refer to any stereoisomer that is not an enantiomer ). Generally, unless otherwise explicitly indicated or the specific context implies otherwise, when the compound of the present invention can exist in one or more such optical forms, the term "compound of the present invention" used herein refers to all such possible optical forms (e.g., all possible mirror image isomers or stereoisomers respectively), and includes them. Also, when the compound of the present invention can exist in one or more such optical forms, the term "compound of the present invention" refers to each of such optical forms in a substantially pure form (and / or substantially isolated form), as well as mixtures of two or more such possible optical forms including, but not limited to, racemic mixtures (in any ratio). - The compound of the present invention can also be in the form of a suitable prodrug, for example, a compound that is converted to the compound of the present invention upon administration to a subject and / or under physiological conditions (administered or used). For example, IYAKUHIN no KAIHATSU (Development o f Pharmaceuticals), Vol.7, Design of Molec ular Prodrugs, p.163-198 (1990); E. B. Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987); and T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series (1982). ules, p. 163 - 198, Published by HIROKAWA SHO See TEN (1990). - The compounds of the present invention can be appropriately labeled with a suitable label (for example, an atom, group, moiety or entity that can generate (can be used to generate) a detectable signal under appropriate conditions). Some specific but non - limiting embodiments of suitable labels include radioisotopes (for example, 2 2 H, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) and fluorescent or phosphorescent labels. Such labeled compounds can be used for purposes known per se using appropriate techniques for detecting the label, for example, for tissue distribution / permeation studies, as well as for PK and other pharmacological studies, and in the fields such as medical diagnosis. For example, the radioactive labeled compounds of the present invention can be used as tracers in positron emission tomography (PET) technology. - As will be apparent to those skilled in the art from further description herein, in some cases, as further shown herein, different moieties or structural elements of the compounds of the present invention can be directly linked (i.e., via a covalent bond) or via an appropriate linking group or cross - linking group. When such a linking group (also referred to herein as an "alkylene linking group") is present, it is generally a C or C alkylene group (preferably a methylene group, also referred to herein as a "methylene linking group"), and each carbon atom in the alkylene linking group can be independently and optionally appropriately substituted (the carbon atoms 1 2 preferably is a methylene group, also referred to herein as a "methylene linking group"), and each carbon atom in the alkylene linking group can be independently and optionally appropriately substituted (the carbon atoms in the alkylene linking group), and each carbon atom can be independently and optionally appropriately substituted (the carbon atoms ​​​​​​​(such as one or two methyl groups per one), preferably unsubstituted (i.e., -CH 2 - linking group). Alternatively, such an alkylene linking group may be, as further described herein, a carbonyl (i.e., -(C=O)-) group. - When an atom is substituted with a fluorine atom, the substituent is also referred to as a "fluorine" or "fluoro" substituent (the same terms apply when a carbon atom is substituted with another halogen such as chlorine or bromine). - The term "biological equivalent" when used with respect to a compound, group or moiety, has its ordinary meaning in the art and has similar physical or chemical properties, and as a result, refers to a compound, group or moiety having generally similar biological activity to the compound, group or moiety (Friedman HL(1951),NASNRS 206:295- 358). Generally, a biological equivalent obtained by substituting an atom or group of atoms with another broadly similar atom or group of atoms may have one or more enhanced properties (e.g., reduced toxicity, improved bioavailability, modified or improved activity, or improved metabolic profile) compared to the original compound, group or moiety. See, for example, Meanwell, T actics in Contemporary Drug Design pp.28 3-380, Topics in Medicinal Chemistry, Volu me 9, 2014. 3-380, Topics in Medicinal Chemistry, Volu me 9, 2014. - The term "pharmacophore" generally refers to the commonly used IUPAC definition, i.e., "a collection of steric and electronic features necessary to ensure optimal supramolecular interactions with a specific biological target and to elicit (or block) its biological response". For example, ​ "Glossary of terms used in medicinal che mistry (IUPAC Recommendations 1998)" by We rmuth et al., Pure and Applied Chemistry, 70(5):1129 - 1143(1998). See also. - The term "alkyl" is defined as a straight - or branched - chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12 carbon atoms, particularly 1 to 8 carbon atoms ("C 1 ~ 8 alkyl" or "C 1 ~C 8 alkyl"), for example 1 to 6 carbon atoms (" C 1 ~ 6 alkyl" or "C 1 ~C 6 alkyl"), for example 1 to 4 carbon atoms ("C 1 ~4 alkyl" or "C 1 ~C 4 alkyl"), more specifically having 1, 2, 3, 4, 5, 6 , 7, or 8 carbon atoms. For example, as used herein, the terms "C 1 ~ 8 alkyl" and / or "C 1 ~C 8 alkyl" refer to a straight - or branched - chain group of 1 to 8 carbon atoms (e.g., methyl, ethyl, n - propyl, isopropyl, n - butyl, isobut yl, sec - butyl, tert - butyl, n - pentyl, isopentyl, neopentyl or 1 - hexyl, 2 - hexyl, 3 - hexyl, 2 - methyl - 2 - pentyl, 4 - methyl - 2 - pentyl, 3 - methyl - 3 - pentyl, 2 - methyl - 3 - pentyl, 2,3 - dim yl...). (such as ethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.) refers to these, which are optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogen ("haloalkyl" is also called, for example, CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2 CF 3 , CH 2 Cl or CH 2 C H 2 CF 3 , etc.). The terms "C 1 ~ 4 alkyl" and "C 1 ~C 4 alkyl" refer to a straight-chain or branched-chain aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl yl). - The term "C 1 ~C 8 alkoxy" refers to an alkoxy group containing a C 1 ~C 8 alkyl group as defined herein. Similarly, the term "C ~C 1 ~C 6 alkoxy" refers to an alkoxy group containing a C alkyl group as defined herein, and the term "C 1 ~C 6 alkoxy" refers to an alkoxy group containing a C 1 ~C 4 alkyl group as defined herein. The term "C 1 ~C 4 alkoxy" refers to an alkoxy group containing a C - The term "C 1 ~C 8 amine" refers to an amine group NRF R G refers to, wherein R F and R G each is independently hydrogen or a C -C 1 -C 8 alkyl group as defined herein (provided that R F and R G are not both hydrogen). Similarly, the term "C 1 -C 6 amine" refers to an amine group NR F R G wherein R F and R G each is independently hydrogen or a C -C 1 -C 6 alkyl group as defined herein (provided that R F and R G are not both hydrogen), and the term "C -C 1 -C 4 amine" refers to an amine group NR F R G wherein R F and R G each is independently hydrogen or a C -C 1 -C 4 alkyl group as defined herein (provided that R F and R G are not both hydrogen). - The term "cycloalkyl" refers to a saturated cycloalkyl group having 3 to 6 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), preferably unsubstituted or may be substituted (as described herein), but when substituted, most preferably is appropriately substituted only with a C 1 or C 2 alkyl group (preferably 1 or 2 methyl groups ). - The term "heterocyclyl" refers to a non-aromatic ring having 3 to 10 ring atoms, preferably 3, 4, 5 or 6 ring atoms, preferably containing carbon atoms and 1 or 2 hetero atoms (each preferably selected from N, O or S), and each such hetero atom is most preferably bonded to 2 carbon atoms in the ring (and most preferably is not bonded to another hetero atom in the ring), and the non-aromatic ring may be unsubstituted or appropriately substituted (as described herein), but when substituted, most preferably is appropriately substituted only with a C or C 1 alkyl group (preferably 1 or 2 methyl groups). Some representative but non-limiting examples include pyrroline, pyrrolidine, pyrazolidine, imi 2 dazoline, tetrahydrofuran, piperidine, piperazine, morpholine. Such heterocyclyl groups may each be unsubstituted or appropriately substituted (as described herein) when present, but when substituted, most preferably is appropriately substituted only with a C or C alkyl group (preferably 1 or 2 methyl groups). Also, when such a heterocyclyl group contains one or more nitrogen atoms, each such nitrogen atom may be unsubstituted or appropriately substituted with a C alkyl group (preferably a methyl group). ~C 1 or C 2 alkyl group (preferably 1 or 2 methyl groups). Also, when such a heterocyclyl group contains one or more nitrogen atoms, each such nitrogen atom may be unsubstituted or appropriately substituted with a C alkyl group (preferably 1 or 2 methyl groups). Further, when such a heterocyclyl group contains one or more nitrogen atoms, each such nitrogen atom may be unsubstituted or appropriately substituted with a C alkyl group (preferably a methyl group). alkyl group (preferably a methyl group). 1 ~C 3 alkyl group (preferably a methyl group). - The terms "modulate", "modulation", "modulator" and "target" have their ordinary meanings in the art, and in this regard, reference is particularly made to the definitions in WO 98 / 06737. Generally, in the context of the present invention, "modulate" refers to... ​Or "for modulating" generally means reducing or inhibiting the activity of a GPCR, or increasing the activity of a GPCR, when measured using an appropriate in vitro, cellular, or in vivo assay (such as those described in the present specification). In particular, "modulating" or "for modulating" means that when measured using an appropriate in vitro, cellular, or in vivo assay (such as those referred to in the present specification), the activity of the GPCR is reduced or inhibited, or increased, by at least 1%, preferably at least 5%, for example at least 10% or at least 25%, for example at least 50%, at least 60%, at least 70%, at least 80%, or 90% or more, compared to the activity of the GPCR in the same assay under the same conditions but in the absence of the compound, amino acid sequence, or polypeptide (where applicable) of the present invention. As will be apparent to those skilled in the art, "modulating" can also result in a change (either an increase or a decrease) in the affinity, binding activity, specificity, and / or selectivity of the GPCR for one or more of its targets, ligands, or substrates, and / or a change (either an increase or a decrease) in the sensitivity of the GPCR to one or more conditions (such as pH, ionic strength, presence of cofactors, etc.) in the medium or environment in which the GPCR is present, compared to the case where the compound, amino acid sequence, or polypeptide (where applicable) of the present invention is absent under the same conditions. As will be apparent to those skilled in the art, this can also be determined by any appropriate method and / or using any appropriate assay known per se, for example, an assay described in the present specification or an assay described in the prior art cited in the present specification. As will be apparent to those skilled in the art, "modulating" can also result in a change (either an increase or a decrease) in the affinity, binding activity, specificity, and / or selectivity of the GPCR for one or more of its targets, ligands, or substrates, and / or a change (either an increase or a decrease) in the sensitivity of the GPCR to one or more conditions (such as pH, ionic strength, presence of cofactors, etc.) in the medium or environment in which the GPCR is present, compared to the case where the compound, amino acid sequence, or polypeptide (where applicable) of the present invention is absent under the same conditions. As will be apparent to those skilled in the art, this can also be determined by any appropriate method and / or using any appropriate assay known per se, for example, an assay described in the present specification or an assay described in the prior art cited in the present specification. As will be apparent to those skilled in the art, this can also be determined by any appropriate method and / or using any appropriate assay known per se, for example, an assay described in the present specification or an assay described in the prior art cited in the present specification. ​​​​​​​​ can be determined. "Modulating" also refers to one or more biological or physiological mechanisms, effects, responses, functions, pathways or activities involving a GPCR (or involving a substrate, ligand or pathway of a GPCR, e.g., its signaling or metabolic pathways and their associated biological or physiological effects) to bring about a change (i.e., acting as an agonist, antagonist, inverse agonist and / or allosteric modulator, respectively, depending on the GPCR and the desired biological or physiological effect). As will also be apparent to those skilled in the art, such an action as an agonist or antagonist can be determined by any suitable method and / or using any suitable (in vitro and usually cellular or in vivo) assay known per se, e.g., an assay described herein or an assay described in the prior art cited herein. In particular, an action as an agonist or antagonist means that the intended biological or physiological activity (e.g., but not limited to, receptor-mediated signaling etc.) is, under the same conditions, but in the same assay in which the relevant compound, amino acid sequence or polypeptide of the invention is absent, increased or decreased by at least 1%, preferably at least 5%, such as at least 10% or at least 25%, e.g., at least 50%, at least 60%, at least 70%, at least 80%, or 90% or more, respectively, compared to the biological or physiological activity in the same assay. Generally, in the context of this specification and the claims, the invention and the disclosure are not Not limited (as long as the target is modulated as described herein), thus, the modulation is , for example, but not limited to, binding at an orthosteric site or allosteric modulation (i.e., , binding at an allosteric site, e.g., George et al., Nat. Rev . Drug Discov. 1:808 - 820 (2002); Kenakin, Tre nds Pharmacol. Sci. 25:186 - 192 (2002) and Ri os et al., Pharmacol. Ther. 92:71 - 87 (2001) for reference ), reduction or inhibition of the binding of the GPCR to one of its substrates or ligands, and / or may include competition with the natural ligand or substrate for binding to the GPCR, which should be understood. The modulation may also include activation of the GPCR or the mechanism or pathway in which it is involved. The modulation can be reversible or irreversible, but for pharmaceutical and pharmacological purposes, it is usually in a reversible manner. Also, generally, a "modulator" is a compound or factor that can modulate the GPC R, which, as described herein, under physiological conditions and / or the conditions used in the relevant assays or models, biologically enhances, inhibits / reduces, or otherwise changes the functional properties of an activity or process (e.g., of the target, and / or the biological activity of the signal transduction and / or biological pathway in which the target is involved, or the biological readout related to the target or signal transduction), meaning that it can exert an influence or have an impact. In this regard, a modulator can be in vitro (e.g., as part of an assay or screening) and / or in vivo (e.g., when the modulator is administered to an animal (e.g., for veterinary purposes, or in an in vivo as part of a model), a target (i.e., a therapeutic objective, i.e., the prevention or treatment of one or more diseases in the subject that can be prevented or treated by the use of the modulator) when administered) can be used to modulate a target. A modulator or modulator candidate can be identified, tested, and / or further characterized, for example, by primary screening (e.g., screening used to identify modulators of a target from a set or library of test chemicals having unknown activity with respect to the target) and / or secondary assays (e.g., assays used to validate hits in primary screening and / or, when optimizing a hit molecule, e.g., as part of hit-to-lead) and / or a cell model or animal model that allows testing / determination of one or more relevant parameters (i.e., the parameter to be modulated), any in vitro screening or assay that includes the relevant target. For example, such an assay or screening can be configured as an in vitro assay or screening and generally includes binding of a (candidate) modulator to a target, and the signal generated by this binding is measured. Appropriate techniques for such in vitro screening are apparent to those skilled in the art and are described, for example, in Eldefrawi et al., (1987). FASEB J., Vol. 1, pages 262 - 271 and Rauh et al., (1990), Trends in Pharmacol. Sci., vol. 11, pages 325 - 329. For example, such an assay or screening can be a binding assay or screening and / or an assay used to optimize a hit molecule, e.g., as part of hit-to-lead, and / or a cell model or animal model that allows testing / determination of one or more relevant parameters (i.e., the parameter to be modulated), any in vitro screening or assay that includes the relevant target. For example, such an assay or screening can be configured as an in vitro assay or screening and generally includes binding of a (candidate) modulator to a target, and the signal generated by this binding is measured. Appropriate techniques for such in vitro screening are apparent to those skilled in the art and are described, for example, in Eldefrawi et al., (1987). FASEB J., Vol. 1, pages 262 - 271 and Rauh et al., (1990), Trends in Pharmacol. Sci., vol. 11, pages 325 - 329. For example, such an assay or screening can be a binding assay or screening and / or an assay used to optimize a hit molecule, e.g., as part of hit-to-lead, and / or a cell model or animal model that allows testing / determination of one or more relevant parameters (i.e., the parameter to be modulated), any in vitro screening or assay that includes the relevant target. For example, such an assay or screening can be configured as an in vitro assay or screening and generally includes binding of a (candidate) modulator to a target, and the signal generated by this binding is measured. Appropriate techniques for such in vitro screening are apparent to those skilled in the art and are described, for example, in Eldefrawi et al., (1987). FASEB J., Vol. 1, pages 262 - 271 and Rauh et al., (1990), Trends in Pharmacol. Sci., vol. 11, pages 325 - 329. For example, such an assay or screening can be a binding assay or screening and / or an assay used to optimize a hit molecule, e.g., as part of hit-to-lead, and / or a cell model or animal model that allows testing / determination of one or more relevant parameters (i.e., the parameter to be modulated), any in vitro screening or assay that includes the relevant target. For example, such an assay or screening can be configured as an in vitro assay or screening and generally includes binding of a (candidate) modulator to a target, and the signal generated by this binding is measured. Appropriate techniques for such in vitro screening are apparent to those skilled in the art and are described, for example, in Eldefrawi et al., (1987). FASEB J., Vol. 1, pages 262 - 271 and Rauh et al., (1990), Trends in Pharmacol. Sci., vol. 11, pages 325 - 329. For example, such an assay or screening can be a binding assay or screening and / or an assay used to optimize a hit molecule, e.g., as part of hit-to-lead, and / or a cell model or animal model that allows testing / determination of one or more relevant parameters (i.e., the parameter to be modulated), any in vitro screening or assay that includes the relevant target. For example, such an assay or screening can be configured as an in vitro assay or screening and generally includes binding of a (candidate) modulator to a target, and the signal generated by this binding is measured. Appropriate techniques for such in vitro screening are apparent to those skilled in the art and are described, for example, in Eldefrawi et al., (1987). FASEB J., Vol. 1, pages 262 - 271 and Rauh et al., (1990), Trends in Pharmacol. Sci., vol. 11, pages 325 - 329. For example, such an assay or screening can be a binding assay or screening Can be configured as a cleaning, where the (candidate) modulator is detectable from the target Used to replace a detectable ligand (e.g., a radioactive ligand or a fluorescent ligand) from the target, and based on this, the amount of ligand replaced from the target by the modulator is determined. In general, a compound is considered a modulator if it modifies or changes the relevant functional property of a biological activity or process (i.e., the signal or readout in the relevant assay or model) by at least 1 percent, for example at least 5 percent or more, compared to the value obtained when the same assay or model is performed in the absence of the (candidate) modulator. - The term "affinity" means the strength or stability of a molecular interaction. Affinity is generally given by K or the dissociation constant and has units of mol / liter (or M). Affinity can also be expressed as the association constant K which is equal to 1 / K and has units of ( mol / liter) or M Affinity can be determined by methods known per se. D or the dissociation constant and has units of mol / liter (or M). Affinity can also be expressed as the association constant K which is equal to 1 / K A and has units of ( D mol / liter) or M -1 Affinity can be determined by methods known per se. -1 - In this specification and the claims, the term "monocyclic" when referring to a ring system (such as an aliphatic ring system or an aromatic ring system) refers to a ring system that contains or consists essentially of a single ring, the ring of which appropriately contains or consists essentially of carbon atoms and optionally one or more (such as one or two) heteroatoms (the heteroatoms are preferably each independently and appropriately selected, more preferably selected from O, N and / or S). Depending on the atoms present in the ring, the monocyclic ring preferably has 3 to 10 ring atoms. - In this specification and the claims, the term "monocyclic" when referring to a ring system (such as an aliphatic ring system or an aromatic ring system) refers to a ring system that contains or consists essentially of a single ring, the ring of which appropriately contains or consists essentially of carbon atoms and optionally one or more (such as one or two) heteroatoms (the heteroatoms are preferably each independently and appropriately selected, more preferably selected from O, N and / or S). Depending on the atoms present in the ring, the monocyclic ring preferably has 3 to 10 ring atoms. ring system, the ring of which appropriately contains or consists essentially of carbon atoms and optionally one or more (such as one or two) heteroatoms (the heteroatoms are preferably each independently and appropriately selected, more preferably selected from O, N and / or S). It will also be apparent that depending on the atoms present in the ring, the monocyclic ring preferably has 3 to 10 ring atoms. N and / or S). It will also be apparent that depending on the atoms present in the ring, the monocyclic ring preferably has 3 to 10 ring atoms. ring system, the ring of which appropriately contains or consists essentially of carbon atoms and optionally one or more (such as one or two) heteroatoms (the heteroatoms are preferably each independently and appropriately selected, more preferably selected from O, , for example, 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, especially 4, 5 or 6 ring atoms can contain or consist essentially of them.

[0046] Similarly, in this specification and the claims, the term "bicyclic" means that when this term refers to a ring system (such as an aliphatic ring system or an aromatic ring system), it includes or consists essentially of two rings appropriately fused to each other (usually, two fused rings share two ring atoms, and each of the rings forming the bicyclic ring system appropriately contains or consists essentially of carbon atoms and optionally one or more (one or two) heteroatoms (the heteroatoms are preferably each independently and appropriately selected, more preferably selected from O, N and / or S)). Generally, depending on the number of atoms present in each ring, the bicyclic ring can appropriately contain or consist essentially of 8 - 12 atoms, for example , 8, 9, 10, 11 or 12 ring atoms. The fused rings in the bicyclic ring system usually share two carbon atoms, but as will be apparent to those skilled in the art, when a nitrogen atom is appropriately present, it is also possible for the fused rings to share one carbon atom and one nitrogen atom. ) The bicyclic ring system can appropriately contain or consist essentially of two aliphatic rings (in this case too, usually appropriately fused so that two fused rings share two atoms), two aromatic rings (in this case too, usually two fused rings share two atoms and the two rings in the bicyclic ring system are appropriately fused so that the whole forms a conjugated planar ring system), or can appropriately contain or consist essentially of one aromatic ring and one aliphatic ring (in this case too, usually two fused rings share two atoms )

[0047] The bicyclic ring system can appropriately contain or consist essentially of two aliphatic rings (in this case too, usually appropriately fused so that two fused rings share two atoms ), two aromatic rings (in this case too, usually two fused rings share two atoms and the two rings in the bicyclic ring system are appropriately fused so that the whole forms a conjugated planar ring system ), or can appropriately contain or consist essentially of one aromatic ring and one aliphatic ring (in this case too, usually two fused rings share two atoms appropriately contain, or consist essentially of, appropriately condensed as such) will be apparent to those skilled in the art. In this specification, for the sole purpose of convenience and without limiting the scope of the present disclosure or the claims, a bicyclic ring system containing at least one aromatic ring is generally referred to herein as an aromatic ring system regardless of whether the second ring in the ring system is aromatic or aliphatic. Similarly, as will be apparent to those skilled in the art, a bicyclic ring system can also appropriately contain two of the monocyclic ring systems referred to herein that are appropriately fused to each other (i.e., in a bicyclic ring system, two fused rings share at least two ring atoms).

[0048] Similarly, in this specification and the claims, the term "polycyclic" refers to a ring system (such as an aliphatic or aromatic ring system) that contains or consists essentially of two or more rings (such as 2, 3, 4, or 5 rings), and each ring in the ring system is appropriately and independently fused to at least one other ring in the ring system (usually such that two rings fused to each other share two ring atoms). Also in this case, in a polycyclic ring system, each of the rings forming the ring system appropriately contains or consists essentially of carbon atoms and optionally contains one or more (such as one or two) heteroatoms (the heteroatoms are preferably each independently appropriately selected and more preferably selected from O, N, and / or S). As will be apparent to those skilled in the art, the total number of ring atoms in a polycyclic ring system depends on the total number of rings in the ring system, the number of ring atoms in each ring, and the number of ring atoms shared between different rings. The fused rings in a polycyclic bicyclic ring system usually share two carbon atoms, but will be apparent to those skilled in the art. As is the case, when a nitrogen atom is appropriately present, the condensed ring can also share one carbon atom and one nitrogen atom. It is also possible.

[0049] It will also be apparent to those skilled in the art that the polycyclic ring system can appropriately contain or essentially contain only aliphatic rings, can appropriately contain or essentially contain aromatic rings, or can be appropriately composed of one or more aliphatic rings and one or more aromatic rings (in this case as well, for simplicity and without limiting the present disclosure or the claims, a polycyclic ring system containing at least one aromatic ring, regardless of whether the other rings in the system are aromatic and / or aliphatic, is generally referred to herein as an aromatic ring system). Similarly, as will be apparent to those skilled in the art, the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein. It will also be apparent to those skilled in the art that the polycyclic ring system can also be appropriately condensed with each other (i.e., in a polycyclic ring system, two rings that are condensed with each other share at least two ring atoms), and can appropriately contain two or more of the monocyclic ring systems referred to herein.

[0050] In the context of the present specification and the claims, it will also be apparent that the term "tricyclic" refers to a polycyclic ring system consisting essentially of three rings when this term refers to the polycyclic ring systems described in this specification. In the context of the present specification and the claims, it will also be apparent that the term "tricyclic" refers to a polycyclic ring system consisting essentially of three rings when this term refers to the polycyclic ring systems described in this specification. In the context of the present specification and the claims, it will also be apparent that the term "tricyclic" refers to a polycyclic ring system consisting essentially of three rings when this term refers to the polycyclic ring systems described in this specification.

[0051] Also, in the present specification and the claims, when the term "heterocyclic" refers to a ring system (such as an aliphatic or aromatic ring system), it refers to a ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S), and when the term "heteroaromatic" refers to an aromatic ring system, it refers to an aromatic ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S). Also, in the present specification and the claims, when the term "heterocyclic" refers to a ring system (such as an aliphatic or aromatic ring system), it refers to a ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S), and when the term "heteroaromatic" refers to an aromatic ring system, it refers to an aromatic ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S). Also, in the present specification and the claims, when the term "heterocyclic" refers to a ring system (such as an aliphatic or aromatic ring system), it refers to a ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S), and when the term "heteroaromatic" refers to an aromatic ring system, it refers to an aromatic ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S). Also, in the present specification and the claims, when the term "heteroaromatic" refers to an aromatic ring system, it refers to an aromatic ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S). Also, in the present specification and the claims, when the term "heteroaromatic" refers to an aromatic ring system, it refers to an aromatic ring system appropriately containing one or more heteroatoms (preferably each independently selected from N, O, or S).

[0052] In the compounds of the present invention containing the ring systems described herein, the following should be noted is. - The ring system can also be covalently bonded or linked to other parts of the compound of the present invention at any suitable position of the ring system with respect to any other structural element present in or on the ring system, for example, with respect to any heteroatom present in the ring system and / or with respect to any substituent present on the ring system. Also, when the ring system contains one or more nitrogen atoms, the ring system can be covalently bonded or linked to one or more other parts and / or structural elements of the compound of the present invention via the nitrogen atom. And / or, - Each of the atoms constituting the ring system may independently have no substituents or may be appropriately substituted (as defined herein), and the number of possible substituents on a given ring atom depends on the number of additional bonds that can be formed in addition to the bonds that the given ring atom has to other ring atoms (e.g., the number of hydrogen atoms that the ring atom can be appropriately substituted with by suitable substituents). Generally, when one or more such suitable substituents are present, they may be present at any suitable position of the ring system and may also be present with respect to any other structural element of the ring system, for example, with respect to any heteroatom present in the ring system and / or with respect to the position where the ring system is covalently bonded to other parts of the compound of the present invention. Also, when the ring system contains one or more nitrogen atoms, each of the nitrogen atoms may independently be unsubstituted or may be appropriately substituted (as defined herein), and in this case as well, the additional bonds that can be formed in addition to the bonds that the nitrogen ring atom has to other ring atoms element, for example, with respect to any heteroatom present in the ring system and / or with respect to the position where the ring system is covalently bonded to other parts of the compound of the present invention. Also, when the ring system contains one or more nitrogen atoms, each of the nitrogen atoms may independently be unsubstituted or may be appropriately substituted (as defined herein), and in this case as well, ​​​​​​​​​​​​​The number of bonds (e.g., the number of water atoms that the nitrogen atom has, which may be appropriately substituted by suitable substituents) number of elementary atoms) and / or - if the ring system contains one or more heteroatoms, each of the one or more heteroatoms is , with respect to any other structural element present in or on the ring system, e.g. For any further heteroatoms that may be present in and / or in the ring system relative to the position at which the ring system is covalently attached to other moieties of the compounds of the invention. may be in any suitable position (i.e., relative to the carbon atoms in the ring system). It is desirable or intended that one or more of the rings in the ring system containing the heteroatom of If one or more heteroatoms are present in the ring, the resulting ring may not form a conjugated planar ring system. The positions relative to the carbon atoms in the ring and any other heteroatoms in the ring so as to form In addition, if the ring system contains one or more nitrogen atoms, each of the nitrogen atoms should be These are again in addition to the bonds that the nitrogen ring atom has to other ring atoms. Depending on the number of additional bonds that can be attached, they can be appropriately substituted independently (as defined herein). (defined as

[0053] Furthermore, in the present specification and claims, the terms "aliphatic ring" and "aliphatic ring system" are defined as follows: have their ordinary meaning in the art and generally include one or more rings (monocyclic or two or more rings). It is clear that the term refers to aliphatic compounds that contain or essentially consist of the above fused rings. As used herein and conventional in the art, an aliphatic ring is an aliphatic ring. The term system means a ring system having one or more double bonds, unless the ring is an aromatic ring (as defined herein). Also included are rings and ring systems which contain double or triple bonds.

[0054] Also, the term "alicyclic" is used in this specification to refer to non-aromatic ring systems containing only carbon atoms.

[0055] Generally, as will be apparent to those skilled in the art, such aliphatic ring systems can be monocyclic, bicyclic, tricyclic or polycyclic (all described herein), and can contain only carbon atoms, or can preferably contain a suitable number (such as 1, 2, 3 or more, depending on the total number of rings in the aliphatic ring system) of heteroatoms independently selected from carbon atoms and N, S or O. It should also be noted that each atom in such an aliphatic ring system can be suitably substituted (as defined herein). The aliphatic ring system can also appropriately contain one or more double bonds (such as carbon-carbon double bonds), but for the sole purpose of convenience, without limiting the present disclosure or the claims, a ring system containing at least one aromatic ring is generally referred to as an aromatic ring system in this specification. The aliphatic ring systems described herein can also be bridged ring systems, and the terms "bridged" or "bridge" have their ordinary meanings in the art (i.e., such bridged aliphatic ring systems contain two rings sharing three or more atoms, and a bridge containing at least one atom, for example, separating two bridgehead atoms by an alkylene bridge as described herein). Such bridged aliphatic ring systems can also suitably contain one or more heteroatoms. Some specific but non-limiting examples of bridged aliphatic ring systems include bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane, and the following

[0056] The aliphatic ring systems described herein can also be bridged ring systems, and the terms "bridged" or "bridge" have their ordinary meanings in the art (i.e., such bridged aliphatic ring systems contain two rings sharing three or more atoms, and a bridge containing at least one atom, for example, separating two bridgehead atoms by an alkylene bridge as described herein). Such bridged aliphatic ring systems can also suitably contain one or more heteroatoms. Some specific but non-limiting examples of bridged aliphatic ring systems include bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane, and the following include bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane, and the following ​​​​​​​​​​​The bridged ring systems present in the compounds of the present invention exemplified in the experimental section (for example, compound A-1 See 89, A-190, A-232, and A-233). For the purposes of this specification and the claims a direct covalent bond exists between two carbon atoms in the ring, and as a result, the resulting ring system essentially contains two fused rings sharing the two connected ring atoms, a 6 membered ring, 7 membered ring, 8 membered ring, 9 membered ring, or 10 membered ring (for example, decalin or as in the bicyclic diaza structure of formula XC VIII herein) is also considered a "bridged" ring system however, in such a structure, the "bridge" consists of covalent bonds.

[0057] Some specific but non-limiting examples of aliphatic ring systems include, but are not limited to, the following. - Monocyclic aliphatic ring systems containing only carbon atoms: cycloalkanes such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, as well as cycloalkenes such as cyclopentene and cyclohexene, - Monocyclic aliphatic ring systems containing carbon atoms and nitrogen atoms: azetidine, pyrrolidine, 2 -pyrroline, 3-pyrroline, pyrazolidine, imidazolidine, 2-pyrazoline, 2-imi dazoline, piperidine, piperazine, - Monocyclic aliphatic ring systems containing carbon atoms and oxygen atoms: oxetane, tetrahydrof ran, 1,3-dioxolane, tetrahydropyran, 1,4-dioxane, 2H-pyran 4H-pyran, 1,4-dioxin, - Monocyclic aliphatic ring systems containing carbon atoms and sulfur atoms: tetrahydrothiophene (thi olane), 1,2-oxothiolane, 1,3-oxothiolane, - Monocyclic aliphatic ring systems containing carbon atoms and sulfur atoms: tetrahydrothiophene (thi olane), 1,2-oxothiolane, 1,3-oxothiolane, - Monocyclic aliphatic ring systems containing a carbon atom and two different heteroatoms: 1,2-oxa Thiolane, 1,3-oxathiolane, morpholine, thiomorpholine, 1,2-thiazine , 1,4-thiazine, - Bicyclic aliphatic ring systems containing a carbon atom and a nitrogen atom: Pyrrolidine, decahydroiso quinoline, decahydroquinoline, - Bicyclic aliphatic ring systems containing a carbon atom and a sulfur atom, - Bicyclic aliphatic ring systems containing a carbon atom and two or more different heteroatoms.

[0058] Some other examples of aliphatic rings / rings systems will be apparent to those skilled in the art based on further disclosure herein and from the compounds of the invention exemplified in the following experimental section containing such aliphatic rings / rings systems as well.

[0059] Again, when present in the compounds of the invention, such aliphatic ring systems can be appropriately covalently bonded or linked to another part (or two or more other parts) of the compounds of the invention at any suitable position of the ring system (again, depending on whether the atoms present at that position can form a covalent bond with other parts of the compounds of the invention). Also, again, each of the atoms constituting the aliphatic ring system can, independently, have no substituent or be optionally substituted (as defined herein), and the number of possible substituents on a given ring atom depends on the number of covalent bonds that can be formed in addition to the bonds that the ring atom has to other ring atoms. In this specification and the claims, the terms "aromatic ring" or "aromatic ring system" have their ordinary meanings in the art and generally refer to rings that form a conjugated planar ring system

[0060] In this specification and the claims, the terms "aromatic ring" or "aromatic ring system" have their ordinary meanings in the art and generally refer to rings that form a conjugated planar ring system and generally refer to rings that form a conjugated planar ring system ​​​will also be obvious.

[0061] Generally, as will be obvious to those skilled in the art, such aromatic ring systems can be monocyclic, bicyclic, tricyclic or polycyclic (all as described herein), and can contain only carbon atoms or , alternatively, a suitable number (such as 1, 2, 3 or more, depending on the total number of rings in the aromatic ring system) of heteroatoms (preferably each independently selected from N, S or O) can be suitably contained. It should also be noted that each atom in such an aromatic ring system can be suitably substituted (as defined herein). Also, as described herein, for simplicity, a polycyclic ring system containing one or more aliphatic rings in addition to one or more aromatic rings (for example, xanthene) is considered an aromatic ring system.

[0062] Some specific but non-limiting examples of such aromatic ring systems include, but are not limited to, the following: - Monocyclic aromatic ring systems containing only carbon atoms: phenyl, - Monocyclic aromatic ring systems containing carbon atoms and one or more nitrogen atoms: pyrrole, pyrazole - ole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole - ole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3 ,5-triazine, azepine, 1,4-diazepine, - Monocyclic aromatic ring systems containing carbon atoms and oxygen atoms: furan, - Monocyclic aromatic ring systems containing carbon atoms and sulfur atoms: thiophene, - Monocyclic aromatic ring systems containing carbon atoms and two different heteroatoms: thiazole, oxazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1, 2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,5-oxadiazole - - Bicyclic aromatic ring systems containing only carbon atoms: naphthalene, indene, 2,3-dihydro -indene, - Bicyclic aromatic ring systems containing carbon and nitrogen atoms: indole, isoindole , indoline, quinoline, isoquinoline, indolizine, indazole, benzimidazole , quinoxaline, phthalazine, quinazoline, cinnoline, 1,8-naphthyridine , pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido [3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, 4-azaindole , 5-azaindole, 6-azaindole, 7-azaindole, purine, tetrahydro quinoline, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline, - Bicyclic aromatic ring systems containing carbon and oxygen atoms: benzofuran, isobenzofuran , - Bicyclic aromatic ring systems containing carbon and sulfur atoms: benzo[c]thiophene, benzo [b]thiophene, - Bicyclic aromatic ring systems containing carbon and two or more different heteroatoms: benzo [c]isoxazole, benzo[d]isoxazole, benzo[c]thiazole, benzo [d]thiazole, benzo[d]oxazole, benzo[e][1,2]oxazine, benzo [e][1,3]oxazine, benzo[b][1,4]oxazine, - Tricyclic and polycyclic ring systems: anthracene, phenanthrene, pyrene, benzo(a) pyrene, carbazole, alloxazine, acridine, phenazine, phenoxazine, phenothiazine .

[0063] Some other examples of aromatic rings / ring systems will be apparent to those skilled in the art based on the further disclosure herein and from the compounds of the invention exemplified in the experimental section below which contain such aromatic rings / ring systems. will be apparent to those skilled in the art based on the further disclosure herein and from the compounds of the invention exemplified in the experimental section below which contain such aromatic rings / ring systems. will be apparent.

[0064] Again, when present in the compounds of the invention, such aromatic ring systems may be appropriately covalently bonded or linked to another part (or two or more other parts) of the compound of the invention at any suitable position of the ring system (again, depending on whether the ring atom can form a covalent bond in addition to the bond connecting it to another ring atom). Also in this case, each of the atoms constituting the aromatic ring system may independently be unsubstituted or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. will be apparent to those skilled in the art based on the further disclosure herein and from the compounds of the invention exemplified in the experimental section below which contain such aromatic rings / ring systems. or linked (again, depending on whether the ring atom can form a covalent bond in addition to the bond connecting it to another ring atom). Also in this case, each of the atoms constituting the aromatic ring system may independently be unsubstituted or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. depending on whether the ring atom can form a covalent bond in addition to the bond connecting it to another ring atom). Also in this case, each of the atoms constituting the aromatic ring system may independently be unsubstituted or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. or linked (again, depending on whether the ring atom can form a covalent bond in addition to the bond connecting it to another ring atom). Also in this case, each of the atoms constituting the aromatic ring system may independently be unsubstituted or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom. depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom). Also in this case, each of the atoms constituting the aromatic ring system may independently be unsubstituted or optionally substituted (as defined herein), again depending on whether the ring atom can form a covalent bond with such a substituent in addition to the bond connecting it to another ring atom.

[0065] As will be apparent to those skilled in the art, it should also be noted that the ring systems described herein may be appropriately substituted with one or more (but usually only one or two, often only one) oxygen atoms. Some specific but non-limiting examples of ring systems substituted with oxygen atoms include quinolin-2-[1H]-one and isoquinolin-1-[2H]-one. oxygen atoms. Some specific but non-limiting examples of ring systems substituted with oxygen atoms include quinolin-2-[1H]-one and isoquinolin-1-[2H]-one. oxygen atoms. Some specific but non-limiting examples of ring systems substituted with oxygen atoms include quinolin-2-[1H]-one and isoquinolin-1-[2H]-one. include quinolin-2-[1H]-one and isoquinolin-1-[2H]-one. include quinolin-2-[1H]-one and isoquinolin-1-[2H]-one.

[0066] Other examples of ring systems that may be present in the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein and include ring systems present in the compounds of the invention exemplified in the experimental section below. will be apparent to those skilled in the art based on the disclosure herein and include ring systems present in the compounds of the invention exemplified in the experimental section below.

[0067] Some of the compounds of the invention further described herein and exemplified in the experimental section below As illustrated, when the compound contains two or more rings or ring systems (these rings are not fused to a single ring system), the rings may be directly linked, suitably via a covalent bond, or indirectly linked via a suitable (unsubstituted or suitably substituted) alkylene linking group, such as a (unsubstituted or suitably substituted) methylene linking group (further defined herein). In this case, each of such alkylene linking groups may alternatively be a carbonyl group, as referred to herein). As further described herein, as part of their overall structure, the compounds of the invention generally contain an aliphatic ring (further described herein) covalently bonded to an aromatic ring (the aromatic ring is further described herein), i.e., either directly or via an alkylene linking group, particularly a methylene linking group, both as defined herein). The aromatic ring further has an acidic substituent on a carbon atom adjacent to (i.e., ortho to) the carbon atom of the ring to which the aliphatic ring is attached (the acidic substituent is further described herein and is not limited by any hypothesis or explanation, but is considered to be present in the putative binding pocket / binding site on / in the AT2R where the compound of the invention is expected to bind to the AT2R, enabling interaction or improved interaction with one or more of the amino acids in the AT2R sequence). This is schematically shown in the following scheme (Scheme A),

[0068] wherein the aliphatic ring is schematically illustrated using a 6-membered ring and the aromatic ring is schematically illustrated using a 6-membered ring (the aromaticity of the ring is schematically shown using a dashed circle).

[0069] ​​​​​​​​​​​​ [Chemical formula]

[0070] The above Scheme A also shows the numbering system for the atoms of the aliphatic ring and the aromatic ring, which is for convenience purposes only and is used in this specification and the claims without limiting the present disclosure or the claims. Also, for convenience purposes only and without limiting the present disclosure or the claims, the aliphatic ring is also referred to herein as "aliphatic ring A" or "ring A", etc., and is also denoted as "[A]", the aromatic ring is also referred to herein as "aromatic ring B" or "ring B", etc., and is also denoted as "[B]", and the acidic substituent is also referred to herein as "acidic substituent", "substituent D", etc., and is also denoted as "[D]". For further explanation and in the claims, with reference to the above Scheme A: - The position / atom in aromatic ring B indicated as "3" in the above Scheme A is generally also referred to as "the position / atom ortho to the acidic substituent". - The position / atom in aromatic ring B indicated as "4" in the above Scheme A is generally also referred to as "the position / atom meta to the acidic substituent". - The position / atom in aromatic ring B indicated as "5" in the above Scheme A is generally also referred to as "the position / atom para to the acidic substituent". In this specification and the claims, the expression "the position / atom meta to the acidic substituent" refers to the position / atom on aromatic ring B indicated as "4" in the above Scheme A.

[0071] With reference to the above Scheme A, for further explanation and in the claims: - The position / atom in aromatic ring B indicated as "3" in the above Scheme A is generally also referred to as "the position / atom ortho to the acidic substituent". - The position / atom in aromatic ring B indicated as "4" in the above Scheme A is generally also referred to as "the position / atom meta to the acidic substituent". - The position / atom in aromatic ring B indicated as "5" in the above Scheme A is generally also referred to as "the position / atom para to the acidic substituent".

[0072] In this specification and the claims, the expression "the position / atom meta to the acidic substituent" refers to the position / atom on aromatic ring B indicated as "4" in the above Scheme A. Used only for illustration (also referred to herein as "other ortho positions on the aromatic ring") (not the position / atom on aromatic ring B shown as "6" in Scheme A above). It should be noted.

[0073] Regarding aliphatic ring A, as further described herein, aliphatic ring A can be an unsubstituted or substituted (as further described herein) bridged ring system (as further described herein), or an unsubstituted or substituted (as further described herein) fused ring system, or an unsubstituted or substituted (as further described herein) spiro-type ring system, and can essentially consist of. It should also be noted that some specific but non-limiting examples of such fused ring systems or spiro-type ring systems are shown herein as Formulas LXXXV and XCII, Formulas XCVIII and Formula C, respectively.

[0074] More generally, aliphatic ring A may be a biological equivalent (as defined herein) of the ring structure of Scheme C herein, particularly the ring structure of Scheme D herein. Suitable biological equivalents will be apparent to those skilled in the art based on the disclosure herein.

[0075] Regarding aromatic ring B, when the ring B is a 5-membered ring, the same numbering system is used, and the position / atom where aromatic ring B is attached to aliphatic ring A is also shown as position "1", but it should be noted that there is no position / atom shown as "6" in Scheme A above.

[0076] Similarly, regarding aliphatic ring A, when the ring A is a 5-membered ring, the same numbering system shown in Scheme A is used, and the position / atom where aromatic ring system C is linked is again shown as position "1", but the position / atom shown as "6" in Scheme A above should be noted that there is none. Also, for the aliphatic ring A, when the ring A is a 7-membered ring the same numbering system as shown in Scheme A is used, and the position / atom where the aromatic ring system C is linked to the aliphatic ring A is shown as position "1", and in the aliphatic ring A, between position / atom "1" and position / atom "6", there is a further position / atom herein referred to as position / atom "7". Similarly, when the ring A is an 8-membered ring, as shown in Scheme A there are further position / atoms "7" and "8" between positions "1" and "6").

[0077] Also, referring to Scheme A above, this is for convenience only and without limiting the present disclosure or the scope of the claims. In further description and claims, the position / atoms on the aliphatic ring A respectively shown as "1" and "4" in Scheme A are also called the position / atoms in the ring A that are "opposite" to each other. Similarly, when the aliphatic ring A is a 5-membered ring each of position / atoms "3" and "4" is considered to be opposite to the position / atom of position "1" in the ring A. When the aliphatic ring A is a 7-membered ring each of position / atoms "4" and "5" is considered to be opposite to the position / atom of position "1" in the ring A. When the aliphatic ring A is an 8-membered ring, positions "4", "5" and "6" (especially position "5") are considered to be opposite to position "1" in the ring. When the aliphatic ring A is a 9-membered ring, positions "5

[0078] " and "6" are considered to be opposite to position "1" in the ring A. When the aliphatic ring A is a 10-membered ring positions "5", "6" and "7" (especially position "6") are considered to be opposite to position "1" in the ring A ​​​​Considered to be opposite (as further described herein, aromatic ring B is at position "1" one of the positions / atoms in ring A opposite to the atom of, i.e., the atom / position where aromatic ring system C is attached to such an 8-, 9- or 10-membered aliphatic ring A). Based on the disclosure herein, when ring A is a bridged ring system or a spiro ring system, which position / atom in ring A should be considered "opposite" to position "1" is essentially the same consideration and will be apparent to those skilled in the art.

[0079] From further description herein, the compounds of the present invention generally preferably include a second aromatic ring system (different from aromatic ring B), and this second aromatic ring system is at the position / atom on the aliphatic ring A indicated as "1" in the above formula (i.e., the position / atom "opposite" to the position / atom where aromatic ring B is attached) either directly or via an alkylene linking group, particularly a methylene linking group (both are defined herein and may be a carbonyl group as referred to herein). It will also be apparent to those skilled in the art that they are covalently bonded. Generally, again for convenience only and not limiting the present disclosure or the claims, this second aromatic ring system (further described herein) is also referred to herein as "aromatic ring system C" or "ring system C", represented as "[C]", and the position / atom on the aliphatic ring A to which the aromatic ring system C is attached is schematically shown in Scheme A above and is considered to be position "1" of the aliphatic ring A for the purpose of applying the numbering system further described in the preceding paragraph.

[0080] Thus, generally, the compounds of the present invention can be schematically represented as having the following overall structure. Scheme B:​​​​​ [Aromatic ring system C]-[Aliphatic ring A]-[Aromatic ring B] In the formula, - The aromatic ring system C, the aliphatic ring A, and the aromatic ring B are each as further described herein as follows, and - The aromatic ring system C is directly covalently bonded to the aliphatic ring A or is linked to the aliphatic ring A via an alkylene linking group ( as defined herein and which may be a carbonyl group as referred to herein), in particular a methylene linking group (as defined herein), either way it is, and - - The aliphatic ring A is directly covalently bonded to the aromatic ring B or is linked to the aromatic ring B via an alkylene linking group ( as defined herein and which may be a carbonyl group as referred to herein), in particular a methylene linking group (as defined herein), either way it is, and - The aromatic ring system C and the aromatic ring B are linked to the aliphatic ring A at opposite ring atoms within the aliphatic ring A (as further defined herein).

[0081] In particular, the compounds of the present invention can be schematically represented as having the following overall structure shown in Scheme B below, where in the formula, - The aromatic ring system C is a ring system containing one or more rings, at least one of which is an aromatic ring (all of the rings may be aromatic rings at most), and this ring system is as further described herein (optionally and appropriately substituted as further described herein). (can be). and - The aliphatic ring A has the overall structure schematically represented by the following Scheme C,

[0082] ​ [Chemical formula] In the formula, each C is a carbon atom, and each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one of the atoms Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), v and w are as further defined herein, and the R groups present and each R group present are independently as further defined herein (wherein one of the R or R bonded to the carbon chain, and one of the R or R bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, preferably, at least one of the atoms Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), v and w are as further defined herein, and the R groups present and each R group present are independently as further defined herein (wherein one of the R or R bonded to the carbon chain, and one of the R or R bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, preferably, at least one of the atoms Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), v and w are as further defined herein, and the R groups present and each R group present are independently as further defined herein (wherein one of the R or R bonded to the carbon chain, and one of the R or R bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, x and and each R y group are independently as further defined herein (wherein C (v) one of the R or R bonded to the carbon chain, and one of the R or R bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, x or R y bonded to the carbon chain, and one of the R or R (w) bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, x or R y bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, bonded to the carbon chain together form an alkylene bridge or a covalent bond, and as a result, the resulting structure is a bridged ring system or a fused ring system, both of which are as further described herein), more specifically, it is the overall structure schematically represented by the following Scheme D, i.e.,

[0083] [Chemical formula] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one of the atoms Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), and each of R to R 5 ~ R 12 is independently as further defined herein (wherein one of R 5 or R 8 and one of R or R 9 or R 12 together form an alkylene bridge or a covalent bond , As a result, the resulting structures are each a crosslinked ring system or a fused ring system, both as further described herein ), or, in the formula, the aliphatic ring A is one of the ring systems of formula XCIX or C respectively,

[0084]

Chemical formula

[0085]

Chemical formula

[0086]

Chemical formula

[0087]

Chemical formula

[0088] As will be apparent to those skilled in the art from further disclosure herein, preferred embodiments, when referring to or described herein with respect to one of the aromatic ring system C, aliphatic ring A, aromatic ring B and / or substituent D and / or any substituent or combination of substituents This preferred embodiment The sample is preferably appropriately combined with the embodiments cited or described herein as being preferred with respect to the aromatic ring system C, the aliphatic ring A, the aromatic ring B, the substituent D and / or any other substituent or combination of substituents (it should also be understood that the same applies with the necessary modifications to the embodiments cited or described herein as being "more preferred", "particularly preferred" and "most preferred" for each of the aromatic ring system C, the aliphatic ring A, the aromatic ring B, the substituent D and / or said substituent or combination of substituents). Here too, each of the aromatic ring system C, the aliphatic ring A, the aromatic ring B and the acidic substituent D, and the alkylene linking group C R

[0089] R and C (m) R A R B and C (n) R C R D (when present) and the substituents R 1 ~R 12 (when present) are each generally as further described herein obtainable and preferably each follows the preferred embodiments described herein for each of them.

[0090] Thus, as further described herein, in a first specific but non-limiting embodiment the compounds of the invention have the following structure (Formula I):

[0091]

Chemical formula

[0092]

Chemical formula

[0093]

Chemical formula

[0094]

Chemical formula

[0095] In a more specific but non-limiting embodiment, the compounds of the present invention have the following structure (Formula II ):

[0096]

Chemical formula

[0097]

Chemical formula

[0098]

Chemical formula

[0099]

Chem.

[0100] In a more specific but non-limiting embodiment, the compounds of the present invention have the following structure (Formula II I):

[0101]

Chem.

[0102]

Chem.

[0103]

Chem.

[0104]

Chem.

[0105] As further described herein, according to a preferred but non-limiting embodiment of the present invention, the compound of the present invention has the following structure (formula IV): In the formula, the aromatic ring system represented by [C], the acidic substituent represented by [D], each of X, Y and Z,

[0106]

Chem.

[0107] As further described herein, according to a more preferred but non - limiting embodiment of the present invention, the compounds of the present invention have the following structure (Formula V):

[0108]

Chemical formula

[0109] As further described herein, according to a particularly preferred but non - limiting embodiment of the present invention, the compounds of the present invention have the following structure (Formula VI):

[0110]

Chemical formula

[0111] In a specific but non-limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of formula I, formula II, formula III, formula IV, formula V and / or formula VI), - The group R 1 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 3 or C 4 cycloalkyl, CF 3 , C 1 ~C 8 alko xy, amine (-NH 2 ) or C 1 ~C 2 substituted amine (for example, dimethylamine or die thylamine) and cyano.

[0112] In another specific but non-limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of formula I, formula I I, formula III, formula IV, formula V and / or formula VI), - The group R 2 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 1 ~C 8 alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethylamine) consisting of is selected from the group.

[0113] In another specific but non-limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of formula I, formula I I, formula IV and / or formula V), - group R 3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~ 8 alkyl (e.g., sec-butyl and especially iso-butyl), e.g., flu rine-substituted methyl group (e.g., trifluoromethyl and CHF 2 ), C 1 ~C 8 alkoxy, -O-CF 3 , methoxyethyloxy (-O-(CH 2 )) 2 - O-CH 3 ) or difluoroethoxy (-O-CH 2 -CHF 2 ), cycloalkyl (e.g g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH 2 -cyclo alkyl, -O-CH 2 -cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl , -N(C 1 ~C 3 ), -NH-heteroalkyl, -N(C 1 ~C 3 ), heteroaryl (e.g., oxirane), -CH 2-heterocyclic yl, -O-CH 2 -heterocyclyl (e.g., -O-CH 2 -oxirane), -O-hetero cyclic, -NH-heterocyclic, -N(C 1 ~C 3 )-heterocyclic, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH 3 , -CH=C(CH 3 ) 2 or -CH =CH 2 ), or, allyl or methyl-substituted allyl (e.g., -CH 2 CH=CH 2 ), iso butenyl or methyl-substituted isobutenyl (e.g., =C(CH 3 )) 2 and cyano selected from the group consisting of.

[0114] In a particularly preferred embodiment of the present invention, the group R 3 is isobutyl (i.e., as in the compounds of the present invention of formula III and / or formula VI).

[0115] In a more specific but non-limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of formula I, formula I I, formula IV and / or formula V), - the group R 1 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 3 or C 4 cycloalkyl, CF 3 , C 1 ~C 8 alk oxy, amine (-NH 2 ), or C 1 ~C 2 substituted amine (e.g., dimethylamine selected from the group consisting of or diethylamine), and cyano, and / or - group R 2 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 1 ~C 8 alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethylamine) from the group consisting of, and / or - group R 3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~ 8 alkyl (e.g., sec-butyl and especially iso-butyl), e.g., flu rine-substituted methyl group (e.g., trifluoromethyl and CHF 2 ) C 1 ~C 8 alkoxy, -O-CF 3 、methoxyethyloxy (-O-(CH 2 )) 2 - O-CH 3 ) or difluoroethoxy (-O-CH 2 -CHF 2 )、cycloalkyl (e.g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH 2 -cycl loalkyl, -O-CH 2 -cycloalkyl, -O-cycloalkyl, -NH-cycloal kyl, -N(C 1 ~C 3 )-cycloalkyl, -NH-heteroalkyl, -N(C 1 ~ C 3 )-heteroalkyl, heterocyclyl (e.g., oxirane), -CH 2-heterocyclyl Krill, -O-CH 2 -heterocyclyl (e.g., -O-CH 2 -oxirane), -O- heterocyclyl, -NH-heterocyclyl, -N(C 1 ~C 3 )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH 3 , -CH=C(CH 3 ) 2 or is -CH=CH 2 ), or allyl or methyl-substituted allyl (e.g., -CH 2 CH= CH 2 ), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH 3 ) 2 ) and selected from the group consisting of cyano, and most preferably isobutyl (i.e., as in the compounds of the invention of formula I II and / or formula VI).

[0116] In particular, according to a last aspect of the compounds of the invention (in particular, the compounds of the invention of formula I, formula II, formula IV and / or formula V ), - group R 1 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 3 or C 4 cycloalkyl, CF 3 , C 1 ~C 8 alkoxy , amine (-NH 2 ), or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethyl amine), and selected from the group consisting of cyano, - group R 2is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 1 ~C 8 alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethylamine) selected from the group, - group R 3 is preferably H, halogen (F, Cl, Br or I, and preferably, F or Cl), C 1 ~ 8 alkyl (e.g., sec-butyl, and especially, iso-butyl) , e.g., fluorine-substituted methyl group (e.g., trifluoromethyl and CHF 2 ), C 1 ~C 8 alkoxy, -O-CF 3 , methoxyethyloxy (-O-(CH 2 )) 2 -O-CH 3 ), or difluoroethoxy (-O-CH 2 -CHF 2 ), cycloalkyl (e.g., cyclo propoxy, cyclobutoxy or cyclopentoxy), -CH 2 -cycloalkyl, -O -CH 2 -cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C 1 ~C 3 ))-cycloalkyl, -NH-heteroalkyl, -N(C 1 ~C 3 ))-hetero alkyl, heterocyclyl (e.g., oxirane), -CH 2 -heterocyclyl, -O-C H 2 -heterocyclyl (e.g., -O-CH2 -oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C 1 -C 3 )-heterocyclyl, vinyl or methyl substitution vinyl (e.g., -CH=CHCH 3 , -CH=C(CH 3 ) 2 or -CH=CH 2 ), or allyl or methyl-substituted allyl (e.g., -CH 2 CH=CH 2 ), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH 3 )) 2 and is selected from the group consisting of cyano, and most preferably is isobutyl (i.e., as in the compounds of the present invention of formula III and / or formula VI). )

[0117] In the compounds of the present invention described herein, when referring to the atom represented by the letter Q (e.g., as in the compounds of formulas IV, V, and VI), such an atom Q may each independently be a carbon atom or a nitrogen atom, and preferably, when there are two such atoms Q in the aliphatic ring A described herein, at least one such atom Q is a nitrogen atom, and more preferably, both such atoms Q in the aliphatic ring A are each nitrogen atoms. atom. In the compounds of the present invention described herein, when the group R is present (e.g., as in the compounds described by formulas I, II, III, IV, V, and VI), the group R is,

[0118] when present, preferably selected from the group consisting of H or halogen (F, Cl, Br, or I, preferably F or 4 Cl). II, III, IV, V, and VI), the group R 4 is, when present, preferably selected from the group consisting of H or halogen (F, Cl, Br, or I, preferably F or Cl). ​

[0119] In the compounds of the invention described herein, the group R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and / or R 12 is present (for example, as in the compounds described by Formulas IV, V, and VI), such group R , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and / or R 12 is, when present, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF 3 or isopropyl.

[0120] In the compounds of the invention described herein, the group R A , R B , R C and / or R D is present (for example, as in the compounds described by Formulas I, II, III, IV, V, and VI, it is understood that the compounds of Formulas III and IV do not contain the group R or R C or R D ), such group R , R A. , R B , R C and / or R D is, when present, independently selected from hydrogen, methyl and / or trifluoromethyl, or, when present, R R A +R B forms, together with the carbon atom to which it is attached, a carbonyl (C=O) group, and / or, R C +RD When present, they combine with the carbon atoms to which they are attached to form a carbonyl (C=O) group (in other words, R +R A +R B When present, are together replaced by a single oxygen atom such that the oxygen atom and the carbon atom to which it is attached form a carbonyl group, and / or R +R C +R D When present, are together replaced by a single oxygen atom such that the oxygen atom and the carbon atom to which it is attached together form a carbonyl group), preferably each is a hydrogen atom.

[0121] Generally, the compounds of the present invention have an affinity for AT2R (when measured according to the protocol described in Example 2 below) that is better than 1.0×10 M (i.e., better than 10 micromoles), preferably better than 1.0×10 -5 M (i.e., better than 1 micromole), more preferably better than 1.0×10 M (i.e., better than 0.1 micromole), even more preferably better than 1.0×10 -6 M (i.e., better than 10 nanomoles). In this regard, (i +R -7 +R +R -8 +R +R ) in this specification, in accordance with generally accepted scientific practice, 10 -5 is also written as "E -05", 10 -6 is also written as "E-06", etc., and , (ii) by way of example, for the purposes of this specification and the claims, for example, an affinity of 1.0× 10 -8 M (10 nanomoles) is, for example, 1.0×10 -6 M (1 micromole ) is considered to be "better" than the affinity of For example, it should be noted that an affinity of 5 nanomolar is considered to be better than an affinity of 10 nanomolar.]

[0122] Therefore, in a more specific but non-limiting embodiment, the present invention relates to the following. - A compound of the present invention (further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar. Specifically, - A compound of formula I (further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar. More specifically, - A compound of formula IV (further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar. Even more specifically, - A compound of formula IV (further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar. ​​​The compound of formula II (further described herein) is also good. More specifically, - The affinity for AT2R (measured according to the protocol described in Example 2 below) is better than 10 micromoles, preferably better than 1 micromole, and more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, for the compound of formula V (further described herein). More specifically, - The affinity for AT2R (measured according to the protocol described in Example 2 below) is better than 10 micromoles, preferably better than 1 micromole, and more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, for the compound of formula III (further described herein). More specifically, - The affinity for AT2R (measured according to the protocol described in Example 2 below) is better than 10 micromoles, preferably better than 1 micromole, and more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, for the compound of formula VI (further described herein).

[0123] In a more specific but non-limiting embodiment, the present invention relates to (i) an aromatic ring system [C], an aliphatic ring [A], an aromatic ring [B], and an acidic substituent [D], each further described herein, (ii) substituents present in such compounds of the present invention (such substituents may each independently be as further described herein for the particular substituents involved), and specific combinations of such substituents present in the compounds of the present invention, and ( and specific combinations of such substituents present in the compounds of the present invention, and ( and specific combinations of such substituents present in the compounds of the present invention, and ( iii) m and n (each independently, as described herein, may be 0 or 1) are such that the compound of the invention has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar (and such combinations), for the compounds of the invention as further described herein. In particular, the invention relates to substituents R, R, R, and R on aromatic ring [B], each (when such a substituent is present on aromatic ring [B], according to the further definitions given herein), and to specific combinations of such substituents R, R, R, and R present on aromatic ring [B], each of which is such that the compound of the invention has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar (and such combinations), for such compounds of the invention. That is, each is such that the compound of the present invention has an affinity for AT2R that is better than 10 micromoles or more, preferably better than 1 micromole or more, more preferably better than 0.1 micromole or more, and even more preferably better than 10 nanomoles or more (measured according to the protocol described in Example 2 below). (And such a combination), (further described herein) for the compounds of the present invention. In particular, the present invention relates to the substituent R on the aromatic ring [B] . 1 R 2 R 3 R 4 and R each (when such a substituent is present on the aromatic ring [B], according to the further definitions given herein), and also to the specific combination of such substituents R R 1 R 2 R 3 R 4 and R present on the aromatic ring [B], each of which is such that the compound of the present invention has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole or more, more preferably better than 0.1 micromole or more, and even more preferably better than 10 nanomoles or more (measured according to the protocol described in Example 2 below). (And such a combination), for such compounds of the present invention. In a more specific but non-limiting aspect, the present invention relates to the following. - A compound of formula I (further described herein), wherein (i) each is an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D] as further described herein, and (ii)

[0124] More specifically but non-limitingly, the present invention relates to the following. - A compound of formula I (further described herein), wherein (i) each is an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D] as further described herein, and (ii) as further described herein, and (ii) For each of X, Y, and Z present in the compound of formula I, and for specific combinations of atoms X, Y, and Z, and (iii) for substituents R present in the compound of formula I, 1 R 2 R 3 and R 4 (when present), and for each of such substituents R 1 R 2 R 3 and R 4 specific combinations, and (iv) m and n (as described herein, each independently may be 0 or 1), and (v) for substituents R A R B R C and R D (when present), and for each of such substituents R A R B R C and R D specific combinations, and (vi) any additional substituents present in such compounds of formula I (e.g., on aromatic ring system [C] and / or aliphatic ring system [A] as further described herein), and specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, even more preferably better than 10 nanomolar (measured according to the protocol described in Example 2 below), (and is such a combination), of compounds. More specifically, - a compound of formula IV (further described herein) wherein (i) each is as described herein (and is such a combination), of compounds. a compound. More specifically, - a compound of formula IV (further described herein) wherein (i) each is as described herein The further described aromatic ring system [C] and acidic substituent [D], and (ii) each atom Q (as described in the present specification, may independently be a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom), and (iii) each of X, Y, and Z present in the compound of formula IV, and specific combinations of the atoms X, Y, and Z, and (iv) the substituent R present in the compound of formula IV 1 , R 2 , R 3 and R 4 each (when present ) and specific combinations of such substituents R 1 , R 2 , R 3 and R 4 , and (v) each of the substituents R 5 ~R 12 present in the compound of formula IV (when present) and specific combinations of such substituents R like R 5 ~R 12 , and (vi) m and n (as described in the present specification, may each independently be 0 or 1), and (vii) the substituents R present in the compound of formula I V A , R B , R C and R D each (when present), and specific combinations of such substituents R A , R B , R C and R D , and (viii) any further substituents present in such a compound of formula IV (for example, on the aromatic ring system [C] ), and specific combinations of such substituents present in the compound of formula IV are, each, such that the compound of formula IV has, for AT2R, better than 10 micromoles, ​Preferably better than 1 micromole, more preferably better than 0.1 micromole and even more preferably better than 10 nanomoles of affinity (measured according to the protocol described in Example 2 below) ), of a compound (and such a combination) ). More specifically,[[]] - A compound of formula II (further described herein), wherein (i) each is an aromatic ring system [C], an aliphatic ring [A] and an acidic substituent [D] further described herein, and (ii ) the substituents R 1 , R 2 , R 3 , R 4 and R 1 (when present), each of and such substituents R 2 , R 3 , R 4 and R A specific combinations of and (iii) m and n (each independently may be 0 or 1 as described herein) ), and (iv) the substituents R B , R C , R D and R A each (when present), and such substituents R B , R C , R D and R 1 specific combinations of and (v) any further substituents present in such a compound of formula II (e.g. aromatic ring system [C] and / or aliphatic ring system [A] further described herein) above), and specific combinations of such substituents present in such a compound of formula II are each such that the compound of formula II has, for AT2R, better than 10 micromoles, Preferably better than 1 micromole, more preferably better than 0.1 micromole and even more preferably better than 10 nanomoles of affinity (measured according to the protocol described in Example 2 below ), and such a combination ), a compound. More specifically - A compound of formula V (further described herein), wherein (i) each is an aromatic ring system [C] and an acidic substituent [D] further described herein, and (ii) each atom Q (as described herein, independently may be a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom), and (iii) the substituents R in the compound of formula V ), R ), R 1 ), R 2 ), R 3 and R 4 each (if present) and such substituents R 1 ), R 2 ), R 3 and R 4 and specific combinations, and (v) the substituents R in the compound of formula V 5 ~R 12 each (if present) and such substituents R 5 ~R 12 and specific combinations, and (vi) m and n (as described herein, each may independently be 0 or 1), and (vi) the substituents R A ), R B ), R C and R D each (if present), and such substituents R A ), R B ), R C and R Dcertain combinations, and (viii) any further substituents present in such compounds of formula V (e.g., on aromatic ring system [C]), and such specific combinations of substituents present in such compounds of formula IV are each such that the compound of formula IV has an affinity for AT2R that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar (measured according to the protocol described in Example 2 below) (and is such a combination). - a compound of formula III (further described herein) comprising (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each further described herein, and (ii) the substituents R and R and R (when present) in such compound of formula III, each, and such specific combinations of such substituents R and R and R more specifically - a compound of formula III (further described herein) comprising (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each further described herein, and (ii) the substituents R and R and R 1 (when present) in such compound of formula III, each, and such specific combinations of such substituents R 2 and R 4 (when present), and (iii) m (which may be 0 or 1 as described herein), and (iii) the substituents R and R 1 (when present) in such compound of formula III, each, and such specific combinations of such substituents R 2 and R 4 (when present), and (iv) any further substituents present in such compound of formula III (e.g., on aromatic ring system [C] and / or aliphatic ring system [A] as further described herein), and such specific combinations of such substituents present in such compound of formula III - a compound of formula III (further described herein) comprising (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each further described herein, and (ii) the substituents R and R A (when present) in such compound of formula III, each, and such specific combinations of such substituents R B (when present), and (iii) m (which may be 0 or 1 as described herein), and (iii) the substituents R and R A (when present) in such compound of formula III, each, and such specific combinations of such substituents R B (when present), and (iv) any further substituents present in such compound of formula III (e.g., on aromatic ring system [C] and / or aliphatic ring system [A] as further described herein), and such specific combinations of such substituents present in such compound of formula III - a compound of formula III (further described herein) comprising (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each further described herein, and (ii) the substituents R and R Certain combinations of substituents such as those, each cause the compound of formula III to have, against the AT2R a better affinity than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) and such compounds are (and are such combinations). More specifically,[[]] - A compound of formula VI (further described herein), comprising (i) an aromatic ring system [C] and an acidic substituent [D], each further described herein and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, preferably at least one Q is a nitrogen atom), and (iii) substituents R 1 [[]] 2 [[]] 4 [[]] 1 2 [[]] 2 [[]] 4 [[]] 4 [[]]each (if present) and such substituents R 1 [[]] 2 [[]] 2 [[]] 4 [[]] 4 [[]] 4 [[]] 5 [[]] 12 [[]] 5 [[]] 12 [[]]each (if present) and such substituents R 5 [[]] 12 [[]] 12 [[]] 12 [[]] specific combinations, and (v) m (which may be 0 or 1, as described herein), and further (vi) substituents R A [[]] B [[]] B [[]]each (if present)[[]] and such substituents R A [[]] B [[]] B [[]]specific combinations, and (vii) of formula VI Any further substituents present in such compounds (e.g., on the aromatic ring system [C]), and the specific combinations of such substituents present in the compound of formula VI are each , such that the compound of formula VI has an affinity for the AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) ), and (and such combinations are ) compounds.

[0125] For the purposes of each of the above aspects of the invention and the further aspects of the invention described herein, the substituent may, to the extent permitted by the definition of the substituent, further description of the related compounds and / or the context, be a hydrogen atom (i.e., it is meant that the relevant position in the compound of the invention is unsubstituted). It should be noted.

[0126] As further described herein, the aromatic ring system C can be a monocyclic, bicyclic or polycyclic ring system, provided that at least one of the rings present in the ring system is an aromatic ring. According to a preferred embodiment, essentially all of the rings present in the aromatic ring system C are aromatic rings (although this is not essential).

[0127] Generally, as long as the aromatic ring system C contains at least one aromatic ring, it will be apparent to those skilled in the art from the description herein that the exact nature or structure of the aromatic ring system C is not important, but the aromatic ring system C is preferably a monocyclic or bicyclic ring system.

[0128] The aromatic ring system C is at the ring atoms that form part of the aromatic rings present within the aromatic ring system C and is preferably (but not necessarily) suitably linked to the aliphatic ring A (i.e., either directly or via an alkylene linking group as defined herein, in particular a methylene linking group, both as defined herein).

[0129] The ring atoms constituting the aromatic ring system C can preferably consist entirely of carbon atoms, or the aromatic ring system C can preferably contain one or more heteroatoms (where any heteroatoms present are preferably each independent, but are preferably selected from N, S or O). When the aromatic ring system C preferably contains at least one heteroatom, each of the rings constituting the aromatic ring system C can preferably contain no heteroatoms or can preferably contain one or more heteroatoms, provided that the total number of heteroatoms in the entire aromatic ring system C is at least 1.

[0130] As will be apparent to those skilled in the art, when the aromatic ring system C contains at least one heteroatom, the number of heteroatoms in the aromatic ring system C usually depends on the total number of rings in the aromatic ring system C and the number of atoms in each ring. Generally, when the aromatic ring system C contains at least one heteroatom, the 5-membered rings forming part of the aromatic ring system C can preferably contain up to 3 (e.g., 0, 1, 2 or 3) heteroatoms, and the 6-membered rings forming part of the aromatic ring system C can preferably contain up to 3 (e.g., 0, 1, 2 or 3) heteroatoms, provided that the total number of heteroatoms in the entire aromatic ring system C is at least 1. When the aromatic ring system C is a bicyclic or polycyclic ring system, it is possible for two rings within the ring system to share a nitrogen atom. ​​​​​​​​​​​​​​​In addition, when the aromatic ring system C contains at least one heteroatom and is a monocyclic ring, In this case, the total number of heteroatoms in the aromatic ring system C may suitably be 1, 2 or 3. Generally, when the aromatic ring system C contains two or more heteroatoms, the heteroatoms are preferably may be the same or different (again, as noted herein, preferably or at least one of the heteroatoms is a nitrogen atom.

[0131] As can be seen from the various formulae given herein, the aromatic ring system C is an atomic group in the aliphatic ring A. The atom Q to which the aromatic ring system C is attached is a nitrogen atom. In some cases, the aromatic ring system C is joined to the aromatic ring system C not through a nitrogen atom in the aromatic ring system C (i.e. In the case where the aromatic ring system C contains at least one nitrogen atom, preferably (this carbon atom is preferably an aromatic carbon atom, as referred to herein) forms part of an aromatic ring in the aromatic ring system C, but this is also not critical) and linked (i.e. directly or via an alkylene linking group as defined herein, in particular either through a methylene linking group, both as defined herein), which is The compound to be used is generally one in which the aromatic ring system C is connected to such a nitrogen atom in the aromatic ring system C. For pharmaceutical use, unless linked to the remainder of the molecule via a carbonyl linking group This is because it is assumed that the ion exchange rate is not sufficiently stable.

[0132] In a preferred, but non-limiting embodiment, this embodiment is achieved by the use of compounds of the invention as shown in the experimental section below. The aromatic ring system C is also illustrated by some of the non-limiting examples: containing a heteroatom (preferably, at least one of said heteroatoms is a nitrogen atom) ), (ii) at a carbon atom within an aromatic ring system C that forms part of an aromatic ring within the aromatic ring system C (where the aromatic ring system C is a monocyclic ring, this ring essentially forms the aromatic ring system C), linked to the aliphatic ring A (i.e., either directly via a covalent bond or via an alkylene linking group further described herein ), such that, (iii) further, the aromatic ring to which the aliphatic ring A is linked (i.e., in addition to the carbon atom to which the aliphatic ring A is linked) contains at least one (e.g., 1 or 2) heteroatom selected from N, S, and O (preferably, at least one of said heteroatoms is a nitrogen atom).

[0133] Examples of aromatic ring systems that can exist as aromatic ring system C in the compounds of the present invention will be apparent to those skilled in the art based on the disclosure herein and generally include monocyclic, bicyclic, and polycyclic aromatic ring systems as referred to herein.

[0134] Some preferred but non-limiting examples of aromatic ring systems that can exist as aromatic ring system C in the compounds of the present invention will be apparent to those skilled in the art based on further disclosure herein and include the following.

[0135] An unsubstituted or appropriately substituted pyrazolyl group (e.g., a pyrazol-3-yl group), for example, - 2,5-dimethylpyrazol-3-yl, - 1-methylpyrazol-3-yl, - 2-methylpyrazol-3-yl,

[0136] An unsubstituted or substituted imidazolyl group (e.g., an imidazol-2-yl group or imidazole -4-yl group), for example, - 1-methylimidazol-2-yl, - 1-methylimidazol-4-yl, - 3-methylimidazol-4-yl, - 2,3-dimethylimidazol-4-yl,

[0137] unsubstituted or substituted triazolyl group (e.g., 1,2,4-triazol-3-yl group), for example, - 4-methyl-1,2,4-triazol-3-yl,

[0138] pyrazinyl group, unsubstituted or substituted pyrimidinyl group (e.g., 2-pyrimidinyl or 4-pyrimidinyl group), for example for example, - 2-pyrimidine, - 4-[2-methyl]-pyrimidine,

[0139] unsubstituted or substituted pyridazinyl group (e.g., 3-pyridazinyl group), for example, - 6-methyl-3-pyridazine, - 5-methyl-3-pyridazine, - 6-methoxy-3-pyridazine,

[0140] unsubstituted or substituted pyridyl group (e.g., 2-pyridyl group), for example, - 4-chloro-2-pyridyl, - 5-chloro-2-pyridyl, - 3-chloro-2-pyridyl, - 4-methoxy-2-pyridyl, - 5-methoxy-2-pyridyl, - 4-fluoro-2-pyridyl, - 5-fluoro-2-pyridyl, - 4-methoxy-3,5-dimethyl-2-pyridyl, - 3,5-dimethyl-2-pyridyl, - 3-methoxy-2-pyridyl, - 5-Methyl-2-pyridyl, - 4-(Trifluoromethyl)-2-pyridyl, - 3-Methyl-2-pyridyl, - 4-Methyl-2-pyridyl, - 5-Chloro-3-fluoro-2-pyridyl, - 4-Methoxy-3-methyl-2-pyridyl, - 3-Chloro-5-fluoro-2-pyridyl, - 4,5-Dimethoxy-2-pyridyl, - 4-Chloro-5-fluoro-2-pyridyl, - 3,5-Difluoro-2-pyridyl,

[0141] Unsubstituted or substituted indazole group, for example, - 1-Methyl-indazole,

[0142] Unsubstituted or substituted imidazo[1,2-a]pyridine group, for example, - Imidazo[1,2-a]pyridine,

[0143] Unsubstituted or substituted quinoline group, for example, - 2-Quinoline,

[0144] Unsubstituted or substituted quinazoline group, for example, - 2-Quinazoline,

[0145] Unsubstituted or substituted quinoxaline group, for example, - 2-Methyl-3-quinoxaline,

[0146] Unsubstituted or substituted oxazole group (for example, 1,4-oxazole group), for example, - 1,4-Oxazole,

[0147] Unsubstituted or substituted isoxazole group (for example, isoxazole group), for example, - 5-Methyl-isoxazole,

[0148] Unsubstituted or substituted oxadiazole group (e.g., 1,2,4-oxadiazole group), for example for example - 1,2,4-oxadiazole, - 3-methyl-1,2,4-oxadiazole, - 5-methyl-1,2,4-oxadiazole, - 5-methyl-1,3,4-oxadiazole,

[0149] Unsubstituted or substituted benzoxazole group (e.g., 1,3-benzoxazole group), for example , - 2-[1,3-benzoxazole],

[0150] Unsubstituted or substituted oxazolopyridine group (e.g., oxazolo[4,5-b]pyridine group ), for example, - oxazolo[4,5-b]pyridine,

[0151] Unsubstituted or substituted thiazole group (e.g., 2-thiazole group or 4-thiazole group), for example for example - 5-methyl-4-thiazole, - 5-methyl-2-thiazole, - 2-methyl-thiazole,

[0152] Unsubstituted or substituted benzothiazolyl group (e.g., 1,3-benzothiazol-2-yl group ), for example, - 1,3-benzothiazol-2-yl,

[0153] Unsubstituted or substituted pyrimidinone group (e.g., pyrimidin-4-one group), for example, - 2-methyl-1H-pyrimidin-4-one, - 6-methyl-1H-pyrimidin-4-one,

[0154] Unsubstituted or substituted quinazolin-4-one group (e.g., quinazolin-4-one group), for example , - quinazolin-4-one, - 2-ethyl-3-quinazolin-4-one,

[0155] unsubstituted or substituted quinolinone group (e.g., quinolin-2-one group), for example, - 1-methyl-quinolin-2-one,

[0156] unsubstituted or substituted bicyclic pyrimidinone group, for example, - 1-methyl-7H-pyrazolo[3,4-d]pyrimidin-4-one, - 8-methyl-pyrido[1,2-a]pyrimidin-4-one, - 1-methyl-pyrazolo[1,5-a]pyrimidin-7-one, - pyrido[1,2-a]pyrimidin-4-one, - 6-methyl-pyrido[1,2-a]pyrimidin-4-one, - 3-methyl-thiazolo[3,2-a]pyrimidin-5-one.

[0157] As will be apparent to those skilled in the art based on the disclosure herein, aromatic ring system C may also be appropriately substituted by one or more (e.g., 1, 2, 3, or 4) appropriate substituents at one or more ( e.g., 1, 2, 3, or 4) appropriate positions / ring atoms of aromatic ring system C with appropriate substituents (defined herein). Appropriate substituents will be apparent to those skilled in the art and include, for example, the substituents present on aromatic ring system C in the compounds of the invention described in the experimental section below, as well as other appropriate substituents mentioned herein. In specific but non-limiting embodiments of the invention, aromatic ring system C does not have a carboxylic acid (COOH) group. e.g., 1, 2, 3, or 4) of the invention as described in the experimental section below, as well as other appropriate substituents mentioned herein. In specific but non-limiting embodiments of the invention, aromatic ring system C does not have a carboxylic acid (COOH) group. As will be apparent to those skilled in the art based on the disclosure herein, aromatic ring system C may also be appropriately substituted by one or more (e.g., 1, 2, 3, or 4) appropriate substituents at one or more ( e.g., 1, 2, 3, or 4) appropriate positions / ring atoms of aromatic ring system C with appropriate substituents (defined herein). Appropriate substituents will be apparent to those skilled in the art and include, for example, the substituents present on aromatic ring system C in the compounds of the invention described in the experimental section below, as well as other appropriate substituents mentioned herein. In specific but non-limiting embodiments of the invention, aromatic ring system C does not have a carboxylic acid (COOH) group. As will be apparent to those skilled in the art based on the disclosure herein, aromatic ring system C may also be appropriately substituted by one or more (e.g., 1, 2, 3, or 4) appropriate substituents at one or more ( e.g., 1, 2, 3, or 4) appropriate positions / ring atoms of aromatic ring system C with appropriate substituents (defined herein). Appropriate substituents will be apparent to those skilled in the art and include, for example, the substituents present on aromatic ring system C in the compounds of the invention described in the experimental section below, as well as other appropriate substituents mentioned herein. In specific but non-limiting embodiments of the invention, aromatic ring system C does not have a carboxylic acid (COOH) group.

[0158] As generally mentioned herein, the total number of appropriate substituents on aromatic ring system C is generally not critical and usually depends on the size of aromatic ring system C and the number of ring atoms in aromatic ring system C. As generally mentioned herein, the total number of appropriate substituents on aromatic ring system C is generally not critical and usually depends on the size of aromatic ring system C and the number of ring atoms in aromatic ring system C. It exists. Usually, the total number of substituents is as follows. - When the aromatic ring system C is a monocyclic 5-membered ring, it is 0, 1, 2 or 3, preferably 0, 1 or 2, - When the aromatic ring system C is a monocyclic 6-membered ring, it is 0, 1, 2 or 3, preferably 0, 1 or 2, - When the aromatic ring system C is a bicyclic ring system, it is 0, 1, 2, 3, 4 or 5, preferably 0 、1, 2 or 3.

[0159] According to a specific but non-limiting embodiment, each of one or more substituents on the aromatic ring system C is 、methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, cyano / nitrile 、halogen atom (especially fluorine or chlorine), C 1 ~C 4 amine or oxygen atom, each appropriately and independently selected from one or more of them (that is, the oxygen is linked to the carbon atom to form a carbonyl group together, and the carbon atom can form such a carbonyl group ). ).

[0160] In one non-limiting embodiment of the present invention, the aromatic ring system C is any of the following. - A monocyclic 5- or 6-membered aromatic ring system, preferably a monocyclic 5- or 6-membered aromatic ring system containing at least one nitrogen atom, or or - A bicyclic aromatic ring system (as defined herein) in which each ring is a 5- and / or 6-membered aromatic ring (that is, the whole bicyclic ring system forms a conjugated planar ring system), preferably, each ring is a 5- or 6-membered aromatic ring, and the aromatic ring to which the aliphatic ring [A] is linked contains at least one nitrogen atom in the bicyclic aromatic ring system.

[0161] As already generally described herein for the aromatic ring system C, the aromatic ring system C is respectively a monocyclic or bicyclic aromatic ring system composed of one or two 5-membered rings and / or 6-membered rings wherein, when present, at least one heteroatom (each such heteroatom is preferably independent, but is suitably selected from O, N or S, and preferably at least one of the heteroatoms present is a nitrogen atom) is suitably included, and the total number of heteroatoms in the aromatic ring system C is in the case of a monocyclic ring system, preferably 1 or 2, and in the case of a bicyclic ring system, preferably 1, 2, 3 or 4. Also, as exemplified by some of the non-limiting examples of the compounds of the present invention shown in the experimental section below, such an aromatic ring system C composed of one or two 5-membered rings and / or 6-membered rings respectively is preferably further such that an aliphatic ring A is linked to a carbon atom within the aromatic ring system C (i.e., either directly via a covalent bond or via an alkylene linking group further described herein), and this carbon atom forms part of an aromatic ring within the aromatic ring system C (this ring essentially forms the aromatic ring system C when the aromatic ring system C is a monocyclic ring), where this aromatic ring, in addition to this one carbon atom to which the aliphatic ring A is linked, contains at least one (e.g., one or two) heteroatoms selected from N, S and O (preferably at least one of the heteroatoms present is a nitrogen atom).

[0162] Some non-limiting examples of aromatic ring systems that can exist as the aromatic ring system C in the compounds of the present invention include the following ((i) in Tables A, B, C and D below, when the atoms "A" or "Q" and the groups R, R1, R2, R3 and R4 are referred to, such Atoms A and Q and such groups R, R1, R2, R3, and R4 are as defined in Tables A - D herein, (ii) the definitions of atoms A and Q and groups R, R1, R2, R3, and R4 given in Tables A - D below apply only to the structures shown in said tables and are not to be understood as applying to any other atoms, groups, structures, or formulas described in this specification). as defined in the following Tables A - D, and (ii) the definitions of atoms A and Q and groups R, R1, R2, R3, and R4 given in the following Tables A - D apply only to the structures shown in said tables and are not to be understood as applying to any other atoms, groups, structures, or formulas described in this specification). as defined in the following Tables A - D, and (ii) the definitions of atoms A and Q and groups R, R1, R2, R3, and R4 given in the following Tables A - D apply only to the structures shown in said tables and are not to be understood as applying to any other atoms, groups, structures, or formulas described in this specification). It should be understood that they do not apply to any other atoms, groups, structures, or formulas described in this specification). ).

[0163] [Table 1]

[0164] [Table 2]

[0165] [Table 3] Some specific examples include the following ring systems.

[0166] [Table 4]

[0167] [Table 5] Some preferred examples include the following ring systems.

[0168] [Table 6] The following ring systems are particularly preferred.

[0169] [Table 7]

[0170] Thus, according to one non-limiting aspect of the present invention, the aromatic ring system C is of formula VII - LXX selected from the group consisting of aromatic rings / rings systems of XIII.

[0171] According to a preferred but non-limiting embodiment of the present invention, the aromatic ring system C is of formula LIX - LXXXI selected from the group consisting of aromatic rings / rings systems of II.

[0172] According to a particularly preferred but non-limiting embodiment of the present invention, the aromatic ring system C is of formula LXXIII - selected from the group consisting of aromatic rings / rings systems of LXXXIII.

[0173] Thus, in a further aspect, the present invention relates to the following. - A compound of the present invention (further described herein), wherein the aromatic ring system C is of formula VI selected from the group consisting of aromatic rings / rings systems of I - LXXXIII, preferably of formula LIX - LXXXI selected from the group consisting of aromatic rings / rings systems of II, more preferably of formula LXXIII - LXXXIII selected from the group consisting of aromatic rings / rings systems of, a compound, Specifically, - A compound of formula I (further described herein), wherein the aromatic ring system C is of formula VII selected from the group consisting of aromatic rings / rings systems of ~ LXXXIII, preferably of formula LIX - LXXXII selected from the group consisting of aromatic rings / rings systems of I, more preferably of formula LXXIII - LXXXIII selected from the group consisting of aromatic rings / rings systems of, a compound, Even more specifically, - A compound of formula IV (further described herein), wherein the aromatic ring system C is of formula VI selected from the group consisting of aromatic rings / rings systems of I - LXXXIII, preferably of formula LIX - LXXXI selected from the group consisting of aromatic rings / rings systems of II, more preferably of formula LXXIII - LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - A compound of formula II (further described herein), wherein aromatic ring system C is of formula VI Selected from the group consisting of aromatic rings / ring systems of I to LXXXIII, preferably of formula LIX to LXXXI Selected from the group consisting of aromatic rings / ring systems of II, more preferably of formula LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - A compound of formula V (further described herein), wherein aromatic ring system C is of formula VII Selected from the group consisting of aromatic rings / ring systems of ~LXXXIII, preferably of formula LIX to LXXXII Selected from the group consisting of aromatic rings / ring systems of I, more preferably of formula LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - A compound of formula III (further described herein), wherein aromatic ring system C is of formula V Selected from the group consisting of aromatic rings / ring systems of II to LXXXIII, preferably of formula LIX to LXXX Selected from the group consisting of aromatic rings / ring systems of III, more preferably of formula LXXIII to LXXXII A compound selected from the group consisting of aromatic rings / ring systems of I, More specifically, - A compound of formula VI (further described herein), wherein aromatic ring system C is of formula VI Selected from the group consisting of aromatic rings / ring systems of I to LXXXIII, preferably of formula LIX to LXXXI Selected from the group consisting of aromatic rings / ring systems of II, more preferably of formula LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, Here, such a compound of the present invention (i.e., the compound of the present invention according to any of the foregoing aspects) preferably further has such a compound having, with respect to AT2R, 10 micromolar ​ Better than Ru, preferably better than 1 micromole, more preferably better than 0.1 micromole Better than Ru, even more preferably better than 10 nanomoles of affinity (measured according to the protocol described in Example 2 below) (as described further in the specification). As further described in the specification).

[0174] As generally described in the present specification, for each of the aromatic rings / rings systems represented by Formulas VII to LXXXIII respectively, when such a ring or ring system is present as the aromatic ring system C in the compounds of the present invention, such an aromatic ring or ring system may be appropriately substituted with one or more (e.g., 1, 2 or 3) additional substituents (wherein suitable substituents will be apparent to those skilled in the art and include, for example, the substituents present on the aromatic ring system C in the compounds of the present invention exemplified in the experimental section below, as well as other suitable substituents described in the present specification) (or, in the case of an aromatic ring of Formulas VII to LXXXIII already having one or more substituents, may be appropriately further substituted is not excluded). However, for each of the aromatic rings / rings systems represented by Formulas VII to LXXXIII, particularly when such an aromatic ring or ring system is shown to already have one or more substituents in one of Formulas VII to LXXXIII, it is generally preferred that these exist as the aromatic ring system C in the compounds of the present invention that do not have such (additional) substituents. Also, in a specific but non-limiting embodiment of the present invention the aromatic ring system C does not have a carboxylic acid (COOH) group. Therefore, preferably, the aromatic ring or rings present as the aromatic ring system C in the compounds of the present invention In the case of an aromatic ring of Formulas VII to LXXXIII already having one or more substituents, may be appropriately further substituted it is generally preferred that these exist as the aromatic ring system C in the compounds of the present invention that do not have such (additional) substituents. Also, in a specific but non-limiting embodiment of the present invention the aromatic ring system C does not have a carboxylic acid (COOH) group. Therefore, preferably, the aromatic ring or

[0175] rings present as the aromatic ring system C in the compounds of the present invention The ring system preferably consists of an aromatic ring / ring system having the structures described in Formulas VII - LXXXIII. One of them, more preferably, an aromatic ring / ring system having the structures described in Formulas LIX - LXXXIII, and most preferably, an aromatic ring / ring system consisting of one of the structures described in Formulas LXXIII - LXXXIII.

[0176] Some specific but non - limiting examples of the compounds of the present invention containing the aromatic ring system C described herein (including particularly preferred such compounds of the present invention) will be apparent to those skilled in the art based on the disclosure of this specification and / or as exemplified in the following experimental section as follows.

[0177] As mentioned herein, the aromatic ring C is directly connected via a covalent bond, but preferably or via an alkylene linking group (as defined herein and which may be a carbonyl group as mentioned herein), particularly a methylene linking group (as defined herein), to an aliphatic ring which is further described and referred to herein as the "aliphatic ring A" or "ring A", and is also represented as "[A]".

[0178] The aliphatic ring A is generally a 5 - membered, 6 - membered, 7 - membered, 8 - membered, 9 - membered or 10 - membered ring, preferably a 5 - membered, 6 - membered or 7 - membered ring, most preferably a 6 - membered ring, and the ring consists essentially of carbon atoms and one or more (e.g., 1 or 2) heteroatoms (which, when present, are preferably each independently selected from O, S and N, but most preferably, as further described herein, nitrogen atoms). Also, the aliphatic ring A may appropriately have one or more double bonds (provided that the presence of these bonds does not make the aliphatic ring A an aromatic ring system) as appropriate. While the possibility of containing is not excluded, preferably, a compound containing the unsaturated ring A is usually expected to be not sufficiently stable in pharmaceutical uses, so the ring A is completely saturated (i.e., there is no double bond in the ring).

[0179] The aliphatic ring A is preferably a monocyclic ring, but as further described herein, the aliphatic ring A contains a total of 7 to 12 atoms (including alkylene bridges), preferably a total of 7, 8 or 9 atoms (including alkylene bridges), and forms part of a "bicyclic" structure, and an appropriate alkylene bridge (defined herein) containing 1 or 2 carbon atoms is appropriately included, and it may be a bridged monocyclic ring. For example, without limitation, the aliphatic ring A is a cyclohexane, piperidine or piperazine ring containing an appropriate alkylene bridge (defined herein) containing 1 or 2 carbon atoms (e.g., 3,8-diazabicyclo [3.2.1]octane and 2,5-diazabicyclo[2.2.1]heptane (see also Formulas LXXXV and XCII herein) etc., which appropriately bridges positions "2" and "6", positions "2" and "5", positions "3" and "6" or positions "3" and "5" in the aliphatic ring A ). In the following experimental section, Compounds A-189 and A-190 provide some specific but non-limiting examples of the compounds of the present invention containing a bridged aliphatic ring A. Also, as generally mentioned herein, two of the ring atoms appropriately "bridge" by a covalent bond so as to form a system containing two fused rings sharing the two "bridging" atoms, and aliphatic 5-membered, 6-membered, 7-membered, 8-membered, 9-membered and 10-membered aliphatic ring systems (e.g., the aliphatic ring system of Formula X CVIII and the aliphatic ring systems present in Compounds A-232 and A-233 . As generally mentioned in this specification, two of the ring atoms appropriately "bridge" by a covalent bond so as to form a system containing two fused rings sharing the two "bridging" atoms, and aliphatic 5-membered, 6-membered, 7-membered, 8-membered, 9-membered and 10-membered aliphatic ring systems (e.g., the aliphatic ring system of Formula X CVIII and the aliphatic ring systems present in Compounds A-232 and A-233 ). is also considered to be a crosslinked ring structure for the purposes of this specification and the claims. Such a crosslinked ring structure or fused ring structure, if present, is also optionally and suitably substituted with one or more substituents independently selected from the substituents referred to herein for groups R x or R y or R 5 ~R 12 respectively. Aliphatic ring A is also exemplified by, for example, a spiro-type structure represented by the following formula C,

[0180] such as a spiro-type structure (preferably having any such spiro structure containing a total of 7 to 10 atoms). Such a spiro-type structure, if present, is also optionally and suitably substituted with one or more substituents independently selected from the substituents referred to herein for groups R or R and / or R x or R y and / or R 5 ~R 12 respectively. As further described herein, aliphatic ring A is preferably such that aromatic ring system C is linked to aliphatic ring A via an alkylene linking group (where aromatic ring B is directly linked to aliphatic ring A),

[0181] or aromatic ring B is linked to aliphatic ring A via an alkylene linking group (where aromatic ring system C is directly linked to aliphatic ring A), more preferably such that aromatic ring system C is linked to aliphatic ring A via an alkylene linking group (where aromatic ring B is directly linked to aliphatic ring A), linked to aromatic ring system C (either directly or via an alkylene linking group as further described herein), and also linked to aromatic ring B (here too, either directly or via an alkylene linking group as further described herein), more preferably such that aromatic ring system C is linked to aliphatic ring A via an alkylene linking group (where aromatic ring B is directly linked to aliphatic ring A), linked to aromatic ring system C (either directly or via an alkylene linking group as further described herein), is linked via an alkylene linking group further described in the specification. As used herein As described herein, when present, the alkylene linking group is preferably a methylene linking group (i.e., in Formulas I-VI, represented as "C (m) R A R B " and "C (n) R C R D ", respectively). Also, as mentioned herein, when such a linking group is present, it may be a carbonyl group instead of a methylene group (i.e., C ( m) R A R B or C (n) R C R D is C=O).

[0182] Also, as further described herein, aromatic ring system C and aromatic ring B are most preferably opposite each other in the aliphatic ring A and are linked to the aliphatic ring A at atoms in the aliphatic ring A (as defined herein).

[0183] Also, as further described herein, the aliphatic ring A preferably contains at least one nitrogen atom, and the nitrogen atom is linked to the aromatic ring system C or aromatic ring B either directly or via a methylene linking group further described herein. More preferably, the aliphatic ring A contains two nitrogen atoms, one of the nitrogen atoms being linked to the aromatic ring system C either directly or via a methylene linking group further described herein, and the other of the nitrogen atoms being linked to the aromatic ring B either directly or via a methylene linking group further described herein. Again, when the aliphatic ring A has one such nitrogen atom or ​​​​​​ When containing two such nitrogen atoms, the aromatic ring system C and the aromatic ring B are each linked The ring atoms in the ring A to which they are attached are most preferably located opposite to each other in the aliphatic ring A (as defined in this specification).

[0184] In a specific but non-limiting preferred embodiment, the aliphatic ring A described in this specification consists of carbon atoms and 0, 1 or 2 (preferably 1 or 2, more preferably 2) nitrogen atoms, and in particular, the aliphatic ring A has a total of 5, 6 or 7 (preferably 6) ring atoms (excluding any carbon atoms present in the alkylene bridge if an alkylene bridge is present), such that it contains. Thus, generally, the aliphatic ring A can have an overall structure that can be schematically represented as follows (Scheme C):

[0185] (Scheme C):

[0186]

Chemical formula

[0187] Also, as described and exemplified herein, ring A may be an alkylene bridge (see herein). (also defined in Scheme C, but not shown in Scheme C) or a covalent bond (also defined in Scheme C, but not shown in Scheme C) (not shown in the figure) in which the aryl group is preferably a ring bridged by One end of the alkylene bridge or covalent bond is C (v) The carbon atoms constituting the carbon chain represented by and the other end of the alkylene bridge or covalent bond is linked to one of (w) Table by As will be appreciated by those skilled in the art, When ring A is bridged by an alkylene bridge, C (v) R on the carbon chain represented by x or R y One of the following: (w) R on the carbon chain represented by x or R y Of is substituted by an alkylene bridge and ring A is bridged by a covalent bond, C (v) R on the carbon chain represented by x or R y One of the above, and C (w) Represented by R on the carbon chain x or R yOne of them is replaced by said covalent bond.

[0188] Most preferably, ring A is not substituted by an oxygen atom (i.e., such that the oxygen forms a carbonyl group with the ring carbon atom to which it is attached). ).

[0189] As described above, ring A may also be exemplified by, for example, a spiro-type structure represented by the following formula C. As exemplified, it may be a spiro-type structure (preferably having such a spiro structure containing a total of 7 to 10 atoms). Considering the number of available (remaining) covalent bonds on each carbon atom present in such a spiro structure, if possible, each carbon atom in such a spiro-type structure may also appropriately have group R as defined herein and / or group R as defined herein. x and / or group R y appropriately.

[0190] Referring to Scheme C and Scheme D, the aliphatic ring A is linked to the aromatic ring system C at one of the atoms Q in the aliphatic ring A and is also linked to the aromatic ring B at another one of the atoms Q in the aliphatic ring A. For this purpose, the two atoms Q are preferably in opposite positions to each other in the aliphatic ring A (further defined herein). For example, when the aliphatic ring A is a 6-membered ring, the aromatic ring system C is preferably linked to the ring atom of the aliphatic ring A at position "1", and the aromatic ring B is preferably linked to the ring atom of the aliphatic ring A at position "4" (the numbering of positions / atoms in the aliphatic ring A is as described herein). Similarly, when the aliphatic ring A is a 7-membered ring, the aromatic ring system C is preferably linked to the ring atom of the aliphatic ring A at position "1", and the aromatic ring B is preferably linked to the ring atom of the aliphatic ring A at position "4" or (the numbering of positions / atoms in the aliphatic ring A is as described herein). "1", and the aromatic ring B is preferably linked to the ring atom of the aliphatic ring A at position "4" (the numbering of positions / atoms in the aliphatic ring A is as described herein). ). ). Similarly, when the aliphatic ring A is a 7-membered ring, the aromatic ring system C is preferably linked to the ring atom of the aliphatic ring A at position "1", and the aromatic ring B is preferably linked to the ring atom of the aliphatic ring A at position "4" or ​is attached to the ring atom of the aliphatic ring A at position "5" (the position / atom in the aliphatic ring A numbering is as described herein).

[0191] Also, as further described herein, the aliphatic ring A is directly attached to the aromatic ring system C (i.e., , via a covalent bond between one of the atoms Q and a ring atom in the aromatic ring system C), or an alkylene linking group that links an atom Q in the aliphatic ring A to a ring atom in the aromatic ring system C (as defined herein), in particular a methylene linking group (as defined herein), may be linked (as further described herein, the said ring atom in the aromatic ring system C is preferably a carbon atom present in the aromatic ring in the aromatic ring system C, and this aromatic ring preferably contains at least one heteroatom, in particular at least one nitrogen atom). Also, as further described herein, the aliphatic ring A is directly attached to the aromatic ring B (i.e., via a covalent bond between another atom Q and a ring atom in the aromatic ring B), or an alkylene linking group that links another atom Q in the aliphatic ring A to a ring atom in the aromatic ring B (as defined herein), in particular a methylene linking group (as defined herein), may be linked (as further described herein , the said ring atom in the aromatic ring B is in the ortho position with respect to the acidic substituent D). In the above formulas I-V I, this is respectively represented by "-C R I where, m may be 0 or 1, and n may be 0 or 1 (each of (m) R A R B -", and "-C (n) R C R D - ", where m may be 0 or 1, and n may be 0 or 1 (each of m = 0 or n = 0, meaning that a direct covalent bond exists), and as a result , the sum of m + n may be 2, 1, or 0. Most preferably, at least one such alkylene linking group (as defined herein), particularly at least one such meth ylene linking group (as defined herein) is present, and m = 1 and n = 0, or m = 0 and n = 1, meaning that the sum of m + n is 1 or 0 (where m and n are both either 0 or 1, and the sum of m + n is either 0 or 2 respectively, which is less preferred). According to a particularly preferred embodiment, m = 1 and n = 0 ( as in the case of the structures of Formulas III and VI).

[0192] According to a preferred embodiment of the ring represented by Scheme C where v is 2 and w is 2, it will be apparent to those skilled in the art that the aliphatic ring A is a 6-membered ring. In such a 6-membered ring , each carbon atom is preferably independently optionally (independently) substituted with one or two suitable substituents selected from hydrogen, methyl, ethyl, halogen (particularly fluorine ( F)), CF 3 and isopropyl.

[0193] Such a 6-membered ring can also be schematically represented by the following structure (Scheme D) , where the optional substituents are shown as R 5 ~R 12 :

[0194] [Chemical Structure Diagram] wherein, - Each Q is independently a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom, more preferably both Q atoms are nitrogen atoms, - R 5 , R​​6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each of which is preferably independently selected from hydrogen, methyl, ethyl, halogen (especially fluorine (F)), CF 3 and isopropyl pyril.

[0195] By way of some preferred but non-limiting examples, the aliphatic ring A is, for example, - a (optionally appropriately substituted) cyclohexane ring, wherein the aromatic ring system C is linked at the "1" position of the cyclohexane ring (i.e., either directly or via an alkylene linking group, especially a methylene linking group, both as defined herein), the aromatic ring B is linked at the "4" position of the cyclohexane ring (i.e., either directly or via an alk ylene linking group, especially a methylene linking group, both as defined herein ), and may be a cyclohexane ring, Specifically, - a (optionally appropriately substituted) piperidine ring, wherein the aromatic ring system C is piper linked to the nitrogen atom of the idine ring (i.e., either directly or via an alkylene linking group as defined herein ), and the aromatic ring B is linked at the "4" position of the piperidine ring (i.e., either directly or via an alkylene linking group, especially a methylene linking group, either of which is defined herein) (or vice versa, where the aromatic ring B is linked to the nitrogen atom and the aromatic ring system C is linked at the "4" position), and may be a piperidine ring, More specifically, - a (optionally appropriately substituted) piperazine ring, wherein the aromatic ring system C is "1 is linked to the nitrogen atom at the " " position (i.e., either directly or via an alkylene linking group, particularly a methylene linking group, both of which are defined herein), and aromatic ring B is linked to the nitrogen atom at the "4" position of the piperazine ring (i.e., either directly or via an alkylene linking group, particularly a methylene linking group, both of which are defined herein), and may be a piperazine ring. As described herein, as an alternative to the structure of Scheme C or Scheme D, aliphatic

[0196] ring A may be one of the ring systems of Formula XCIX or C: In the formula, when the ring system of Formula XCIX or Formula C exists, each is preferably independently

[0197]

Chemical formula

[0198] Some non-limiting examples of aliphatic rings that may be present in the compounds of the present invention as aliphatic ring A include the following. are as follows.

[0199]

Table 8

[0200]

Table 9

[0201] Based on the disclosure herein and the compounds of the present invention exemplified in the following experimental section, those skilled in the art will clearly As is clear, the aliphatic ring A (in its various embodiments disclosed herein) may be un substituted or substituted. As will be apparent to those skilled in the art, when the aliphatic ring A is unsubstituted each R in Scheme C x and R y and each R in Scheme D 5 ~R 12 is a hydrogen atom.

[0202] Also, as mentioned herein, when the aliphatic ring A is substituted, each substituent present is generally independently selected from the group consisting of methyl, ethyl, fluoro (F), CF 3 and isopropyl (preferably independently selected from the group consisting of methyl, ethyl and isopropyl ). Thus, generally, as will be apparent to those skilled in the art, when the aliphatic ring A is substituted, each R in Scheme C and R and each R in Scheme D x and R y and each R in Scheme D ~R 5 ~R 12 is independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF 3 and isopropyl (preferably independently selected from the group consisting of methyl, ethyl and isopropyl), provided that (i) with respect to Scheme C, at least one of the groups R and R x and R y is selected from the group consisting of methyl, ethyl, fluoro (F), CF 3 and isopropyl (preferably selected from the group consisting of methyl, ethyl and isopropyl ), and / or (ii) with respect to Scheme D, the groups R 5 ~R 1 2At least one of them is methyl, ethyl, fluoro (F), CF 3 and isopropyl selected from the group consisting of (preferably selected from the group consisting of methyl, ethyl and isopropyl selected).

[0203] When the aliphatic ring A is substituted with two or more substituents described herein, the substituents may preferably be the same or different. Also, each of the substituents may appropriately be present on different carbon atoms in the aliphatic ring A, but it is also possible for one carbon atom in the aliphatic ring A to appropriately have two such substituents (provided that such a carbon atom can appropriately have two substituents). Also, those skilled in the art will appreciate that when a carbon atom in the aliphatic ring A has a single substituent, such a carbon atom may also appropriately have a hydrogen atom as well.

[0204] Those skilled in the art will also appreciate that the maximum number of substituents that can be present on the aliphatic ring A depends on the number of carbon atoms present in the aliphatic ring A and the number of substituents that each such carbon atom can have will also be apparent. Thus, by way of example and not limitation, in the 6-membered aliphatic ring A schematically represented by Scheme D, the maximum number of substituents that can be present on ring A is 8 (i.e., when each of R ~R 5 ~R 12 is a substituent described herein).

[0205] Generally but not limitedly, the total number of substituents on ring A is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, more preferably 0, 1 or 2. Here too, as described herein, such substituents may be the same or different Although it can be present on different carbon atoms in the aliphatic ring A, one carbon atom in the aliphatic ring A can appropriately have two such substituents (however, such a carbon atom can appropriately have two substituents). In one embodiment, although specific but non-limiting, the total number of substituents on the ring A is 0, 1, 2, 3 or 4 (preferably 0, 1 or 2), and any substituent present on the aliphatic ring A is preferably

[0206] independently selected from methyl, ethyl and isopropyl (preferably methyl). Here too, as described herein, such substituents may be the same or different and can be present on different carbon atoms in the aliphatic ring A, but one carbon atom in the aliphatic ring A can appropriately have two such substituents (however, such a carbon atom can appropriately have two substituents). Some preferred but non-limiting examples of the compounds of the present invention in which the aliphatic ring A is substituted are shown in the following experimental section as compounds A-173 to A-188, compounds A-216 to A-218, compounds A-222 to A -224 and compounds A-226 to A-229. It should be noted that the aliphatic ring A in other compounds of the present invention can be substituted in the same manner as in one of compounds A-173 to A-188, compounds A -216 to A-218, compounds A-222 to A-224 and compounds A-226 to A-22 9 (i.e., having the same substituent on the same carbon atom). (In other words, other compounds of the present invention are compounds A-173 to A-188, compounds A-216 to A-218, compounds A-222 It is also possible to have two such substituents (however, such a carbon atom can appropriately have two substituents).

[0207] Some preferred but non-limiting examples of the compounds of the present invention in which the aliphatic ring A is substituted are shown in the following experimental section as compounds A-173 to A-188, compounds A-216 to A-218, compounds A-222 to A -224 and compounds A-226 to A-229. It should be noted that the aliphatic ring A in other compounds of the present invention can be substituted in the same manner as in one of compounds A-173 to A-188, compounds A -216 to A-218, compounds A-222 to A-224 and compounds A-226 to A-22 9 (i.e., having the same substituent on the same carbon atom). (In other words, other compounds of the present invention -216 to A-218, compounds A-222 to A-224 and compounds A-226 to A-22 9 (i.e., having the same substituent on the same carbon atom). It should be noted that (in other words, other compounds of the present invention are compounds A-173 to A-188, compounds A-216 to A-218, compounds A-222 -216 to A-218, compounds A-222 to A-224 and compounds A-226 to A-22 ~A-224 and a substituted aliphatic ring present in one of the compounds such as compound A-226~A-229 (which may contain the same substituted aliphatic ring A as the aliphatic ring A).

[0208] Also, when the aliphatic ring A is substituted with one or more substituents described herein, the substituents may be appropriately present on any carbon atom in the aliphatic ring A that can appropriately have one or more such substituents. According to one specific but non-limiting embodiment, when the aliphatic ring A is substituted with one or more substituents described herein, at least one of these substituents is present on a carbon atom adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked in the ring A. According to a still more specific but non-limiting embodiment, when the aliphatic ring A has 1, 2, 3 or 4 such substituents (described herein), especially when it has 1 or 2 such substituents, all such substituents are appropriately present on one or both of the carbon atoms adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked in the ring A. Here too, such substituents are preferably independently selected from methyl, ethyl and isopropyl, and most preferably methyl. (preferably the nitrogen atom). According to an even more specific but non-limiting embodiment, in the compounds of the present invention, the aliphatic ring A is unsubstituted or substituted with 1 or 2 substituents (preferably 1 substituent) selected from methyl, ethyl and isopropyl (preferably methyl), and the substituent is present on a carbon atom in the aliphatic ring A adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked. (described herein). In the ring A, on one or both of the carbon atoms adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked. Here too, such substituents are preferably independently selected from methyl, ethyl and isopropyl, and most preferably methyl. preferably methyl. Such substituents are preferably independently selected from methyl, ethyl and isopropyl, and most preferably methyl. preferably methyl.

[0209] In an even more specific embodiment, in the compounds of the present invention, the aliphatic ring A is unsubstituted or substituted with 1 or 2 substituents (preferably 1 substituent) selected from methyl, ethyl and isopropyl (preferably methyl), and the substituent is present on a carbon atom in the aliphatic ring A adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked. (preferably the nitrogen atom). In the aliphatic ring A, on the carbon atom adjacent to the carbon or nitrogen atom (preferably the nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is linked. (preferably the nitrogen atom).

[0210] A further aspect of the invention relates to a compound of the invention (in particular, a compound of formula I, II, III, IV, V or VI), wherein the aliphatic ring A is unsubstituted or substituted as described herein (in particular, as described in the preceding paragraph), and such a compound of the invention preferably further has an affinity for AT2R that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar (measured according to the protocol described in Example 2 below), and the rest is as further described in this specification. Some specific but non-limiting examples of the compounds of the invention containing the aliphatic ring A described herein (including particularly preferred such compounds of the invention) will be apparent to those skilled in the art based on the disclosure herein and / or as exemplified in the experimental section below. As described herein, the aromatic ring B is generally a 6-membered aromatic ring containing carbon atoms and may optionally (and appropriately) contain 1, 2 or 3 nitrogen atoms, provided that the aromatic ring B may still have an acidic substituent D in the ortho position with respect to the aliphatic ring A (i.e., as further described herein). Also, when the aromatic ring B contains more than one nitrogen atom, preferably, on the aromatic ring B (i.e., at the position on the aromatic ring B described herein as preferred for such substituents)

[0211]

[0212] ​​​​​​​​​​​​​​​Or may still have one or more substituents or combinations of such substituents described herein as being present, more preferably on aromatic ring B (i.e., for such substituents, respectively, especially or most preferably at the positions on aromatic ring B described herein ), and may still have one or more substituents or combinations of such substituents described herein as being present, respectively, especially or most preferably at the positions on aromatic ring B described herein. Or may still have one or more substituents or combinations of such substituents described herein as being present, respectively, especially or most preferably such that it can still have one or more substituents or combinations of such substituents described herein as being present, more preferably on aromatic ring B

[0213] Some preferred examples of aromatic rings capable of forming a 6-membered ring within aromatic ring B are phenyl (benzene), pyridin-2-yl, and 1,4-pyrimidin-2-yl, and phenyl is most preferred. As described herein, most preferably, aromatic ring B is a 6-membered ring, but in the present invention

[0214] it is not excluded that, in its broadest sense, aromatic ring B can be a 5-membered aromatic ring (optionally and appropriately containing 1 or 2 heteroatoms selected from O, N, or S), provided that such a 5-membered aromatic ring is preferably such that it can still have one or more substituents or combinations of such substituents described herein as being present on the 6-membered aromatic ring B and more preferably, when such a 5-membered aromatic ring is present instead of the 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a biological equivalent of the 6-membered aromatic ring B described herein, more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme E, and even more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme F and may still have one or more substituents or combinations of such substituents described herein as being present on the 6-membered aromatic ring B. Or may still have one or more substituents or combinations of such substituents described herein as being present on the 6-membered aromatic ring B and more preferably, when such a 5-membered aromatic ring is present instead of the 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a biological equivalent of the 6-membered aromatic ring B described herein, more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme E, and even more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme F and more preferably, when such a 5-membered aromatic ring is present instead of the 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a biological equivalent of the 6-membered aromatic ring B described herein, more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme E, and even more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme F and more preferably, when such a 5-membered aromatic ring is present instead of the 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a biological equivalent of the 6-membered aromatic ring B described herein, more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme E, and even more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme F and more preferably, when such a 5-membered aromatic ring is present instead of the 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a biological equivalent of the 6-membered aromatic ring B described herein, more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme E, and even more preferably a biological equivalent of the 6-membered aromatic ring B represented by Scheme F Biological equivalents of the aromatic ring B, most preferably the 6-membered aromatic ring B represented by Scheme G are biological equivalents of

[0215] When a bicyclic aromatic ring system is used as the aromatic ring B, it is often difficult to obtain compounds that cannot appropriately contain the preferred substituents (such as an isobutyl group at the 5-position and one fluorine at the 3- or 4-position) described herein for the aromatic ring B. Therefore, the aromatic ring B is most preferably a monocyclic ring such as those described herein (e.g., an isobutyl group at the 5-position and one fluorine at the 3- or 4-position) For this reason, many compounds are obtained that cannot appropriately contain the preferred substituents (such as an isobutyl group at the 5-position and one fluorine at the 3- or 4-position) described herein for the aromatic ring B. Therefore, the aromatic ring B is most preferably a monocyclic ring and is most preferably a monocyclic ring

[0216] As further described herein, the aromatic ring B has an acidic substituent (i.e., acidic substituent D) on the carbon atom of ring B adjacent to the carbon atom to which the aliphatic ring A is attached to the aromatic ring B The acidic substituent D can be any suitable acidic group or substituent (suitable groups / substituents will be apparent to those skilled in the art after some trial and error, optionally, based on the disclosure of this specification) and may be, preferably, a carboxylic acid group (i.e., -C(=O)-OH group), an acylsulfonamide group (e.g., but not limited to, the general formula CONHSO R or SO NHCOR, wherein R is -C ~C 2 alkyl, CH 2 ~C 1 ~C 8 alkyl, CH 2 (C 1 ~C 8 cycloal kyl), CH 2 (heterocyclyl having 1 to 6 ring atoms), C 1 ~C 8 alkoxy or is C 1 ~C 8 amine, an acylsulfonamide group), a tetrazole group or a biological equivalent of a tetrazole group (as defined herein) (e.g., but not limited to, 4H - selected from the group consisting of a (1,2,4 - oxadiazol - 5 - one group), more preferably a tetrazole or a bioequivalent thereof, and most preferably a tetrazole.

[0217] Also, as further described herein, aromatic ring B is preferably methyl, ethyl, propyl, isopropyl, cyclopropyl, methylcyclopropyl, n - butyl, sec - butyl, isobutyl, cyclobutyl, methylcyclobutyl, vinyl, allyl, isobutene nyl, trifluoromethyl, methoxy, ethoxy, n - propoxy, isopropoxy, i sobutoxy, difluoroethoxy, methoxyethyloxy, fluorine, chlorine, cyano, ox ysilane, cyclopropoxy, cyclobutoxy, cyclopentoxy, N - acetyl, substituted and unsubstituted carbamoyl, and has at least one additional substituent selected from the group consisting of When this substituent (if present) is most preferably on a carbon atom in ring B that is para to the position in ring B of the carbon atom to which acidic substituent D is attached (for example, when aromatic ring B is a 6 - membered aromatic ring such as a phenyl ring, the "5" position according to the numbering system used), in which case the substituent is substituent R as shown in the following schemes E and F and in further schemes and formulas provided herein to form. The substituent is preferably an i 3 sobutyl group and is exemplified by the compounds of formulas III and VI, for example.

[0218] As further described herein, acidic substituent [D] and methyl, ethyl, propi l, isopropyl, n - butyl, sec - butyl, isobutyl, methoxy, ethoxy, n - propoxy, isopropoxy, methylmethoxy, and the like selected from the group consisting of In addition to one further substituent which, as referred to herein, is preferably isobutyl and is in the para position to the acidic substituent D, the aromatic ring B may optionally be further appropriately substituted with one or more (such as one or two) suitable substituents (as defined herein), and such substituents are shown as R in Schemes E - G and Formulas I - V I herein. I. 1 R 2 and R 4 as shown.

[0219] Thus, by way of a specific but non - limiting embodiment, the aromatic ring B may have the general structure schematically represented as follows (Scheme E): In the formula,

[0220]

Chemical formula

[0221] Preferably, only one of X, Y and Z is a nitrogen atom (the others of X, Y and Z are carbon atoms), more preferably only one of Y and Z is a nitrogen atom (X is a carbon atom and the others of Y and Z are also carbon atoms), even more preferably Z is a nitrogen atom (both X and Y are carbon atoms). Most preferably, all of X, Y and Z are carbon atoms (i.e., ring B is a substituted phenyl ring without nitrogen atoms).

[0222] According to a preferred but non-limiting embodiment, the aromatic ring B can be generally represented by the following overall structure (Scheme F):

[0223]

Chemical formula

[0224] In a particularly preferred but non-limiting embodiment, aromatic ring B can be generally represented as follows having the overall structure (Scheme G):

[0225]

Chemical formula

[0226] ​The compounds of the present invention containing the aromatic ring B described in this specification (some specific but non-limiting such compounds of the present invention) include, but are not limited to, some examples that will be apparent to those skilled in the art based on the disclosure of this specification and / or as exemplified in the following experimental section as follows.

[0227] In a specific but non-limiting embodiment, the present invention relates to compounds of formula I:

[0228]

Chemical formula

[0229]

Chemical Structure

[0230]

Chemical Formula

[0231]

Chemical Formula

[0232] As further described herein, in certain embodiments, the invention relates to compounds of formula I having an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar. In more specific embodiments, the invention relates to (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each further described herein, and (ii) each of X, Y, and Z present in the compound of formula I, and a specific combination of atoms X, Y, and Z, and (iii) the substituents R 1 R 2 R 3 R 4 (when present), each, and a specific combination of such substituents R 1 R 2 R 3 R 4 0 or 1, as described herein, and (v) the substituents R A R B R C R D (when present), each, and a specific combination of such substituents R A R B R C R D ​​​​​​​​​​​The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. On the aliphatic ring system [A]), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I. The substituents thus formed (for example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and the specific combinations of such substituents present in the compound of formula I are each such that the compound of formula I has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and are such combinations), and relate to compounds of formula I.

[0233] More specifically but without limitation, the present invention relates to compounds of formula II:

[0234]

Chemical formula

[0235]

Chemical formula

[0236]

Chemical formula

[0237] [Chemical formula] In the formula, when present, the respective ring systems of formula XCIX or formula C are each preferably independently hydrogen, methyl, ethyl, fluorine (F), CF 3 and may be optionally and suitably substituted with one or more suitable substituents selected from the group consisting of isopropyl, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group (for example, general formula CONHSO R or SO 2 NHCOR, wherein R is -C 2 ~C 1 ~C 8 alkyl, C H 2 (C 1 ~C 8 cycloalkyl), CH 2 (heterocyclyl having 1 to 6 ring atoms ), C 1 ~C 8 alkoxy or C 1 ~C 8 an acylsulfonamide group which is an amine), tet razole group or a group which is a biological equivalent of a tetrazole group (as defined herein) (e.g for example, but not limited to, 4H-1,2,4-oxadiazol-5-one group) selected from the group and is more preferably tetrazole or its biological equivalent, and most preferably tetrazole, - R 1 is H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~ C8 Alkyl, C 3 or C 4 Cycloalkyl, CF 3 , C 1 ~C 8 Alkoxy, amine( -NH 2 ) or C 1 ~C 2 Substituted amine (e.g., dimethylamine or diethylamine) and Selected from the group consisting of cyano, -R 2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~ C 8 Alkyl, C 1 ~C 8 Alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~ C 2 Selected from the group consisting of substituted amine (e.g., dimethylamine or diethylamine) , -R 3 is H, halogen (F, Cl, Br or I, and preferably, F or Cl), C 1 ~ 8 Alkyl (e.g., sec-butyl, and especially, iso-butyl), e.g., fluorine Substituted methyl group (e.g., trifluoromethyl and CHF 2 ), C 1 ~C 8 Alkoxy, - O-CF 3 , methoxyethyloxy (-O-(CH 2 )) 2 -O-CH 3 ) or difluoro Ethoxy (-O-CH 2 -CHF 2 )), cycloalkyl (e.g., cyclopropoxy, cy clobutoxy or cyclopentoxy), -CH 2 -cycloalkyl, -O-CH 2 -cyclo Lower alkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C 1 ~C 3 )-si Chloroalkyl, -NH-heteroalkyl, -N(C 1 ~C 3 )-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH 2 -heterocyclyl, -O-CH 2 -hetero si Cryl (e.g., -O-CH 2 -oxirane), -O-heterocyclyl, -NH-hetero Cyclyl, -N(C 1 -C 3 )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., , -CH=CHCH 3 , -CH=C(CH 3 ) 2 Or -CH=CH 2 ), or allyl or Methyl-substituted allyl (e.g., -CH 2 CH=CH 2 ), isobutenyl or methyl-substituted iso Butenyl (e.g., =C(CH 3 ) 2 ) and selected from the group consisting of cyano, most preferably Is isobutyl, -R 4 Is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl). As further described herein, the present invention, in certain embodiments, has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, of the formula II thereof

[0238] As further described herein, the present invention, in certain embodiments, has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, of the formula II thereof Is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, of the formula II thereof Is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, of the formula II thereof Is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, of the formula II thereof relates to compounds such as. In a more specific embodiment, the present invention provides (i) each of which is further described herein the aromatic ring system [C], aliphatic ring [A] and acidic substituent [D] described in, and (ii) the substituent R present in the compound of formula II 1 R 2 R 3 and R 4 (when present) each respectively, and such substituents R 1 R 2 R 3 and R 4 and specific combinations of, and (i ii) m and n (as described herein, each may independently be 0 or 1 ), and (iv) the substituents R present in the compound of formula II A R B R C and R D each (when present), and such substituents R A R B R C and R D D and specific combinations of, and (v) any further substituents present in such compounds of formula II (e.g. such as those further described herein on the aromatic ring system [C] and / or aliphatic ring system [A] ), and specific combinations of such substituents present in the compound of formula II are such that each, the compound of formula II has an affinity for AT2R that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar and even more preferably better than 10 nanomolar (measured according to the protocol described in Example 2 below ), and (and such combinations are), compounds of formula II (further described herein).

[0239] ​ In a more specific, but non-limiting embodiment, the present invention relates to a compound of formula III:

[0240] [ka] During the ceremony, [C] is a monocyclic or polycyclic, preferably monocyclic or bicyclic, aromatic ring system, (i) the aromatic ring system contains at least one aromatic ring, and (ii) the aromatic ring system contains at least one aromatic ring. through a carbon atom present in at least one aromatic ring (i.e., directly through a covalent bond) or, if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) said at least one bond (either through At least one aromatic ring (i.e., an aromatic ring containing the carbon atom to which the remainder of the compound of formula III is attached) is The aromatic ring preferably contains at least one (e.g., one or two) heteroatoms. The atoms (if present) are preferably each independently suitably selected from N, S and O. and more preferably, at least one of the heteroatoms, if present, is a nitrogen atom. The aromatic ring system represented as [C] is preferably an aromatic ring system of the formulae VII to LXXXIII From the group consisting of rings / ring systems, more preferably from the aromatic rings / ring systems of the formulae LIX to LXXXIII From the group consisting of: still more preferably from the aromatic rings / ring systems of the formulae LXXIII to LXXXIII and an aromatic ring or ring system selected from the group consisting of: m is 1 or 0, - R A and R B Each of, when present, is selected from hydrogen, methyl and / or trifluoromethyl. are independently selected from RA +R B When present, they are combined with a carbon atom to form a carbonyl (C=O) group (in other words, R A. +R B are combined to be substituted by a single oxygen atom, and the carbon atom to which the oxygen atom is bonded forms a carbonyl group), preferably each is a hydrogen atom, - [A] is any of the ring systems schematically represented by the following Scheme C,

[0241]

Chemical formula

[0242]

Chemical formula

[0243]

Chemical formula

[0244] As further described herein, the present invention, in certain embodiments, has an affinity for AT2R measured according to the protocol described in Example 2 below) that is better than 10 micromoles, preferably better than 1 micromole, more preferably 0.1 micromole ​Better than molar, and more preferably better than 10 nanomolar, of formula III Relating to such compounds. In a more specific embodiment, the present invention provides (i) each of which is described herein Further described aromatic ring system [C], aliphatic ring [A] and acidic substituent [D], and (ii ) Substituents R present in the compound of formula III 1 , R 2 And R 4 (When present) each , And such substituents R 1 , R 2 And R 4 Of specific combinations, and (iii) m (As described herein, may be 0 or 1), and (iii) the substituents R present in the compound of formula II I And R A And R B Each (when present), and such Substituents R A And R B Of specific combinations, and (iv) any further substituents present in such compounds of formula III (For example, on the aromatic ring system [C] and / or aliphatic ring system [A] further described herein), and such in the compound of formula III Specific combinations of substituents are such that the compound of formula III is, for AT2R Has an affinity better than 10 micromolar, preferably better than 1 micromolar, more preferably Preferably better than 0.1 micromolar, even more preferably better than 10 nanomolar (Measured according to the protocol described in Example 2 below) such that (And such combinations), compounds of formula III (further described herein Described).

[0245] In another preferred but non-limiting embodiment, the present invention relates to compounds of formula IV:

[0246] [Chemical formula] wherein, - [C] is a monocyclic or polycyclic (preferably monocyclic or bicyclic) aromatic ring system, (i) The aromatic ring system contains at least one aromatic ring, (ii) the aromatic ring system is linked to the remainder of the compound of formula IV via a carbon atom present in at least one aromatic ring (i.e., directly via a covalent bond, or if an alkylene linking group is present, (m) the alkylene linking group -C A R B -), and (iii) at least one of the at least one aromatic ring (i.e., the aromatic ring containing the carbon atom to which the remainder of the compound of formula IV is linked) preferably contains at least one (e.g., 1 or 2) heteroatom, and the heteroatom(s) (if present) are preferably each independently appropriately selected from N, S, and O, more preferably, at least one of the heteroatom(s) (if present) is a nitrogen atom, and the aromatic ring system represented as [C] is preferably selected from the group consisting of aromatic rings / ring systems of formulas VII - LXXXIII, more preferably selected from the group consisting of aromatic rings / ring systems of formulas LIX - LXXXIII, even more preferably selected from the group consisting of aromatic rings / ring systems of formulas LXXIII - LXXXIII, - m is 1 or 0, n is 1 or 0, and the sum of m and n is either 2, 1, or 0, preferably 1 or 0 (when m = 0, R A. and R B do not exist; when n = 0, R C and R Dis understood to be absent), and m is preferably 1. n is preferably 0; - R A , R B , R C and R D When present, is hydrogen, methyl and / or trifluoro. R is independently selected from the group consisting of methyl and methyl; A +R B If present, they are bonded to the carbon Together with an atom, it forms a carbonyl (C=O) group, or R C +R D exists When they are combined with the carbon atom to which they are attached, they form a carbonyl (C=O) group. (In other words, R A +R B are taken together and replaced by a single oxygen atom, Form a carbonyl group with the carbon atom to which the oxygen atom is bonded, or C +R D exists When the oxygen atom is replaced by a single oxygen atom, the oxygen atom is bonded to the forming a carbonyl group with the carbon atom in Each Q is independently a carbon atom or a nitrogen atom, preferably at least one Atom Q is a nitrogen atom, more preferably both atoms Q are nitrogen atoms, - R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each of which is independently Preferred are hydrogen, methyl, ethyl, fluoro (F), and CF 3 and the group consisting of isopropyl may be suitable substituents independently selected from - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acylsulfonamide group (for example, the general formula CONHSO 2 R or SO 2 NHCOR, where R is - C 1 ~C 8 alkyl, CH 2 (C 1 ~C 8 cycloalkyl), CH 2 (heterocyclyl having 1 to 6 ring atoms ), C 1 ~C 8 alkoxy or C 1 ~C 8 amine acylsulf onamide group), a tetrazole group or a biological equivalent of a tetrazole group (as defined herein ), a group (for example, but not limited to, 4H-1,2,4-oxadiazole- 5-one group) selected from the group consisting of, more preferably a tetrazole or its biological equivalent , and most preferably a tetrazole, - X and Y are each either a nitrogen atom or a carbon atom, and both X and Y are carbon atoms, or only one of X or Y is a nitrogen atom (the other of X and Y is a carbon atom), - Z is a nitrogen atom or a carbon atom, - R 1 is, when present, H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 3 or C 4 cycloalkyl, CF 3 , C 1 ~C 8 alk oxy, amine (-NH 2 ) or C 1 ~C 2 substituted amine (for example, dimethylamine or die selected from the group consisting of thiamine) and cyano, - R 2 when present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~C 8 alkyl, C 1 ~C 8 alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethylamine) consisting of selected from the group, - R 3 is H, halogen (F, Cl, Br or I, and preferably, F or Cl), C 1 ~ 8 alkyl (e.g., sec-butyl, and especially, iso-butyl), e.g., fluorine substituted methyl group (e.g., trifluoromethyl and CHF 2 ), C 1 ~C 8 alkoxy, - O-CF 3 , methoxyethyloxy (-O-(CH 2 )) 2 -O-CH 3 ) or difluoro ethoxy (-O-CH 2 -CHF 2 ), cycloalkyl (e.g., cyclopropoxy, si clobutoxy or cyclopentoxy), -CH 2 -cycloalkyl, -O-CH 2 -si cloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C 1 ~C 3 )-si cloalkyl, -NH-heteroalkyl, -N(C 1 ~C 3 )-heteroalkyl, hetero seryl (e.g., oxirane), -CH 2 -heteroseryl, -O-CH2 -heterocyclyl acryloyl (e.g., -O-CH 2 -oxiranyl), -O-heterocyclyl, -NH-hetero cyclyl, -N(C 1 -C 3 )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., , -CH=CHCH 3 , -CH=C(CH 3 ) 2 or -CH=CH 2 ), or allyl or methyl-substituted allyl (e.g., -CH 2 CH=CH 2 ), isobutenyl or methyl-substituted iso butenyl (e.g., =C(CH 3 ) 2 ) and is selected from the group consisting of cyano, most preferably is isobutyl, - R 4 when present, is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or more preferably Cl), provided that - X, Y and Z are selected such that the resulting ring structure forms an aromatic ring (i.e., a planar conjugated ring) (i.e., from carbon atoms or nitrogen atoms respectively), and further provided that when - X is a nitrogen atom, R is absent, 1 and further provided that when - Y is a nitrogen atom, R is absent, 2 and further provided that when - Z is a nitrogen atom, R is absent. 4 As further described herein, in certain embodiments, the present invention has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar

[0247] As further described herein, in certain embodiments, the present invention has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar and further provided that is good, preferably better than 1 micromole, more preferably better than 0.1 micromole, and even more preferably better than 10 nanomoles, for compounds of formula IV. In a more specific embodiment, the present invention relates to (i) each aromatic ring system [C] and acidic substituent [D] as further described herein, and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, preferably at least one Q is a nitrogen atom), and (iii) each of X, Y, and Z present in the compound of formula IV, and specific combinations of atoms X, Y, and Z, and (iv) each of the substituents R, R, R, and R (when present) in the compound of formula IV and specific combinations of such substituents R, R, R, and R, and (v) each of the substituents R to R (when present) in the compound of formula IV and such specific combinations of substituents R to R, and (vi) m and n (which may each independently be 0 or 1, as described herein), and (vii) each of the substituents R, R, R, and R (when present) in the compound of formula IV, and specific combinations of such substituents R, R, R, and R, and (viii) formula as described herein. Preferably, at least one Q is a nitrogen atom. In the compound of formula IV, each of X, Y, and Z, and specific combinations of atoms X, Y, and Z are present. And (iv) each of the substituents R, R, R, and R (when present) in the compound of formula IV, and specific combinations of such substituents R, R, R, and R. And (v) each of the substituents R to R (when present) in the compound of formula IV and specific combinations of such substituents R to R. 1 R 2 R 3 R 4 And R (when present). And specific combinations of such substituents R, R, R, and R. 1 R 2 R 3 R 4 And R. In the compound of formula IV, each of the substituents R to R (when present). 5 R 12 To R. And specific combinations of such substituents R to R. 5 R 12 To R. And (vi) m and n (which may each independently be 0 or 1, as described herein). In the compound of formula IV, each of the substituents R, R, R, and R (when present). A R B R C R D And R. And specific combinations of such substituents R, R, R, and R. A R B R C R D And (viii) formula Any further substituents present in such compounds of formula IV (e.g., on the aromatic ring system [C] ), as well as specific combinations of such substituents present in the compounds of formula IV. The compounds of formula IV have a potent potency of greater than 10 micromolar for the AT2R, respectively. Preferably better than 1 micromolar, more preferably better than 0.1 micromolar and even more preferably with an affinity of better than 10 nanomolar (see the process described in Example 2 below). (and combinations thereof) ), relating to a compound of formula IV (further described herein).

[0248] In a more preferred but non-limiting embodiment, the present invention relates to a compound of formula V:

[0249] [ka] During the ceremony, [C] is a monocyclic or polycyclic, preferably monocyclic or bicyclic, aromatic ring system, (i) the aromatic ring system contains at least one aromatic ring, and (ii) the aromatic ring system contains at least one aromatic ring. through a carbon atom present in at least one aromatic ring (i.e., directly through a covalent bond) or, if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) said at least one one aromatic ring (i.e., the aromatic ring containing the carbon atom to which the remainder of the compound of formula V is attached); Preferably, the heteroatom ( (when present) are preferably each independently suitably selected from N, S and O, more preferably Preferably, at least one of the heteroatoms (if present) is a nitrogen atom, [C] The aromatic ring system represented by is preferably an aromatic ring / ring system of Formulas VII to LXXXIII selected from the group consisting of, more preferably an aromatic ring / ring system selected from the group consisting of Formulas LIX to LXXXIII and even more preferably an aromatic ring / ring system selected from the group consisting of Formulas LXXIII to LXXXIII is an aromatic ring or ring system selected from - m is 1 or 0, n is 1 or 0, and the sum of m and n is either 2, 1 or 0, preferably 1 or 0 (when m = 0, R and R A. and R B do not exist, and when n = 0, it is understood that R C and R D do not exist), m is preferably 1 and n is preferably 0, - R A , R B , R C and R D , when present, are independently selected from hydrogen, methyl and / or trifluoro methyl, and R A + R B , when present, together with the carbon atom to which they are attached, form a carbonyl (C=O) group, or R + R C + R D is, when present , together with the carbon atom to which they are attached, form a carbonyl (C=O) group (in other words, R A + R B are together replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached, or R + R C + R D is, when present , together replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached (which form a carbon atom and a carbonyl group), preferably each is a hydrogen atom, - Each Q is independently a carbon atom or a nitrogen atom, preferably at least one atom Q is a nitrogen atom, more preferably both atoms Q are nitrogen atoms, - R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 each independently is preferably a suitable substituent independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF 3 and isopropyl, and may be an appropriate substituent, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., the general formula CONHSO 2 R or SO 2 NHCOR, wherein R is - C 1 ~C 8 alkyl, CH 2 (C 1 ~C 8 cycloalkyl), CH 2 (heterocyclyl having 1 to 6 ring atoms ), C 1 ~C 8 alkoxy or C 1 ~C 8 amine acylsulfonamide group), a tetrazole group or a biological equivalent of a tetrazole group (as defined herein ), a group selected from the group consisting of (e.g., but not limited to, 4H-1,2,4-oxadiazole- 5-one group), more preferably a tetrazole or its biological equivalent and most preferably a tetrazole, - R is H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ​1 ~ C 8 alkyl, C 3 or C 4 cycloalkyl, CF 3 , C 1 ~C 8 alkoxy, amine( -NH 2 ) or C 1 ~C 2 substituted amine (e.g., dimethylamine or diethylamine) and selected from the group consisting of cyano, -R 2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C 1 ~ C 8 alkyl, C 1 ~C 8 alkoxy, cycloalkyl, amine (-NH 2 ) or C 1 ~ C 2 substituted amine (e.g., dimethylamine or diethylamine) selected from the group consisting of , -R 3 is H, halogen (F, Cl, Br or I, and preferably, F or Cl), C 1 ~ 8 alkyl (e.g., sec-butyl, and especially, iso-butyl), e.g., fluorine substituted methyl group (e.g., trifluoromethyl and CHF 2 ), C 1 ~C 8 alkoxy, - O-CF 3 , methoxyethyloxy (-O-(CH 2 )) 2 -O-CH 3 ) or difluoro ethoxy (-O-CH 2 -CHF 2 ), cycloalkyl (e.g., cyclopropoxy, cy clobutoxy or cyclopentoxy), -CH 2 -cycloalkyl, -O-CH2 -cyclo lower alkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C 1 ~C 3 )-cyclo chloroalkyl, -NH-heteroalkyl, -N(C 1 ~C 3 )-heteroalkyl, hetero cyclyl (e.g., oxirane), -CH 2 -heterocyclyl, -O-CH 2 -hetero cyclyl (e.g., -O-CH 2 -oxirane), -O-heterocyclyl, -NH-hetero cyclyl, -N(C 1 -C 3 )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., , -CH=CHCH 3 , -CH=C(CH 3 ) 2 or -CH=CH 2 )), or allyl or methyl-substituted allyl (e.g., -CH 2 CH=CH 2 ), isobutenyl or methyl-substituted iso butenyl (e.g., =C(CH 3 ) 2 ) and is selected from the group consisting of cyano, most preferably is, isobutyl, - R 4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0250] As further described herein, the present invention, in certain embodiments, has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar, of the formula V thereof ​​​​ relates to compounds such as. In a more specific embodiment, the present invention provides (i) an aromatic ring system [C] and an acidic substituent [D], each further described herein , and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom, as described herein), and (iii) the substituents R present in the compound of formula V , R 1 , R 2 , R 3 and R 4 each (when present), and specific combinations of such substituents R 1 , R 2 , R 3 and R 4 , and (v) the substituents R present in the compound of formula V 5 ~R 12 each (when present), and specific combinations of such substituents R 5 ~R 12 , and (vi) m and n (which may each independently be 0 or 1, as described herein), and (vi) the substituents R present in the compound of formula V A , R B , R C and R D each (when present), and specific combinations of such substituents R A , R B , R C and R D , and (viii) any further substituents (e.g., on the aromatic ring system [C]) present in such compounds of formula V, and specific combinations of such substituents present in such compounds of formula V each independently result in the compound of formula V having an affinity for AT2R that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and most preferably better than 0.01 micromolar than 0.1 micromolar, and most preferably better than 0.01 micromolar Preferably better than 0.1 micromole, more preferably better than 10 nanomoles having an affinity (measured according to the protocol described in Example 2 below) such that the compound of formula V (further described herein is) and such combinations thereof.

[0251] In a particularly preferred but non-limiting embodiment, the invention relates to compounds of formula VI:

[0252]

Chemical formula

[0253] As further described herein, in certain embodiments, the present invention has an affinity for AT2R (measured according to the protocol described in Example 2 below) that is better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar, for compounds of formula VI. In a more specific embodiment, the present invention relates to (i) an aromatic ring system [C] and an acidic substituent [D], each as further described herein, and (ii) each atom Q (which, as described herein, may independently be a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom), and (iii) the substituents R 1 , R 2 , and R 4 , each (if present) in the compound of formula VI and certain combinations of such substituents R 1 , R 2 , and R 1 4 , and (iv) the substituents R 2 5 to R 12 , each (if present) in the compound of formula VI and certain combinations of such substituents R 5 12 to R 4 , and (v) m (which, as described herein, may be 0 or 1), and A B , each (if present) in the compound of formula VI, and certain combinations of such substituents R A B , and (vii) any additional substituents (e.g., on the aromatic ring system [C]) present in a compound of formula VI of A B A B such, and (vii) any additional substituents (e.g., on the aromatic ring system [C]) present in a compound of formula VI of such, and (vii) any additional substituents (e.g., on the aromatic ring system [C]) present in a compound of formula VI of A B A B such, and (vii) any additional substituents (e.g., on the aromatic ring system [C]) present in a compound of formula VI of A B A B such, and (vii) any additional substituents (e.g., on the aromatic ring system [C]) present in a compound of formula VI of The specific combination of such substituents present in the compound of formula VI, respectively, is such that the compound of formula VI has an affinity for AT2R that is better than 10 micromoles, preferably better than 1 micromole, more preferably better than 0.1 micromole, even more preferably better than 10 nanomoles (measured according to the protocol described in Example 2 below) (and such combinations). Compound.

[0254] The compounds of the invention according to each of formulas I to VI (including the preferred, more preferred, particularly preferred, and / or most preferred compounds), and / or the compounds of the invention according to various aspects and preferred aspects of the invention defined with reference to one of formulas I to VI Some specific but non-limiting examples of which will be apparent to those skilled in the art based on the disclosure herein, and / or as exemplified in the experimental section below. The compounds of the invention can be used in the prevention, treatment and / or management of pain, particularly chronic pain, such as the chronic pain conditions described herein. Accordingly, in a further aspect, the invention relates to the use of the compounds of the invention (e.g., the compounds of formula I as defined herein, specifically the compounds of formula II as defined herein, more specifically the compounds of formula III as defined herein, preferably the compounds of formula IV as defined herein, more preferably the compounds of formula V as defined herein, even more preferably the compounds of formula VI as defined herein) in the prevention, treatment and / or management of pain, particularly chronic pain.

[0255]

[0256] ​​​​​​​​​

[0257] In a further aspect, the present invention relates to the prevention, treatment and / or management of pain, particularly the prevention of chronic pain, the use of a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of formula I as defined herein, specifically a compound of formula II as defined herein, more specifically a compound of formula III as defined herein, preferably a compound of formula IV as defined herein, more preferably a compound of formula V as defined herein, even more preferably a compound of formula V I as defined herein) in the prevention, treatment and / or management of pain. Such pharmaceutical compositions are generally as further described herein and generally contain a pharmaceutically active amount, e.g., an amount of a compound of the present invention as described herein in a dosage regimen suitable for administering to a subject (e.g., as a single or multiple administrations / doses per day) in an amount that enables administration of the compound of the present invention to the subject. as further described herein, generally containing a pharmaceutically active amount, e.g., a dosage of a compound of the present invention as described herein, using a suitable dosing regimen (e.g., as a single or multiple administrations / doses per day) to enable administration of the compound of the present invention to the subject.

[0258] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of pain, particularly chronic pain, in a subject, comprising administering to the subject (i.e., a subject in need of such prevention, treatment or management) a pharmaceutically active amount of a compound of the present invention or a pharmaceutical composition comprising the same (e.g., according to a suitable dosing regimen further described herein).

[0259] For the treatment of chronic pain (including further conditions described herein related to chronic pain such as neuropathic pain and inflammatory pain), usually, the compound or composition of the present invention is administered for a long period (e.g., for at least one week, e.g., at least one month, e.g., at least three months or more, and / or until the pain is reduced or resolved), e.g., as part of a chronic treatment regimen for the management of chronic pain. must be administered or used as a part, or as part of an overall treatment regimen will be apparent to those skilled in the art. Such chronic treatment regimens or pain management regimens, and the use of the compounds or compositions of the invention as part of such regimens, will be determined by the treating physician based on the overall condition of the patient, the nature and cause of the pain, and / or the specific pain condition involved, as well as other relevant factors apparent to the clinician These treatment regimens and dosing regimens form a further aspect of the invention. These treatment regimens and dosing regimens form a further aspect of the invention.

[0260] The compounds and compositions of the invention can be used specifically in the prevention, treatment and / or management of pain, particularly chronic pain, such as (chronic) neuropathic pain. Such neuropathic pain can be neuropathic pain originating from the peripheral part of the nervous system (e.g., trigeminal neuralgia or post-herpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or nerve root disorders), or can originate from the central nervous system and / or involve the central nervous system in neuropathic pain (e.g., in the case of chronic neuropathic pain resulting from spinal cord injury or brain injury, stroke or multiple sclerosis Such use and corresponding / treatment methods form a further aspect of the invention. Such use and corresponding / treatment methods form a further aspect of the invention. Such use and corresponding / treatment methods form a further aspect of the invention.

[0261] In a specific but non-limiting embodiment, the compounds and compositions of the invention (e.g., compounds of formula I as defined herein, specifically compounds of formula II as defined herein, more specifically compounds of formula III as defined herein, preferably compounds of formula IV as defined herein, more preferably compounds of formula V as defined herein, even more preferably the compounds of the present specification compounds of formula III as defined herein, preferably compounds of formula IV as defined herein, more preferably compounds of formula V as defined herein, even more preferably the compounds of the present specification compounds of formula III as defined herein, preferably compounds of formula IV as defined herein, more preferably compounds of formula V as defined herein, even more preferably the compounds of the present specification The compound of formula VI defined in the book, or a pharmaceutical composition containing the same, can be used in the prevention, treatment and / or management of (peripheral) neuropathy. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of chronic NP after peripheral nerve injury. Such uses and corresponding / related treatment methods form further aspects of the present invention.

[0262] In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention.

[0263] In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the present specification, or a pharmaceutical composition containing the same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related treatment methods form further aspects of the present invention. In another specific but non-limiting aspect, the compounds and compositions of the present invention (e.g., the compound of formula I defined in the present specification, specifically the compound of formula II defined in the present specification, more specifically the compound of formula III defined in the present specification, preferably the compound of formula IV defined in the present specification, more preferably the compound of formula V defined in the present specification, even more preferably the compound of formula VI defined in the...

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, [C] is a monocyclic or polycyclic (preferably monocyclic or bicyclic) aromatic ring system, (i) the aromatic ring system comprises at least one aromatic ring; and (ii) the aromatic ring system is via a carbon atom present in said at least one aromatic ring (i.e., via a covalent bond) directly, or when an alkylene linking group is present, said alkylene linking group -C （ｍ） R Ａ R Ｂ - (either via a -) to the remainder of said compound of formula I; At least one aromatic ring (i.e., the carbon atom to which the remainder of the compound of formula I is attached) The aromatic ring (containing an aromatic ring containing an aromatic atom) preferably contains at least one (e.g., one or two) heteroatoms. and the heteroatoms, if present, are preferably each independently selected from N, S and O. and more preferably, at least one of said heteroatoms (if present) is suitably selected from is a nitrogen atom, and the aromatic ring system represented as [C] is preferably represented by formula VII-L From the group consisting of aromatic rings / ring systems of formulae LIX to LXXXII, more preferably From the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXII, even more preferably I, - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1, or 0. m is preferably 1 or 0 (when m=0, R Ａ． and R Ｂ does not exist, and n If = 0, R Ｃ and R Ｄ is understood to be absent), and m is preferably 1. n is preferably 0; - R Ａ , R Ｂ , R Ｃ and R Ｄ Each of, when present, is selected from hydrogen, methyl and / or trimethylsilyl. fluoromethyl; or Ａ +R Ｂ If they exist, they are Together with the carbon atom to which it is attached, forms a carbonyl (C=O) group, or R Ｃ +R Ｄ When present, together with the carbon atom to which they are attached, form a carbonyl (C=O ) group (in other words, R Ａ +R Ｂ together and replaced by a single oxygen atom to form a carbonyl group together with the carbon atom to which the oxygen atom is bonded, or Ｃ + R Ｄ are taken together, if present, replaced by a single oxygen atom, form a carbonyl group with the carbon atom to which the alkyl group is bonded), each of which is preferably a hydrogen atom. can be, [A] is any of the ring systems generally represented by Scheme C below, 【Chemistry 2】 wherein each atom Q is independently a carbon atom or a nitrogen atom (preferably at least one more preferably, one atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms; v is and w is an integer from 1 to 4 (i.e., 1, 2, 3, or 4); 1, 2, 3 or 4), and the sum of (v+w) is 3, 4, 5, 6, 7 or 8 (preferably or 3, 4 or 5, and more preferably, v and w are both 2), the difference (v -w) is either 1, 0, or -1, and each R ｘ and each R ｙ I like Preferably, each independently is hydrogen, methyl, ethyl, fluorine (F), or CF ３ and from isopropyl and in particular a ring system as generally represented by Scheme D below, 【Chemistry 3】 wherein each atom Q is independently a carbon atom or a nitrogen atom (preferably at least one more preferably, one atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms; ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ and R １２ Each of the is preferably independently water Fluorine, methyl, ethyl, fluoro (F), CF ３ and isopropyl or a ring system of formula XCIX or C, 【Chemistry 4】 wherein said ring systems of formula XCIX or formula C, when present, are each preferably independently , hydrogen, methyl, ethyl, fluorine (F), CF ３ and isopropyl and optionally being suitably substituted with one or more suitable substituents as provided herein; The acidic substituent represented by [D] is a carboxylic acid (—COOH) group, an acylsulfonyl group, An amide group (e.g., a group represented by the general formula CONHSO ２ R or SO ２ NHCOR, where R Ha-C １ ~C ８ Alkyl, CH ２ (C １ ~C ８ Cycloalkyl), CH ２ (1 to 6 rings Heterocyclyl having a C atom １ ~C ８ Alkoxy or C １ ~C ８ Amine a tetrazole group or a bioisostere of a tetrazole group (as used herein) (for example, but not limited to, 4H-1,2,4-oxadiazo More preferably, the tetrazole or its biological equivalent is selected from the group consisting of tetrazole, tetrazole-5-one ... is preferably an isomeric equivalent, most preferably tetrazole; X and Y are each either a nitrogen atom or a carbon atom, and both X and Y are or only one of X and Y is a nitrogen atom (the other of X and Y is a carbon atom); (which is an elementary atom) Z is a nitrogen atom or a carbon atom, - R １ When present, represents H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~C ８ Alkyl, C ３ Or C ４ Cycloalkyl, CF ３ , C １ ~C ８ Arco amine (-NH ２ ) or C １ ~C ２ Substituted amines (e.g., dimethylamine or diethylamine) ethylamine) and cyano; - R ２ When present, represents H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, cycloalkyl, amine (-NH ２ ) or C １ ~C ２ Consists of substituted amines (e.g., dimethylamine or diethylamine) is selected from the group - R ３ is H, halogen (F, Cl, Br or I, and preferably F or Cl), C １ ~ ８ Alkyl (eg, sec-butyl, and especially iso-butyl), such as fluorine Substituted methyl groups (e.g., trifluoromethyl and CHF ２ ), C １ ~C ８ Alkoxy, - O-CF ３ , methoxyethyloxy (-O-(CH ２ ) ２ -O-CH ３ ) or difluoro Ethoxy (-O-CH ２ -CHF ２ ), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) chlorobutoxy or cyclopentoxy), -CH ２ -cycloalkyl, -O-CH ２ - Shik -cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C １ ~C ３ ) - C Chloroalkyl, -NH-heteroalkyl, -N(C １ ~C ３ )-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH ２ -heterocyclyl, -O-CH ２ - Heterosi Kryl (e.g., -O-CH ２ -oxirane), -O-heterocyclyl, -NH-hetero Cyclyl, -N(C １ ~C ３ )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g. , -CH=CHCH ３ , -CH=C(CH ３ ) ２ or -CH=CH ２ ), or allyl or is a methyl-substituted aryl (e.g., -CH ２ CH=CH ２ ), isobutenyl or methyl substituted isobutenyl Sobutenyl (e.g., =C(CH ３ ) ２ ) and cyano, most preferred or isobutyl, - R ４ When present, it is H or a halogen (F, Cl, Br or I, preferably F or is selected from the group consisting of Cl; however, - X, Y and Z are such that the resulting ring structure forms an aromatic ring (i.e. a planar conjugated ring). (i.e., from carbon atoms or nitrogen atoms, respectively); Furthermore, however, When X is a nitrogen atom, R １ does not exist, Furthermore, however, When Y is a nitrogen atom, R ２ does not exist, Furthermore, however, When Z is a nitrogen atom, R ４ does not exist, a compound.

2. A compound of formula V, 【Chemistry 5】 During the ceremony, [C] is a monocyclic or polycyclic (preferably monocyclic or bicyclic) aromatic ring system, (i) the aromatic ring system comprises at least one aromatic ring; and (ii) the aromatic ring system is via a carbon atom present in said at least one aromatic ring (i.e., via a covalent bond) directly, or when an alkylene linking group is present, said alkylene linking group -C （ｍ） R Ａ R Ｂ - (via any one of the preceding groups) to the remainder of the compound of formula V; at least one aromatic ring (i.e., the carbon atom to which the remainder of the compound of formula V is attached); The aromatic ring preferably contains at least one (e.g., one or two) heteroatoms. and the heteroatoms, if present, are preferably selected independently from N, S and O. Preferably, at least one of said heteroatoms (if present) is nitrogen. The aromatic ring system represented as [C] is preferably represented by the formulae VII to LXX XIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII From the group consisting of aromatic rings / ring systems, even more preferably those of the formulae LXXIII to LXXXIII an aromatic ring or ring system selected from the group consisting of: aromatic rings / ring systems; - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1, or 0. m is preferably 1 or 0 (when m=0, R Ａ and R Ｂ does not exist, and n= If 0, R Ｃ and R Ｄ is understood to be absent), m is preferably 1, , n is preferably 0; - R Ａ , R Ｂ , R Ｃ and R Ｄ When present, is hydrogen, methyl and / or trifluoro. R is independently selected from methyl; Ａ +R Ｂ If present, they are bonded to the carbon Together with the atom, forms a carbonyl (C=O) group, or R Ｃ +R Ｄ exists When they are combined with the carbon atom to which they are attached, they form a carbonyl (C=O) group. (In other words, R Ａ +R Ｂ are taken together and replaced by a single oxygen atom, Form a carbonyl group with the carbon atom to which the oxygen atom is bonded, or Ｃ +R Ｄ exists When taken together, they are replaced by a single oxygen atom, and said oxygen atom is bonded to forming a carbonyl group with the carbon atom in Each Q is independently a carbon atom or a nitrogen atom, preferably at least one Atom Q is a nitrogen atom, more preferably both atoms Q are nitrogen atoms, - R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ and R １２ each of which is independently Preferred are hydrogen, methyl, ethyl, fluoro (F), and CF ３ and the group consisting of isopropyl may be suitable substituents independently selected from The acidic substituent represented by [D] is a carboxylic acid (—COOH) group, an acylsulfonyl group, An amide group (e.g., a group represented by the general formula CONHSO ２ R or SO ２ NHCOR, where R Ha-C １ ~C ８ Alkyl, CH ２ (C １ ~C ８ Cycloalkyl), CH ２ (1 to 6 rings Heterocyclyl having a C atom １ ~C ８ Alkoxy or C １ ~C ８ Amine a tetrazole group or a bioisostere of a tetrazole group (as used herein) (for example, but not limited to, 4H-1,2,4-oxadiazo More preferably, the tetrazole or its biological equivalent is selected from the group consisting of tetrazole, tetrazole-5-one ... is preferably an isomeric equivalent, most preferably tetrazole; - R １ is H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~ C ８ Alkyl, C ３ Or C ４ Cycloalkyl, CF ３ , C １ ~C ８ Alkoxy, amine ( -NH ２ ) or C １ ~C ２ Substituted amines (e.g., dimethylamine or diethylamine) and and cyano; - R ２ is H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~ C ８ Alkyl, C １ ~C ８ Alkoxy, cycloalkyl, amine (-NH ２ ) or C １ ~ C ２ substituted amines (e.g., dimethylamine or diethylamine); 、 - R ３ is H, halogen (F, Cl, Br or I, and preferably F or Cl), C １ ~ ８ Alkyl (eg, sec-butyl, and especially iso-butyl), such as fluorine Substituted methyl groups (e.g., trifluoromethyl and CHF ２ ), C １ ~C ８ Alkoxy, - O-CF ３ , methoxyethyloxy (-O-(CH ２ ) ２ -O-CH ３ ) or difluoro Ethoxy (-O-CH ２ -CHF ２ ), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) chlorobutoxy or cyclopentoxy), -CH ２ -cycloalkyl, -O-CH ２ - Shik -cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C １ ~C ３ ) - C Chloroalkyl, -NH-heteroalkyl, -N(C １ ~C ３ )-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH ２ -heterocyclyl, -O-CH ２ - Heterosi Kryl (e.g., -O-CH ２ -oxirane), -O-heterocyclyl, -NH-hetero Cyclyl, -N(C １ ~C ３ )-heterocyclyl, vinyl or methyl-substituted vinyl (e.g. , -CH=CHCH ３ , -CH=C(CH ３ ) ２ or -CH=CH ２ ), or allyl or is a methyl-substituted aryl (e.g., -CH ２ CH=CH ２ ), isobutenyl or methyl substituted isobutenyl Sobutenyl (e.g., =C(CH ３ ) ２ ) and cyano, most preferred or isobutyl, - R ４ consists of H or halogen (F, Cl, Br or I, preferably F or Cl). The compound is selected from the group consisting of:

3. A compound of formula VI, 【Chemistry 6】 During the ceremony, [C] is a monocyclic or polycyclic (preferably monocyclic or bicyclic) aromatic ring system, (i) the aromatic ring system comprises at least one aromatic ring; and (ii) the aromatic ring system is via a carbon atom present in said at least one aromatic ring (i.e., via a covalent bond) directly, or when an alkylene linking group is present, said alkylene linking group -C （ｍ） R Ａ R Ｂ - (either via a -) to the remainder of said compound of formula VI; and (iii) The at least one aromatic ring (i.e., the carbon atom to which the remainder of the compound of Formula VI is attached) The aromatic ring (containing an aromatic ring containing an aromatic atom) preferably contains at least one (e.g., one or two) heteroatoms. and the heteroatoms, if present, are preferably each independently selected from N, S and O. and more preferably, at least one of said heteroatoms (if present) is suitably selected from is a nitrogen atom, and the aromatic ring system represented as [C] is preferably represented by formula VII-L From the group consisting of aromatic rings / ring systems of formulae LIX to LXXXII, more preferably From the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXII, even more preferably I, m is 1 or 0, - R Ａ and R Ｂ each independently selected from hydrogen, methyl and / or trifluoromethyl; Selected or R Ａ +R Ｂ If present, together with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R Ａ． +R Ｂ Let's get together and a carbon atom to which the oxygen atom is bonded is replaced by a single oxygen atom. forming a nyl group), preferably each being a hydrogen atom, Each Q is independently a carbon atom or a nitrogen atom, preferably at least one Atom Q is a nitrogen atom, more preferably both atoms Q are nitrogen atoms, - R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ and R １２ each of which is independently Preferred are hydrogen, methyl, ethyl, fluoro (F), and CF ３ and the group consisting of isopropyl may be suitable substituents independently selected from The acidic substituent represented by [D] is a carboxylic acid (—COOH) group, an acylsulfonyl group, An amide group (e.g., a group represented by the general formula CONHSO ２ R or SO ２ NHCOR, where R Ha-C １ ~C ８ Alkyl, CH ２ (C １ ~C ８ Cycloalkyl), CH ２ (1 to 6 rings Heterocyclyl having a C atom １ ~C ８ Alkoxy or C １ ~C ８ Amine a tetrazole group or a bioisostere of a tetrazole group (as used herein) (for example, but not limited to, 4H-1,2,4-oxadiazo More preferably, the tetrazole or its biological equivalent is selected from the group consisting of tetrazole, tetrazole-5-one ... is preferably an isomeric equivalent, most preferably tetrazole; - R １ is H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~ C ８ Alkyl, C ３ Or C ４ Cycloalkyl, CF ３ , C １ ~C ８ Alkoxy, amine ( -NH ２ ) or C １ ~C ２ Substituted amines (e.g., dimethylamine or diethylamine) and and cyano; - R ２ is H, halogen (F, Cl, Br or I, preferably F or Cl), C １ ~ C ８ Alkyl, C １ ~C ８ Alkoxy, cycloalkyl, amine (-NH ２ ) or C １ ~ C ２ substituted amines (e.g., dimethylamine or diethylamine); 、 - R ４ consists of H or halogen (F, Cl, Br or I, preferably F or Cl). The compound is selected from the group consisting of:

4. A pharmaceutical composition comprising a compound of formula I, V or VI, and optionally a pharma- ceutically acceptable carrier. Composition.

5. Compounds of formula I in the prevention, treatment and / or management of pain, in particular chronic pain such as neuropathic pain. The use of a compound of formula I, V or VI or a pharmaceutical composition comprising a compound of formula I, V or VI.

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