Compounds for the treatment of pain, particularly neuropathic pain, and / or other diseases or disorders associated with AT2R and / or AT2R-mediated signaling

Abstract

The present invention relates to compounds that can be used in the prevention, treatment and / or management of pain, in particular chronic pain such as neuropathic pain, and / or other diseases or disorders associated with AT2R and / or AT2R-mediated signaling.

Description

[Technical Field]

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

[0002] Pain can occur in many forms and can have a variety of causes and underlying pathophysiological mechanisms. Pain can be spontaneous, chronic, or acute, and can be caused, for example, by physical injury or potential injury to the body (so-called "nociceptive pain"), or by damage and / or disease to the somatosensory nervous system (so-called "neuropathic pain"), e.g., pain caused by damage or disease to the peripheral nerves (i.e., nerves beyond the brain and spinal cord), also called "peripheral neuropathy" or "neuropathy" for short.

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

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

[0005] Various animal models have been developed to experimentally evaluate the pathophysiological mechanisms underlying characteristic clinical pain states induced by tissue injury, inflammation, neurotrauma, chemotherapeutic agents, and metabolic problems, and these models also enable preclinical evaluation and validation of the therapeutic efficacy of potential analgesics. See, for example, Dubner and Ren, "Assessing transient and persistent pain in animals," In:Textbook of Pain, 4 th edition (Wall and Melzack, Eds.), pp. 359-369, Churchill Livingstone, 1999, 53, 319-334 (also cited in Guindon and Hohmann, supra).

[0006] Additionally, various molecular targets for the prevention, treatment, and / or management of pain have been suggested in the art, including cannabinoid CB2 receptors (see again, e.g., Guindon and Hohmann, supra), NMDA receptors (see, e.g., Parsons, European Journal of Pharmacology, 429 Z2001, 71-78), various ion channels (see, e.g., Dib-Hajj 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), sphingosine-1-phosphate receptors (see, e.g., Welch et al., Biochemical Pharmacology, Volume 84, Issue 12, 15 December 2012, Pages S38-S47), and ATP receptors (see, e.g., Welch et al., Biochemical Pharmacology, Volume 84, Issue 12, 15 December 2012, Pages S38-S47). 1551-1562) and monoacylglycerol lipase (MAGL) (see, for example, WO 2020 / 112905).

[0007] Neuropathic pain is a chronic, secondary pain condition caused by injury and / or disease of the somatosensory nervous system, typically characterized by hyperalgesia and / or allodynia. Neuropathic pain affects approximately 7-10% of the population and can significantly impact quality of life. See, e.g., Szok et al., Behav. Neurol., 2019:8685954; Colloca et al., Nat. Rev. Dis. Primers, 2017 Feb. 16, 3:17002; Alles and Smith, Pharmacol. Rev. 70:315-347, April 2018; and Cavalli et al., Int. J. Immunopathol. Pharmacol., 2019 Jan-Dec, 33, and further references cited therein.

[0008] As mentioned in these references, neuropathic pain (also abbreviated as "NP") is caused by lesions or diseases of the somatosensory system, including peripheral fibers (Aβ, Aδ, and C fibers) and central neurons. Multiple causes of neuropathic pain have been described, including metabolic diseases such as diabetes, cancer and cancer treatments, 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 viruses (e.g., shingles), leprosy, Guillain-Barré syndrome, HIV infection, vascular diseases and vascular malformations, autoimmune conditions, and damage to the nerves or nervous system.

[0009] Thus, chronic neuropathic pain can arise from peripheral parts of the nervous system (e.g., in the case of trigeminal neuralgia or post-herpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or radiculopathy), or it can arise from or involve the central nervous system (e.g., in the case of chronic neuropathic pain that develops as a result of spinal cord or brain injury, stroke, or multiple sclerosis). As mentioned, when it originates in nerves beyond the brain and central nervous system, it is also called "peripheral neuropathy" or simply "neuropathy."

[0010] As noted by Szok et al. (supra), in 2019 the International Association for the Study of Pain (IASP) published a classification of these qualitatively distinct pain syndromes, recognizing the following subtypes: - 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), chronic central NP associated with brain injury, chronic central pain after stroke, and chronic central NP associated with multiple sclerosis.

[0011] As also stated by Szok et al., "NP conditions are generally under-recognized, under-diagnosed, and under-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. See, for example, Shepherd et al., PNAS, vol. 115, no. 34, E8057-E8066, and Keppel Hesselink and Schatman, Journal of Pain Research, 2017, 10:439-443, and Matavelli and Siragy, J. Cardiovasc. Pharmacol., 2015; 65(3):226-232, and WO 2015 / 003223. Some of the known modulators of AT2R that have been proposed or investigated for the treatment of neuropathic pain include the compounds EMA200 (also known as PD-123319), EMA300, EMA400 (also known as PD-126055), and EMA401 / olodanrigan (see, e.g., Smith et al., Pain Medicine 2013, 14:692-705; Anand et al., Mol. Pain 2015, 11:38; and WO 2006 / 066361), the compound PD-123177 (see, e.g., Singh and Karnik, J. Cell. Signal., 2016 June, 1(111)), and the compound known as C-38 (see, e.g., Wallinder et al., ACS Med. Chem. Lett., 2015, 6, 2, 178-182; and Isaksson et al., J. Cell. Signal., 2016 June, 1(111)). al., Chemistry Open 2019,8(1),114-125).

[0013] The mechanisms behind the analgesic properties of AT2R antagonists (eg, EMA-401, mentioned below) remain to be further elucidated. Some researchers have reported that preclinical studies suggest that the analgesic properties of AT2R antagonists may be explained by a mechanism involving modulation of macrophage-mediated neuroimmune interactions (Shepherd et al., J. Neurosci., 2018, 38(32):7032-7057 and Shepherd et al., Proc. Natl. Acad. Sci. USA, 2018 Aug 21;115(34):E8057-E8066). However, based on the finding that AT2R is co-localized with TRPV1 in human dorsal root ganglia (DRG), other researchers have suggested that AT2R plays a role in nociception by capsaicin-sensitive sensory neurons and that AT2R antagonists may inhibit pain responses as well as 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 (see, 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-Jeanneret, J. Med. Chem., 2020, 63, 5, 1978-1995; Zhang et al., Nature, 2017; 544(7650):327-332; Kemp et al., Circ. Res., 2014; 115(3):388-399; Namsolleck et al. al., Curr. Hypertens. Rep., (2014) 16:416; Steckelings et al., Curr. Opin. Pharmacol., 2011 Apr;11(2):187-92; Mehta and Griendling, Am. J. Physiol. Cell Physiol., 292:C82-C97, 2007; Carey and Padia, Endocrine Hypertension, Volume 19, ISSUE 3, P84-87, April 01, 2008; and Singh and Karnik (supra), as well as some of the further references cited therein.

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

[0016] Some of the major 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 for the MAS receptor.

[0017] Angiotensins include the octapeptide Ang II and its natural degradation product Ang III (both known to be ligands for AT1R and AT2R), the hexapeptide Ang(1-7) (known to be an endogenous ligand for the MAS receptor), Ang IV (a natural degradation product of Ang II, the primary ligand for AT4R), and Ang I (a decapeptide precursor of Ang II, which itself appears to have no major known direct biological activity).

[0018] Ang II has been described as a central peptide hormone of the RAS, and is known to be a potent hypertensive hormone and a major regulator of aldosterone secretion by the adrenal cortex, which promotes sodium retention by the kidney. Therefore, it is an important effector controlling blood pressure and blood volume in the cardiovascular system. Ang II is also used as a drug (marketed under the trade name GIAPREZA®) for the treatment of vasodilatory shock.

[0019] Ang II and its natural degradation product, Ang III, are known to act (primarily) through AT1R and AT2R, 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. AT1R activation has been described to induce biological effects such as, but not limited to, cell dedifferentiation and proliferation, vasoconstriction, antinatriuresis, aldosterone secretion, and sympathetic activation, ultimately resulting in hypertension. AT2R activation has been described to induce, among other biological effects, cell differentiation and proliferation inhibition / apoptosis, vasodilation, and natriuresis, potentially lowering blood pressure and resulting in antihypertensive effects in kidney disease, and to have protective functions for various tissues and organs.

[0020] 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 generally decreases after birth, and in adults, it is mainly present at prominent levels in the myometrium, with lower levels in the adrenal gland and fallopian tube. Other than the above, the expression level of AT2R is generally low in healthy adult tissues, but it is known to be strongly upregulated under pathological conditions such as tissue damage and injury (including vascular injury, neuronal injury, myocardial infarction, and cerebral ischemia), and AT2R is also thought to provide endogenous protection against inflammation, oxidation, and apoptosis processes, mainly by antagonizing AT1R.

[0021] In particular, as explained by Anand (supra), "Ang II and AT2R are co-expressed in human nociceptive sensory neurons, and levels of Ang II, the major endogenous ligand in human peripheral nerves, are preserved after injury. [...] Thus, increased Ang II / AT2R signaling in DRG neurons secondary to peripheral nerve injury may have an important role in chronic pain mechanisms, including neuropathic pain." Anand also hypothesizes that the mechanism of action of the known AT2R antagonist EMA401 "appears to involve inhibition of enhanced Ang II / AT2R-induced p38 and p42 / p44 MAPK activation, and thus inhibition of DRG neuron hyperexcitability and DRG neuron sprouting." Similarly, Smith et al. (2013) (supra) described that analgesic doses of the AT2R antagonist EMA300 blocked enhanced angiotensin II / AT2R signaling in the dorsal root ganglion, which in turn inhibited p38 MAPK and p44 / p42 MAPK activation in the ipsilateral lumbar DRG of nerve-injured rats.

[0022] Although antagonists of the AT2R, such as EMA401, have shown efficacy in treating post-herpetic neuralgia in human subjects (see, e.g., Rice et al., The Lancet, Volume 383, pp. 1637-1647, May 10, 2014), and in preclinical pain models of shingles, diabetes, osteoarthritis, HIV, and chemotherapy (see, e.g., WO 2006 / 066361 and Anand et al., supra), known AT2R antagonists have so far appeared to have limited success in (further) clinical development.

[0023] Rice et al., "Pain," March 1, 2021, reported the results of two multicenter, randomized, double-blind, phase 2b studies evaluating the analgesic efficacy and safety of EMA401 in patients with postherpetic neuralgia and painful diabetic neuropathy. As noted by Rice et al., "The primary outcome in both studies was the weekly mean change in 24-hour mean pain score, measured using the Numerical Rating Scale (NRS), from baseline to week 12. Although not observed in these studies, both studies were terminated early due to preclinical hepatotoxicity during long-term administration." Rice et al. further stated, "Although the early termination of the studies precludes firm conclusions, the consistent clinical improvement in pain intensity reduction across these two studies in two different populations is noteworthy."

[0024] As is evident from the above, there is a continuing need in the art for compounds that can be used to prevent and / or treat pain, particularly chronic pain such as neuropathic pain. In the words of Rice et al., "Existing treatments for peripheral neuropathic pain (PNP) are modestly effective and often poorly tolerated, and the development of improved treatments for these common chronic pain conditions is recognized as a significant unmet need."

[0025] In particular, there is a need for new classes of molecules that target AT2R and / or can be used to modulate the interaction of AT2R with one or more of its ligands (such as AngII), and that can be used for the prevention and / or treatment of various forms of chronic pain, for example chronic pain states caused by and / or associated with injury and / or disease of the somatosensory nervous system (particularly peripheral nerve injury and / or disease), chronic pain states caused by and / or associated with hypersensitivity to pain in response to tissue injury and / or inflammation, and more generally chronic pain states associated with AT2R-mediated signaling, AngII-mediated activation of AT2R, and / or AngII-mediated activated signaling pathways involving p38 MAPK and / or p44 / p42 MAPK. Summary of the Invention

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

[0027] The compounds provided by the present invention (also referred to herein as "compounds of the invention") are as further described herein.

[0028] Without being limited to any particular explanation, hypothesis, or mechanism of action, it is generally believed that the compounds of the present invention are capable of binding to the AT2R in a manner that allows the compounds of the present invention to compete with one or more ligands of the AT2R (particularly one or more natural ligands of the AT2R, such as Ang II) for binding to the AT2R.

[0029] Also, in general, compounds of the invention have favorable selectivity for the AT2R (eg, compared to the AT1R).

[0030] Furthermore, based on their overall chemical structure, the compounds of the present invention are generally expected to contain a pharmacophore that is favorable for clinical and therapeutic use in humans and other mammals. It is also expected that the compounds of the present invention may have certain advantages in terms of safety and tolerability compared to some of the known AT2R modulators described in the art.

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

[0032] In particular, it is contemplated that the compounds of the present invention are capable of modulating (as defined herein), in particular specifically modulating (as defined herein), e.g., inhibiting, angiotensin II receptor type 2, AT2R-mediated signaling, and / or pathways and / or biological processes involving AT2R and / or AT2R-mediated signaling. More particularly, as mentioned herein, it is contemplated that the compounds of the present invention are capable of competing with one or more natural ligands of AT2R for binding to AT2R.

[0033] It is therefore expected that the present compounds and compositions thereof may also be used in the prevention and treatment of diseases and disorders that can be prevented or treated by modulating angiotensin II receptor type 2, AT2R-mediated signaling and / or pathways and / or biological processes involving AT2R and / or AT2R-mediated signaling in a subject in need thereof, in particular by administering to the subject an appropriate treatment or dosing regimen (which may be determined by the treating physician based on the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that may be determined and taken into account as appropriate by the treating physician).

[0034] It is therefore further anticipated that the present compounds and compositions can be used in the prevention and treatment of diseases and disorders that can be prevented or treated by administering to a subject in need thereof a compound capable of competing with the binding of one or more natural ligands to the angiotensin II receptor type 2, in particular by administering to said subject one or more pharmaceutically active amounts (e.g., doses) of a compound of the present invention in accordance with an appropriate treatment or dosing regimen (which may be determined by the treating physician based on the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that will be determined by the treating physician and may be appropriately taken into account). Without being limited to any particular explanation, hypothesis, or mechanism of action, it will be apparent to those skilled in the art that, in general, administration to a subject of a compound capable of competing with the binding of one or more natural ligands to the angiotensin II receptor type 2 will result in a reduction of AT2R-mediated signaling associated with the binding of the ligand(s) to the AT2R and / or the inhibition and / or antagonism of pathways and / or biological processes induced and / or activated by the binding of the ligand(s) to the AT2R.

[0035] Examples of such diseases and disorders associated with AT2R, AT2R-mediated signaling, pathways and / or biological processes involving AT2R and / or AT2R-mediated signaling, and / or the binding of one or more natural ligands to AT2R will be apparent to those skilled in the art (e.g., from the prior art cited herein) and include other diseases and disorders for which the use of known modulators (particularly modulators that compete for ligand binding to AT2R) and / or known inhibitors and / or antagonists of AT2R and / or AT2R-mediated signaling has been described in the art. See, for example, the list of AT2R-mediated diseases and disorders set forth in WO 2019 / 179515. See also 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 state the following about the involvement of AT2R in diabetes, particularly type II diabetes: "This rare variant identified on chromosome Xq23, located near the AGTR2 gene, increases the risk for T2D by approximately two-fold in men, which, to our knowledge, represents the largest effect size identified so far in Europeans and a similar magnitude to other large-effect variants identified in other populations. We used binding and gene reporter analyses to demonstrate the functional role of this variant and propose a possible mechanism behind the pathophysiology of T2D in T risk allele carriers; this rare variant may support a gain of function of AGTR2, which has previously been associated with insulin resistance. AGTR2 therefore appears to be a potential therapeutic target for this disease, consistent with previous studies showing that blockade of the renin-angiotensin system in mice and humans prevents the onset of T2D and restores normoglycemia." "This gene regulates the regulation of angiotensin II (Ang II) II) encodes a G protein-coupled receptor that helps mediate its action (Harrison-Bernard, 2009).Furthermore, the AGTR2 gene is a modulator of insulin sensitivity, and previous studies have shown that blockade of the renin-angiotensin system in mice (Frantz et al., 2013; Leung, 2007) prevents the onset of T2D and restores normoglycemia in humans (Geng et al., 2013)." Therefore, it is expected that the compounds of the present invention can be used for the prevention and treatment of diabetes, particularly type 2 diabetes.

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

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

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

[0039] WO 2020 / 112905 describes compounds and methods for treating diseases using inhibitors of monoacylglycerol lipase (MAGL), the compounds having the formula: 15 Group (R 15 is hydrogen or C1-C6 alkyl) or —C(O)NR 10 R 11 Group (R 10 and R 11 are each independently hydrogen or C1-C6 alkyl).

[0040] [ka]

[0041] Among the diseases mentioned are atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette's 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, post-mastectomy pain syndrome, retrotrigeminal pain, postoperative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vaso-occlusive pain crisis in sickle cell disease, and visceral pain.

[0042] Among various MAGL inhibitors whose detailed chemical structures are listed, WO 2020 / 112905, page 53, paragraph

[0118] describes a compound having the following formula:

[0043] [ka]

[0044] Activity against the AT2R is not described or suggested. Also, as can be seen from Formula B, the MAGL inhibitor has a substituent (i.e., a CF3 group) meta 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) and between the piperazine ring and the carboxyl-substituted pyrazole group of Formula A. Also, in the compounds of Formulas A and B, the substituted pyrazole group is linked to the rest of the molecule via a nitrogen atom in the pyrazole ring rather than a carbon atom.

[0045] In this specification and claims: - If a term is not specifically defined herein, it has its ordinary meaning that would be apparent to one skilled in the art, e.g., as described in standard reference texts in the fields of organic chemistry and / or medicinal chemistry, e.g., Karrer, Organic Chemistry, 3 rdEd, 1947, Vogel, Practical Organic Chemistry, 3 rd Ed, 1964, Roberts and Caserio, Basic Principles of Organic Chemistry, 1 st Ed, 1965, Carey and Sundberg, Advanced Organic Chemistry, 2 nd Ed, 1985, Michael B. Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 1 st Ed, 2020, Jonathan Clayden, Nick Greeves, Stuart Warren, Organic Chemistry, 2 nd Ed, 2012, D. Sriram, Medicinal Chemistry, 2 nd Ed, 2010; and Camille Georges Wermuth, David Aldous, Pierre Raboisson, The Practice of Medicinal Chemistry, 4 th Ed, 2015. Also, see “Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)” by Wermuth et al., Pure and Applied Chemistry, 70(5): 1129 - 1143 (1998). - When a particular embodiment is indicated as being preferred (e.g., preferred for the presence of a particular moiety or structural element of the compounds of the invention and / or a particular preferred substituent or combination of substituents), such embodiment may be combined, as appropriate, with another embodiment that is described as being preferred (e.g., preferred for the presence of another moiety or structural element of the compounds of the invention and / or another preferred substituent or combination of substituents), and such combination of preferred embodiments forms another preferred embodiment of the invention. It is to be understood that the same applies mutatis mutandis to embodiments described herein by "more preferred," "particularly preferred," "even more preferred," "most preferred," or similar / equivalent language. - When structural formulae are used to generally illustrate or define compounds of the invention or aspects or embodiments of the invention, and such structural formulae show atoms for which not all (necessary or possible) bonds / groups / substituents are shown, it is to be understood that the unspecified bond / group / substituent may be subject to further description herein of such compound / aspect / embodiment, and in the absence of such further description may be hydrogen, or each may optionally be suitably and independently selected from suitable substituents (defined herein), but is typically a hydrogen atom. - When reference is made to "suitable substituents," or when it is stated that an atom or position in a compound of the invention may be "suitably substituted," each of these substituents (and combinations thereof) can be suitably selected by one of ordinary skill in the art, optionally after some trial and error. Suitable substituents will be apparent to one of ordinary skill in the art based on the disclosure herein (optionally after some trial and error), and include, for example, the substituents or combinations of substituents present in the compounds of the invention described herein and / or shown in the experimental section below (see compounds A-01 to A-251 in Table 1). Other suitable substituents will be apparent to those of skill in the art based on the disclosure herein, and include, but are not limited to, halogen (i.e., F, Cl, Br, and I), C1-C8 alkyl (particularly C1-C4 alkyl), C1-C8 alkoxy (particularly C1-C4 alkoxy), C1-C8 amine (particularly C1-C4 amine), cyclopropyl, cyclobutyl, trifluoromethyl (CF3), and cyano, as well as, for example, oxygen (i.e., to form a carbonyl group), which may include, for example, one or more of the substituents present in the compounds of the invention exemplified in the experimental section below (see, for example, 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 may be unsubstituted or may be suitably substituted with one, two, or up to three (in the case of a carbon atom) or one or two (in the case of a nitrogen atom) substituents, each of which is appropriately and independently selected from one or more suitable substituents (defined herein). The maximum number of such suitable substituents that may be present at a particular position in a compound of the present invention depends on the number of hydrogen atoms carried by the atom present at that position that may be suitably substituted with a suitable substituent (defined herein), taking into account factors such as the other atoms in the compound of the present invention to which the atom at that position is bonded. It will also be apparent that the total number of substituents that may be present in or on a compound of the present invention (or any structural portion thereof) generally depends on the number of atoms in such compound that are (suitably) available for such substitution (e.g., that carry hydrogen atoms that may 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 (as further described herein), in particular in the form of a pharmaceutically acceptable salt or ester (also as 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 the 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, for example a suitable crystalline form (including a co-crystalline form or co-crystalline salt form), a suitable amorphous form, and / or anhydrous or a suitable hydrate or solvate (including, but not limited to, a hydrate or hemihydrate). The compounds of the present invention (including salts or esters thereof) can generally be present in a solution, for example in a suitable solvent or mixture of solvents, such as a suitable aqueous solvent or buffer. For pharmaceutical use, the compounds of the present invention can 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 clear to those skilled in the art and include, but are not limited to, those mentioned in the further description herein. The compounds of the present invention (or salts or esters thereof) may generally be in pure or essentially pure form, isolated or essentially isolated form, or in suitable mixture with one or more other compounds. If the compound of the present invention contains one or more chiral atoms or centers, it may be in the form of one or more different optical forms, e.g., different enantiomers or different stereoisomeric forms (e.g., in the form of two or more enantiomers or in the form of two or more diastereomers, the terms "diastereomer" or "diastereoisomer" are generally used herein to refer to any stereoisomer that is not an enantiomer). Generally, unless expressly indicated otherwise or the specific context dictates otherwise, when a compound of the present invention can exist in one or more such optical forms, the term "compound of the present invention" as used herein refers to and includes all such possible optical forms (e.g., all possible enantiomers or stereoisomers, respectively). Also, when a compound of the present invention can exist in one or more such optical forms, the term "compound of the present invention" includes each such optical form in essentially pure form (and / or essentially isolated form), as well as mixtures of two or more possible optical forms (in any ratio), including, but not limited to, racemic mixtures. The compounds of the present invention may also be administered or used in the form of suitable prodrugs, for example, compounds that are converted to the compounds of the present invention when administered to a subject and / or under physiological conditions. See, for example, IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, pp. 163-198, Published by HIROKAWA SHOTEN (1990). The compounds of the present invention may be suitably labeled with a suitable label (e.g., an atom, group, moiety, or entity that is capable of producing (or can be used to produce) a detectable signal under appropriate conditions. Some specific, but non-limiting, embodiments of suitable labels include radioisotopes (e.g., 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, for example, for tissue distribution / penetration studies, as well as for PK and other pharmacological studies, and in fields such as medical diagnostics, using appropriate techniques for detecting the label. For example, the radiolabeled 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 the further description herein, in some cases, as further described herein, different moieties or structural elements of the compounds of the present invention can be either directly linked (i.e., via a covalent bond) or linked via a suitable linking or bridging group. When present, such a linking group (also referred to herein as an "alkylene linking group") is generally a C1 or C2 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 independently be optionally substituted (e.g., with one or two methyl groups per carbon atom), as appropriate, but is preferably unsubstituted (i.e., a -CH2- linking group). Alternatively, such an alkylene linking group can be a carbonyl (i.e., -(C=O)-) group, as further described herein. - When an atom is substituted with a fluorine atom, the substituent is also referred to as a "fluorine" or "fluoro" substituent (similar terms apply when a carbon atom is substituted with another halogen, such as chlorine or bromine). The term "bioisostere," when used with respect to a compound, group, or moiety, has its ordinary meaning in the art and refers to a compound, group, or moiety that has similar physical or chemical properties and, as a result, broadly similar biological activity to the compound, group, or moiety (Friedman HL (1951), NASNRS 206:295-358). Typically, a bioisostere, obtained by replacing 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, altered or improved activity, or an improved metabolic profile) compared to the original compound, group, or moiety. See, for example, Meanwell, Tactics in Contemporary Drug Design pp. 283-380, Topics in Medicinal Chemistry, Volume 9, 2014. The term "pharmacophore" usually refers to the commonly used IUPAC definition, i.e., "the collection of steric and electronic features necessary to ensure optimal supramolecular interaction with a particular biological target and to induce (or block) its biological response." See, e.g., "Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)" by Wermuth et al., Pure and Applied Chemistry, 70(5):1129-1143 (1998). - 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, in particular 1 to 8 carbon atoms ("Ci_8 alkyl" or "Ci-C8 alkyl"), for example 1 to 6 carbon atoms ("Ci_6 alkyl" or "Ci-C6 alkyl"), for example 1 to 4 carbon atoms ("C 1~4For example, as used herein, the terms "Ci-8 alkyl" and / or "Ci-C alkyl" refer to a straight or branched chain group of 1 to 8 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 5-methyl-2-pentyl, 6-methyl-2-pentyl, 7-methyl-2-pentyl, 8-methyl-2-pentyl, 9-methyl-2-pentyl, 10-methyl-2-pentyl, 11-methyl-2-pentyl, 12-methyl-2-pentyl, 13-methyl-2-pentyl, 14-methyl-2-pentyl, 15-methyl-2-pentyl, 16-methyl-2-pentyl, 17-methyl-2-pentyl, 18-methyl-2-pentyl, 19-methyl-2-pentyl, 20-methyl-2-pentyl, 21-methyl-2-pentyl, 22-methyl-2-pentyl, 23-methyl-2-pentyl, 24-methyl-2-pentyl, 25-methyl-2-pentyl, 26-methyl-2-pentyl, 27-methyl-2-pentyl, 28-methyl-2-pentyl, 29-methyl-2-pentyl, 30-methyl-2-pentyl, 31-methyl-2-pentyl, 32-methyl-2-pentyl, 33-methyl-2-pentyl, 34-methyl-2-pentyl, 35-methyl-2-pentyl, 36-methyl-2-pentyl, 37-methyl-2-pent The terms "Ci-4 alkyl" and "Ci-C4 alkyl" refer to straight or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). - The term "C1-C8 alkoxy" refers to an alkoxy group containing a C1-C8 alkyl group as defined herein. Similarly, the term "C1-C6 alkoxy" refers to an alkoxy group containing a C1-C6 alkyl group as defined herein, and the term "C1-C4 alkoxy" refers to an alkoxy group containing a C1-C4 alkyl group. - The term "C1-C8 amine" refers to the amine group NR F R G In the formula, R F and R G are each independently hydrogen or a C1-C8 alkyl group as defined herein, provided that R F and R G (wherein both are not hydrogen). Similarly, the term "C1-C6 amine" refers to the amine group NR F R G In the formula, R F and R Gare each independently hydrogen or a C1-C6 alkyl group as defined herein, provided that R F and R G are not both hydrogen), the term "C1-C4 amine" refers to the amine group NR F R G In the formula, R F and R G are each independently hydrogen or a C1-C4 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), which may be unsubstituted or substituted (as described herein), but when substituted is most preferably substituted with C1 or C2 alkyl groups only (preferably one or two methyl groups), as appropriate; - the term "heterocyclyl" refers to a non-aromatic ring having 3 to 10 ring atoms, preferably 3, 4, 5 or 6 ring atoms, suitably containing carbon atoms and 1 or 2 heteroatoms (each suitably selected from N, O or S), where each such heteroatom is most preferably bonded to 2 carbon atoms in the ring (and most preferably not bonded to another heteroatom in the ring), and the non-aromatic ring may be unsubstituted or suitably substituted (as described herein), but when substituted, is most preferably substituted with C1 or C2 alkyl groups only (preferably 1 or 2 methyl groups). Representative, but non-limiting, examples include pyrroline, pyrrolidine, pyrazolidine, imidazoline, tetrahydrofuran, piperidine, piperazine, and morpholine. Each such heterocyclyl group, when present, can be unsubstituted or appropriately substituted (as described herein), but, if substituted, is most preferably substituted only with C1 or C2 alkyl groups (preferably one or two methyl groups). Also, when such a heterocyclyl group contains one or more nitrogen atoms, each such nitrogen atom can be unsubstituted or appropriately substituted with a C1-C3 alkyl group (preferably a methyl group). The terms "modulate," "modulation," "modulator," and "target" have their usual meaning in the art, and in this regard, see inter alia the definitions in WO 98 / 06737. In general, in the context of the present invention, "modulate" or "to modulate" generally means either reducing or inhibiting the activity of a GPCR, or increasing the activity of a GPCR, when measured using a suitable in vitro, cellular, or in vivo assay (such as those described herein). In particular, "modulate" or "to modulate" can mean either reducing or inhibiting the activity of a GPCR by at least 1%, preferably at least 5%, such as 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, or increasing the activity of a GPCR, when measured using a suitable in vitro, cellular, or in vivo assay (such as those mentioned herein), compared to the activity of the GPCR in the same assay under the same conditions but in the absence of a compound, amino acid sequence, or polypeptide (if applicable) of the invention. As will be clear to those skilled in the art, "modulating" may also include causing a change (which may be either an increase or a decrease) in the affinity, avidity, specificity and / or selectivity of a GPCR for one or more of its targets, ligands or substrates, and / or causing a change (which may be either an increase or a decrease) in the sensitivity of a GPCR to one or more conditions in the medium or environment in which it is found (e.g., pH, ionic strength, presence of cofactors, etc.), compared to under the same conditions but in the absence of a compound, amino acid sequence or polypeptide (if applicable) of the invention. As will be clear to those skilled in the art, this may also be determined in any suitable manner and / or using any suitable assay known per se, such as the assays described herein or the prior art cited herein."Modulate" can also mean bringing about a change (i.e., activity as an agonist, antagonist, reverse agonist, and / or allosteric modulator, respectively, depending on the GPCR and the desired biological or physiological effect) in one or more biological or physiological mechanisms, effects, responses, functions, pathways, or activities in which the GPCR is involved (or in which a substrate, ligand, or pathway of the GPCR is involved, e.g., its signal transduction pathways or metabolic pathways and their associated biological or physiological effects). As will also be apparent to those skilled in the art, such action as an agonist or antagonist can be determined in any suitable manner and / or using any suitable (in vitro and usually cellular or in vivo) assays known per se, such as the assays described herein or in the prior art cited herein. In particular, the agonistic or antagonistic action may be such that the intended biological or physiological activity (such as, but not limited to, receptor-mediated signal transduction) is increased or decreased by at least 1%, preferably at least 5%, such as at least 10% or at least 25%, such as at least 50%, at least 60%, at least 70%, at least 80%, or 90% or more, respectively, compared to the biological or physiological activity under the same conditions but in the same assay in the absence of the related compound, amino acid sequence or polypeptide of the invention.In general, within the context of the specification and claims, it should be understood that the invention and disclosure is not limited to any particular mechanism by which a compound, amino acid sequence, or polypeptide of the invention modulates its target (so long as the target is modulated as described herein), and thus modulation can include, for example, but not limited to, binding at an orthosteric site or allosteric modulation (i.e., binding at an allosteric site, see, e.g., George et al., Nat. Rev. Drug Discov. 1:808-820 (2002); Kenakin, Trends Pharmacol. Sci. 25:186-192 (2002) and Rios et al., Pharmacol. Ther. 92:71-87 (2001)), reducing or inhibiting binding of the GPCR to one of its substrates or ligands, and / or competing with a natural ligand or substrate for binding to the GPCR. Modulation can also include activation of the GPCR or a mechanism or pathway in which it is involved. 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 agent that can modulate a GPCR, meaning that it can enhance, inhibit / reduce, or otherwise alter, affect, or influence the functional properties of a biological activity or process (e.g., the biological activity of a target and / or of a signal transduction and / or biological pathway in which the target is involved, or a biological readout associated with the target or signal transduction) under physiological conditions and / or conditions used in a relevant assay or model, as described herein. In this context, a modulator can be used to modulate a target in vitro (e.g., as part of an assay or screen) and / or in vivo (e.g., when the modulator is administered to an animal (e.g., for veterinary purposes or as part of an in vivo model), a subject (i.e., for therapeutic purposes, i.e., for the prevention or treatment of one or more diseases in the subject that can be prevented or treated by use of the modulator)).Modulators or candidate modulators may be identified, tested and / or further characterized by, for example, primary screens (e.g., screens used to identify modulators of a target from a set or library of test chemicals with unknown activity with respect to the target) and / or secondary assays (e.g., assays used to validate hits in the primary screen and / or used in optimizing hit molecules, e.g., as part of hit-to-lead), and / or in vitro screens or assays involving the relevant target, such as cellular or animal models that allow the testing / determination of one or more relevant parameters (i.e., parameters that are modulated). For example, such assays or screens may be configured as in vitro assays or screens, and generally involve binding of a (candidate) modulator to a target and measuring a signal generated by this binding. Suitable techniques for such in vitro screening are clear 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 configured as a binding assay or screening, in which a (candidate) modulator is used to displace a detectable ligand (e.g., a radioactive or fluorescent ligand) from a target, and the amount of ligand displaced from the target by the modulator is determined based on this. Generally, a compound is considered a modulator if it alters or changes the functional property of a biological activity or process (i.e., the signal or readout in a relevant assay or model) by at least 1 percent, for example, at least 5 percent, compared to the value obtained when the same assay or model is performed in the absence of the (candidate) modulator. The term "affinity" refers to the strength or stability of a molecular interaction. Affinity is generally defined as the K Dor dissociation constant, which has units of mol / liter (or M). Affinity is also given by the binding constant, K A can also be expressed as 1 / K D is equal to (mol / liter) -1 (or M -1 The affinity can be determined in a manner known per se. - In the present specification and claims, it will also be clear that the term "monocyclic", when it refers to a ring system (such as an aliphatic or aromatic ring system), refers to a ring system comprising or essentially consisting of a single ring, which ring suitably comprises or essentially consists of carbon atoms and optionally one or more (such as one or two) heteroatoms (heteroatoms are preferably each independently suitably selected, more preferably selected from O, N and / or S). Depending on the atoms present in the ring, a monocyclic ring may suitably comprise or essentially consist of 3 to 10 ring atoms, for example 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, in particular 4, 5 or 6 ring atoms.

[0046] Similarly, in the present specification and claims, the term "bicyclic," when referring to a ring system (such as an aliphatic or aromatic ring system), refers to a ring system comprising or essentially consisting of two rings suitably fused to one another (typically, the two fused rings share two ring atoms, and each of the rings forming the bicyclic ring system suitably comprises or essentially consists of carbon atoms and optionally one or more (e.g., one or two) heteroatoms (heteroatoms are preferably each independently suitably selected, more preferably selected from O, N, and / or S). Generally, depending on the number of atoms present in each ring, a bicyclic ring can suitably comprise or essentially consist of 8 to 12 atoms, e.g., 8, 9, 10, 11, or 12 ring atoms. The fused rings in a bicyclic ring system typically share two carbon atoms, although, as will be apparent to those skilled in the art, it is also possible for the fused rings to share one carbon atom and one nitrogen atom, if nitrogen atoms are suitably present.

[0047] It will also be apparent to those skilled in the art that a bicyclic ring system may suitably comprise or essentially contain two aliphatic rings (again, typically suitably fused so that the two fused rings share two atoms), two aromatic rings (again, typically suitably fused so that the two fused rings share two atoms, with the entirety of the two rings in the bicyclic ring system forming a conjugated planar ring system), or may suitably comprise or essentially consist of one aromatic ring and one aliphatic ring (again, typically suitably fused so that the two fused rings share two atoms). For convenience only herein, and without limiting the scope of the disclosure or claims, bicyclic ring systems containing at least one aromatic ring will be generally referred to herein as aromatic ring systems, regardless of whether the second ring in the ring system is aromatic or aliphatic. As will also be apparent to those skilled in the art, a bicyclic ring system can also suitably include two of the monocyclic ring systems referred to herein that are suitably fused to one another (i.e., such that in the bicyclic ring system, the two fused rings share at least two ring atoms).

[0048] Similarly, in this specification and claims, the term "polycyclic," when referring to a ring system (such as an aliphatic or aromatic ring system), refers to a ring system comprising or consisting essentially of two or more rings (e.g., 2, 3, 4, or 5 rings), each ring in the ring system being suitably and independently fused to at least one other ring in the ring system (usually such that the two fused rings share two ring atoms). Again, in a polycyclic ring system, each of the rings forming the ring system suitably comprises or consists essentially of carbon atoms and may optionally contain one or more (e.g., one or two) heteroatoms (heteroatoms are preferably each suitably independently selected, more preferably selected from O, N, and / or S). As will be apparent to one 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, although as will be apparent to those skilled in the art, it is also possible for the fused rings to share one carbon atom and one nitrogen atom, provided that nitrogen atoms are appropriately present.

[0049] It will also be apparent to those skilled in the art that a polycyclic ring system may suitably comprise or contain essentially or exclusively aliphatic rings, may suitably comprise or contain essentially or exclusively aromatic rings, or may be composed of one or more aliphatic and one or more aromatic rings (again, merely for convenience, and without limiting the scope of the disclosure or claims, a polycyclic ring system containing at least one aromatic ring will generally be referred to herein as an aromatic ring system, regardless of whether the other rings in the system are aromatic and / or aliphatic). As will also be apparent to those skilled in the art, a polycyclic ring system may also suitably comprise two or more of the monocyclic ring systems referred to herein, suitably fused to one another (i.e., such that in the polycyclic ring system, the two rings fused to one another share at least two ring atoms).

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

[0051] Also, in this specification and claims, the term "heterocycle", when this term refers to a ring system (such as an aliphatic or aromatic ring system), refers to a ring system that suitably contains one or more heteroatoms (preferably each independently selected from N, O, or S), and the term "heteroaromatic", when this term refers to an aromatic ring system, refers to an aromatic ring system that suitably contains one or more heteroatoms (preferably each independently selected from N, O, or S).

[0052] In compounds of the present invention containing the ring systems described herein, the following should be noted. - the ring system may be covalently bonded or linked to other moieties of the compounds of the invention at any suitable position on the ring system, also to any other structural element present in or on the ring system, for example to any heteroatom present in the ring system and / or to any substituents present on the ring system. Also, if the ring system contains one or more nitrogen atoms, the ring system may be covalently bonded or linked to one or more other moieties and / or structural elements of the compounds of the invention via said nitrogen atoms. and / or Each atom comprising the ring system may independently be free of any substituents or suitably substituted (as defined herein), with the number of possible substituents on a given ring atom depending on the number of additional bonds that a given ring atom can form in addition to the bonds it has to other ring atoms (e.g., the number of hydrogen atoms that the ring atom has that can be suitably replaced by suitable substituents). Generally, when one or more such suitable substituents are present, they may be located at any suitable position on the ring system, and may also be located at any other structural element of the ring system, for example, at any heteroatom present in the ring system, and / or at the position at which the ring system is covalently bonded to other moieties of the compounds of the invention. Also, when the ring system contains one or more nitrogen atoms, each of the nitrogen atoms may independently be unsubstituted or suitably substituted (as defined herein), again depending on the number of additional bonds that the nitrogen ring atom can form in addition to the bonds it has to other ring atoms (e.g., the number of hydrogen atoms that the nitrogen atom has that can be suitably replaced by suitable substituents). And / or - When the ring system contains one or more heteroatoms, each of the one or more heteroatoms may be in any suitable position in the ring system (i.e., relative to a carbon atom in the ring system) relative to any other structural elements present in or on the ring system, for example, relative to any additional heteroatoms that may be present in the ring system, relative to any substituents present on the ring system, and / or relative to the position at which the ring system is covalently bonded to other moieties of the compounds of the invention. If one or more rings of a ring system containing one or more heteroatoms are desired or intended to be aromatic, the one or more heteroatoms present in the ring should be in a position relative to the carbon atoms in the ring and any other heteroatoms in the ring such that the resulting rings form a conjugated planar ring system. Also, when the ring system contains one or more nitrogen atoms, each of the nitrogen atoms may be independently and appropriately substituted (as defined herein), again depending on the number of additional bonds that the nitrogen ring atom can form in addition to the bonds it has to other ring atoms.

[0053] It should be further apparent that, in this specification and claims, the terms "aliphatic ring" and "aliphatic ring system" have their ordinary meaning in the art and generally refer to an aliphatic compound containing or consisting essentially of one or more rings (such as a single ring or two or more fused rings). As used herein and as customary in the art, the term aliphatic ring system also includes rings and ring systems containing one or more double or triple bonds, so long as the ring is not an aromatic ring (as defined herein).

[0054] Additionally, the term "alicyclic" is used herein to refer to a non-aromatic ring system containing only carbon atoms.

[0055] Generally, as will be apparent to those skilled in the art, such aliphatic ring systems may be monocyclic, bicyclic, tricyclic, or polycyclic (all as described herein) and may contain only carbon atoms or may suitably contain carbon atoms and a suitable number of heteroatoms (such as 1, 2, 3, or more, depending on the total number of rings in the aliphatic ring system) each independently selected from N, S, or O. It should also be noted that each atom in such aliphatic ring systems may be appropriately substituted (as defined herein). Although aliphatic ring systems may also suitably contain one or more double bonds (such as carbon-carbon double bonds), for convenience only, and without limiting the scope of the present disclosure or claims, ring systems containing at least one aromatic ring are generally referred to herein as aromatic ring systems.

[0056] The aliphatic ring systems described herein may also be bridged ring systems, and the terms "bridged" or "bridge" have their usual meaning in the art (i.e., such bridged aliphatic ring systems include two rings that share three or more atoms, and the two bridgehead atoms are separated by a bridge containing at least one atom, e.g., an alkylene bridge as described herein). Such bridged aliphatic ring systems may 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, as well as the bridged ring systems present in the compounds of the present invention exemplified in the experimental section below (see, e.g., compounds A-189, A-190, A-232, and A-233). For purposes of this specification and claims, a 6-, 7-, 8-, 9-, or 10-membered ring in which there is a direct covalent bond between two carbon atoms in the ring, such that the resulting ring system essentially comprises two fused rings that share the two connected ring atoms (e.g., as in decalin or the bicyclic diaza structure of formula XCVIII herein) is also considered a "bridged" ring system, although in such structures the "bridge" consists of a covalent bond.

[0057] Some specific, but non-limiting examples of aliphatic ring systems include, but are not limited to: monocyclic aliphatic ring systems containing only carbon atoms: cycloalkanes such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and cycloalkenes such as cyclopentene and cyclohexene, monocyclic aliphatic ring systems containing carbon and nitrogen atoms: azetidine, pyrrolidine, 2-pyrroline, 3-pyrroline, pyrazolidine, imidazolidine, 2-pyrazoline, 2-imidazoline, piperidine, piperazine, monocyclic aliphatic ring systems containing carbon and oxygen atoms: oxetane, tetrahydrofuran, 1,3-dioxolane, tetrahydropyran, 1,4-dioxane, 2H-pyran, 4H-pyran, 1,4-dioxine, monocyclic aliphatic ring systems containing carbon and sulfur atoms: tetrahydrothiophene (thiolane), 1,2-oxothiolane, 1,3-oxothiolane, monocyclic aliphatic ring systems containing carbon atoms and two different heteroatoms: 1,2-oxathiolane, 1,3-oxathiolane, morpholine, thiomorpholine, 1,2-thiazine, 1,4-thiazine, - bicyclic aliphatic ring systems containing carbon and nitrogen atoms: pyrrolizidine, decahydroisoquinoline, decahydroquinoline, bicyclic aliphatic ring systems containing carbon and sulfur atoms, - a bicyclic aliphatic ring system containing carbon atoms and two or more different heteroatoms.

[0058] Some other examples of aliphatic 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 that contain such aliphatic rings / ring systems.

[0059] Again, when present in a compound of the invention, such an aliphatic ring system may be suitably covalently bonded or linked to another moiety (or two or more other moieties) of a compound of the invention at any suitable position on the ring system (again, depending on whether the atom present at that position is capable of forming a covalent bond with another moiety of a compound of the invention). Again, each of the atoms comprising the aliphatic ring system may independently have no substituents or may be optionally substituted (as defined herein), with the number of possible substituents on a given ring atom depending on the number of covalent bonds that ring atom can form in addition to its bonds to other ring atoms.

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

[0061] In general, as will be apparent to those skilled in the art, such aromatic ring systems may be monocyclic, bicyclic, tricyclic, or polycyclic (all as described herein) and may contain only carbon atoms or may suitably contain a suitable number (one, two, three, or more, etc., depending on the total number of rings in the aromatic ring system) of heteroatoms (preferably each independently selected from N, S, or O). It should also be noted that each atom in such aromatic ring systems may be appropriately substituted (as defined herein). Also, as described herein, for the sole convenience, polycyclic ring systems (e.g., xanthenes) containing one or more aliphatic rings in addition to one or more aromatic rings are considered aromatic ring systems.

[0062] Some specific, but non-limiting examples of such aromatic ring systems include, but are not limited to: - monocyclic aromatic ring systems containing only carbon atoms: phenyl, monocyclic aromatic ring systems containing carbon atoms and one or more nitrogen atoms: pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, azepines, 1,4-diazepines, monocyclic aromatic ring systems containing carbon and oxygen atoms: furan, - monocyclic aromatic ring systems containing carbon 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-naphteridine, 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, tetrahydroquinoline, 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 atoms 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] Several 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 that contain such aromatic rings / ring systems.

[0064] Again, when present in a compound of the invention, such an aromatic ring system may be suitably covalently bonded or linked to another moiety (or two or more other moieties) of a compound of the invention at any suitable position on the ring system (again, depending on whether the ring atom in question is capable of forming a covalent bond in addition to the bond connecting it to the other ring atom), and again, each of the atoms comprising the aromatic ring system may independently bear no substituents or be optionally substituted (as defined herein), again depending on whether the ring atom in question is capable of forming a covalent bond with such substituent in addition to the bond connecting it to the other ring atom.

[0065] It should also be noted that, as will be apparent to one skilled in the art, the ring systems described herein may be suitably 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, isoquinolin-1-[2H]-one.

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

[0067] As further described herein and exemplified by some of the compounds of the invention exemplified in the experimental section below, when a compound contains two or more rings or ring systems (which rings are not fused into a single ring system), the rings may suitably be linked directly via a covalent bond or indirectly via a suitable (unsubstituted or suitably substituted) alkylene linking group (as further defined herein), such as an (unsubstituted or suitably substituted) methylene linking group (wherein, as referred to herein, each such alkylene linking group may alternatively be a carbonyl group).

[0068] As further described herein, as part of their overall structure, the compounds of the present invention generally comprise an aliphatic ring (as further described herein) covalently linked (i.e., either directly or via an alkylene linker, particularly a methylene linker, both as defined herein) to an aromatic ring (as further described herein), which further comprises at least 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, without being limited to any hypothesis or explanation, is believed to enable interaction or improved interaction with the AT2R, particularly with one or more amino acids in the AT2R sequence believed to be present in the putative binding pocket / site on / in the AT2R to which the compounds of the present invention are believed to bind). This is shown schematically in the following scheme (Scheme A), in which the aliphatic ring is schematically illustrated using a six-membered ring and the aromatic ring is schematically illustrated using a six-membered ring (the aromaticity of the ring is generally indicated using a dashed circle).

[0069] [ka]

[0070] Scheme A above also shows a numbering system for the atoms of the aliphatic ring and the aromatic ring, which is used herein for convenience purposes only and without limiting the scope of this disclosure or the claims. Also, for convenience purposes only and without limiting the scope of this disclosure or the claims, the aliphatic ring is also referred to herein as "aliphatic ring A" or "ring A" etc. and is also designated "[A]", the aromatic ring is also referred to herein as "aromatic ring B" or "ring B" etc. and is also designated "[B]", and the acidic substituent is also referred to herein as "acidic substituent", "substituent D" etc. and is also designated "[D]".

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

[0072] It should be noted that in this specification and claims, the expression "position / atom meta to the acidic substituent" is used only to refer to the position / atom on aromatic ring B designated "4" in Scheme A above (and not the position / atom on aromatic ring B designated "6" in Scheme A above, which is also referred to herein as "other ortho positions on the aromatic ring").

[0073] With respect to the aliphatic ring A, as further described herein, it should also be noted that the aliphatic ring A can essentially consist of a bridged ring system (as further described herein), which may be unsubstituted or substituted (as further described herein), or a fused ring system (as further described herein), which may be unsubstituted or substituted (as further described herein), or a spiro ring system, which may be unsubstituted or substituted (as further described herein). Some specific, but non-limiting examples of such fused or spiro ring systems are shown herein as Formulas LXXXV and XCII, XCVIII, and C, respectively.

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

[0075] It should be noted that for aromatic ring B, if said ring B is a five-membered ring, the same numbering system is used and the position / atom where aromatic ring B is attached to aliphatic ring A is also designated as position "1", but there is no position / atom designated as "6" in Scheme A above.

[0076] Similarly, for aliphatic ring A, if ring A is a 5-membered ring, the same numbering system as shown in Scheme A is used, and the position / atom at which aromatic ring system C is connected to aliphatic ring A is again designated as position "1," but it should be noted that there is no position / atom designated as "6" in Scheme A above. Also, for aliphatic ring A, if ring A is a 7-membered ring, the same numbering system as shown in Scheme A is used, and the position / atom at which aromatic ring system C is connected to aliphatic ring A is designated as position "1," and there is an additional position / atom in aliphatic ring A between position / atom "1" and position / atom "6," referred to herein as position / atom "7" (similarly, if ring A is an 8-membered ring, there are additional positions / atoms "7" and "8" between positions "1" and "6" as shown in Scheme A).

[0077] Also, with reference to Scheme A above, again for convenience only, and without limiting the scope of the disclosure or claims, in the further description and claims, the positions / atoms on aliphatic ring A designated "1" and "4," respectively, in Scheme A are also referred to as positions / atoms in ring A that are "opposite" one another. Similarly, if aliphatic ring A is a 5-membered ring, then positions / atoms "3" and "4" are each considered to be opposite the position / atom at position "1" in ring A, and if aliphatic ring A is a 7-membered ring, then positions / atoms "4" and "5" are each considered to be opposite the position / atom at position "1" in ring A.

[0078] When aliphatic ring A is an 8-membered ring, positions "4," "5," and "6" (especially position "5") are considered to be opposite position "1" in the ring; when aliphatic ring A is a 9-membered ring, positions "5" and "6" are considered to be opposite position "1" in ring A; and when aliphatic ring A is a 10-membered ring, positions "5," "6," and "7" (especially position "6") are considered to be opposite position "1" in ring A (as further described herein, aromatic ring B is bonded to such 8-, 9-, or 10-membered aliphatic ring A at one of the positions / atoms in ring A opposite to the atom in position "1," i.e., the atom / position to which aromatic ring system C is bonded). Based on the disclosure herein, it will be clear to one skilled in the art which position / atom should be considered "opposite" to position "1" in ring A when ring A is a bridged or spiro ring system, as essentially the same considerations apply.

[0079] It will also be apparent to those skilled in the art from further description herein that the compounds of the present invention generally and preferably comprise a second aromatic ring system (different from aromatic ring B), which is covalently bonded to the position / atom on aliphatic ring A designated "1" in the formula above (i.e., the position / atom "opposite" the position / atom to which aromatic ring B is attached), either directly or via an alkylene linking group, particularly a methylene linking group (both of which are defined herein and may be a carbonyl group as referred to herein). Generally, again for convenience only and without limiting the scope of the disclosure or claims, the second aromatic ring system (described further herein) is also referred to herein as "aromatic ring system C" or "ring system C," and is designated "[C]," and the position / atom on aliphatic ring A to which the aromatic ring system C is attached is considered position "1" of aliphatic ring A for purposes of applying the numbering system generally shown in Scheme A above and further described in the preceding paragraph.

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

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

[0082] [ka] wherein each C is a carbon atom, 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 any R x group and each R presenty groups are independently as further defined herein, (v) R attached to the carbon chain x or R y One of the following, and C (w) R attached to the carbon chain x or R y taken together form an alkylene bridge or a covalent bond, such that the resulting structure is a bridged ring system or a fused ring system, respectively, both as further described herein), more specifically the overall structure generally represented by Scheme D below:

[0083] [ka] wherein 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); 12 each independently as further defined herein, wherein one of R or R and one of R or R 12 taken together form an alkylene bridge or a covalent bond, such that the resulting structure is a bridged or fused ring system, respectively, both as further described herein), or wherein the aliphatic ring A is a ring system of one of the formulas XCIX or C;

[0084] [ka] wherein said ring systems of formula XCIX or formula C, when present, may each preferably be independently optionally substituted with one or more suitable substituents selected from the group consisting of hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3 and isopropyl; and the aromatic ring B has an overall structure that is schematically represented by Scheme E below,

[0085] [ka] wherein [D] represents an acidic substituent [D] (as further described herein), and each of X, Y, and Z and each of R, R, R, and R (when present) are as further described herein, in particular the overall structure generally represented by Scheme F below:

[0086] [ka] wherein [D] represents an acidic substituent [D] (as further described herein), and each of R, R, R, and R is as further described herein, and more particularly the overall structure generally represented by Scheme G below:

[0087] [ka] wherein [D] represents an acidic substituent [D] (described further herein); and each of R, R, and R is as further described herein; and - the aromatic ring system C is either directly covalently bonded to the aliphatic ring A or is linked to the aliphatic ring A via an alkylene linking group (as defined herein, which may be a carbonyl group as referred to herein), in particular a methylene linking group (as defined herein), and - the aliphatic ring A is either directly covalently bonded to the aromatic ring B or is linked to the aromatic ring B via an alkylene linking group (as defined herein, which may be a carbonyl group as referred to herein), in particular a methylene linking group (as defined herein); and - aromatic ring system C and aromatic ring B are linked to aliphatic ring A at opposite ring atoms (as further defined herein) within aliphatic ring A;

[0088] As will be clear to those skilled in the art from the further disclosure herein, where a preferred embodiment is recited or described herein with respect to one of the aromatic ring system C, the aliphatic ring A, the aromatic ring B and / or the substituent D and / or any substituent or combination of substituents, it should also be understood that this preferred embodiment is preferably combined as appropriate with the embodiments recited 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 (the same applies mutatis mutandis to the embodiments recited or described herein as "more preferred," "particularly preferred" and "most preferred" with respect to 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).

[0089] Again, 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 (m) R A R B and C (n) R C R D (if present) and substituents R1 to R 12 Each of (if present) may generally be as further described herein, preferably according to the respective preferred aspects described for each of them herein.

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

[0091] [ka] During the ceremony, - an aromatic ring system represented by [C], an acidic substituent represented by [D], each of X, Y and Z, each of R1, R2, R3 and R4 (if present), R A , R B , R C and R Dand m and n are each as further defined herein (particularly according to the preferred embodiments described herein for each of these), During the ceremony, [A] represents a ring system as schematically represented by Scheme C below,

[0092] [ka] In the formula, each atom Q and each group R x and R y and each of v and w are as further described herein, in particular a ring system represented generally by Scheme D below:

[0093] [ka] In the formula, each Q and R5 to R 12 each of which is as further described herein, or [A] is a ring system of one of formulas XCIX or C;

[0094] [ka] wherein the ring systems of formula XCIX or formula C, if present, may each be suitably optionally substituted with one or more suitable substituents, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3 and isopropyl.

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

[0096] [ka] During the ceremony, - an aromatic ring system represented by [C], an acidic substituent represented by [D], each of R1, R2, R3 and R4, R A , R B , R C and R D and m and n are each as further defined herein (particularly according to the preferred embodiments described herein for each of these), During the ceremony, [A] represents a ring system as schematically represented by Scheme C below,

[0097] [ka] In the formula, each atom Q and each group R x and R y and each of v and w are as further described herein, in particular a ring system represented generally by Scheme D below:

[0098] [ka] In the formula, each Q and R5 to R 12 each of which is as further described herein, or [A] is a ring system of one of formulas XCIX or C;

[0099] [ka] wherein the ring systems of formula XCIX or formula C, if present, may each be suitably optionally substituted with one or more suitable substituents, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3 and isopropyl.

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

[0101] [ka] During the ceremony, - an aromatic ring system represented by [C], an acidic substituent represented by [D], each of R1, R2 and R4, R A and R B Each of the following, and each m is as further defined herein (particularly according to the preferred embodiments described herein for each of these); During the ceremony, [A] represents a ring system as schematically represented by Scheme C below,

[0102] [ka] In the formula, each atom Q and each group R x and R y and each of v and w are as further described herein, in particular a ring system represented generally by Scheme D below:

[0103] [ka] In the formula, each Q and R5 to R 12 each of which is as further described herein, or [A] is a ring system of one of formulas XCIX or C;

[0104] [ka] wherein the ring systems of formula XCIX or formula C, if present, may each be suitably optionally substituted with one or more suitable substituents, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3 and isopropyl.

[0105] As further described herein, according to a preferred but non-limiting embodiment of the present invention, the compounds of the present invention have the following structure (Formula IV):

[0106] [ka] In the formula, the aromatic ring system represented by [C], the acidic substituent represented by [D], each of X, Y and Z, each of R1, R2, R3 and R4 (if present), R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of R A , R B , R C and R D Each of the following, each Q, and m and n are each as further defined herein (particularly according to the preferred embodiments described herein for each of these):

[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] [ka] In the formula, the aromatic ring system represented by [C], the acidic substituent represented by [D], each of R1, R2, R3 and R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of R A , R B , R C and R D Each of the following, each Q, and m and n are each as further defined herein (particularly according to the preferred embodiments described herein for each of these):

[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] [ka] In the formula, the aromatic ring system represented by [C], the acidic substituent represented by [D], each of R1, R2 and R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of R A and R B Each of the following, each Q, and m are each as further defined herein (particularly according to the preferred embodiments described herein for each of these):

[0111] In a specific, but non-limiting embodiment of the present invention, in the compounds of the present invention (particularly the compounds of the present invention of formula I, formula II, formula III, formula IV, formula V and / or formula VI), The group R1 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano.

[0112] In another specific, but non-limiting embodiment of the present invention, in the compounds of the present invention (particularly compounds of the present invention of formula I, formula II, formula III, formula IV, formula V and / or formula VI), The group R2 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine).

[0113] In another specific, but non-limiting embodiment of the present invention, in the compounds of the present invention (particularly compounds of the present invention of Formula I, Formula II, Formula IV and / or Formula V), the group R3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-8 alkyl (for example sec-butyl and especially iso-butyl), for example fluorine-substituted methyl groups (for example trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxy and cyano.

[0114] In a particularly preferred embodiment of the invention, the group R3 is isobutyl (ie, as in the compounds of the 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 (particularly the compounds of the present invention of Formula I, Formula II, Formula IV and / or Formula V), the group R1 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), and cyano; and / or the group R2 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), and / or The group R3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-8 alkyl (e.g. sec-butyl and especially iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2). C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2), and Preferably, the alkyl group is selected from the group consisting of cyano, and most preferably isobutyl (ie, as in the compounds of the present invention of formula III and / or formula VI).

[0116] In particular, according to the 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), the group R1 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), and cyano; the group R2 is preferably selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), the group R3 is preferably H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g. sec-butyl, and in particular iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g. cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, -NH-heteroalkyl, and is selected from the group consisting of N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, and is most preferably isobutyl (i.e., as in the compounds of the invention of formula III and / or formula VI).

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

[0118] In the compounds of the invention described herein, when the group R4 is present (e.g., as in compounds described by Formulas I, II, III, IV, V and VI), the group R4, when present, is 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 groups R5, R6, R7, R8, R9, R 10 , R 11 and / or R 12 When present (for example, as in compounds described by formulas IV, V and VI), such groups R5, R6, R7, R8, R9, R 10 , R 11 and / or R 12 Each, when present, is preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, or isopropyl.

[0120] In the compounds of the invention described herein, the group R A , R B , R C and / or R D When present (e.g., as in compounds described by Formulas I, II, III, IV, V and VI), compounds of Formulas III and IV have the group R C or R D (it is understood that such groups R A. , R B , R C and / or R Deach, when present, is independently selected from hydrogen, methyl and / or trifluoromethyl, or R A +R B When present, R is taken together with the carbon atom to which it is attached to form a carbonyl (C=O) group, and / or R C +R D When present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A +R B are taken together and replaced by a single oxygen atom to form a carbonyl group together with the carbon atom to which the oxygen atom is attached, and / or R C +R D and when present, are taken together and replaced by a single oxygen atom to form a carbonyl group together with the carbon atom to which said oxygen atom is attached), preferably each are a hydrogen atom.

[0121] In general, compounds of the invention have an activity against the AT2R of 1.0 x 10 -5 M (i.e., better than 10 micromolar), preferably 1.0 x 10 -6 M (i.e., better than 1 micromolar), more preferably 1.0×10 -7 M (i.e., better than 0.1 micromolar), and even more preferably 1.0×10 -8 M (i.e., better than 10 nanomolar) [in this regard, (i) in accordance with generally accepted scientific practice, -5 is also written as "E-05" and -6 is also referred to as "E-06", and (ii) by way of example, for purposes of this specification and claims, e.g., 1.0 x 10 -8 The affinity of M (10 nanomolar) is, for example, 1.0 x 10 -6Note that an affinity of, for example, 5 nanomolar is considered to be "better" than an affinity of, for example, 10 nanomolar.]

[0122] Thus, in more specific but non-limiting aspects, the present invention relates to: - a compound of the invention (further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 particular, - a compound of formula I (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 II (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 V (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 III (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 VI (as further described herein) having an affinity for AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0123] In a more specific, but non-limiting aspect, the present invention relates to compounds of the present invention (as further described herein) in which (i) the aromatic ring system [C], the aliphatic ring [A], the aromatic ring [B], and the acidic substituent [D], each of which is further described herein; (ii) the substituents present in such compounds of the present invention (each such substituent may independently be as further described herein for the particular substituent involved) and the particular combinations of such substituents present in said compounds of the present invention; and (iii) m and n (each of which may independently be 0 or 1, as described herein) are each such (and are such combinations) that said compounds of the present invention have an affinity for the AT2R (as measured according to the protocol described in Example 2 below) of 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 particular, the present invention relates to compounds of the present invention in which each of the substituents R1, R2, R3 and R4 on the aromatic ring [B] (when such substituents are present on the aromatic ring [B], in accordance with the further definitions provided herein), and the specific combinations of such substituents R1, R2, R3 and R4 present on the aromatic ring [B], are such (and are such combinations) that the compounds of the present invention have an affinity for AT2R (measured according to the protocol described in Example 2 below) of less than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0124] In more specific, but non-limiting aspects, the present invention relates to: - a compound of formula I (as further described herein), comprising: (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each of which is further described herein; and (ii) each of X, Y, and Z, and specific combinations of atoms X, Y, and Z, present in the compound of formula I; and (iii) each of the substituents R1, R2, R3, and R4 (if present), and specific combinations of such substituents R1, R2, R3, and R4, present in the compound of formula I; and (iv) m and n (each of which may independently be 0 or 1, as described herein); and (v) a substituent R1, R2, R3, and R4, present in the compound of formula I. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (vi) any further substituents present in such compounds of formula I (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the particular combinations of such substituents present in said compounds of formula I are each such (and are such combinations) that said compounds of formula I have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 (as further described herein) comprising: (i) an aromatic ring system [C] and an acidic substituent [D], each of which is 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, and specific combinations of atoms X, Y, and Z, present in the compound of formula IV; and (iv) each of the substituents R1, R2, R3, and R4, if present, and specific combinations of such substituents R1, R2, R3, and R4, present in the compound of formula IV; and (v) substituents R5 to R6, present in the compound of formula IV. 12 (if present) and each such substituent R5 to R 12 and (vi) m and n (each of which may independently be 0 or 1, as described herein), and (vii) any substituent R present in the compound of formula IV. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (viii) any further substituents present in such compounds of formula IV (e.g., on the aromatic ring system [C]), and the particular combinations of such substituents present in said compounds of formula IV are each such (and are such combinations) that said compounds of formula IV have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 II (described further herein), comprising: (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each of which is further described herein; (ii) each of the substituents R1, R2, R3, and R4 (if present) present in said compound of formula II, and specific combinations of such substituents R1, R2, R3, and R4; and (iii) m and n (each of which may independently be 0 or 1, as described herein); and (iv) a substituent R1 present in said compound of formula II. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (v) any further substituents present in such compounds of formula II (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the particular combinations of such substituents present in said compounds of formula II are each such (and are such combinations) that said compounds of formula II have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 V (as further described herein) comprising: (i) an aromatic ring system [C] and an acidic substituent [D], each of which is further described herein; and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, and preferably at least one Q is a nitrogen atom); and (iii) each of the substituents R1, R2, R3, and R4 (if present) present in said compound of formula V, and specific combinations of such substituents R1, R2, R3, and R4; and (v) substituents R5 to R6 present in said compound of formula V. 12 (if present) and each such substituent R5 to R 12and (vi) m and n (each of which may independently be 0 or 1, as described herein), and (vi) any substituent R present in the compound of formula V. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (viii) any further substituents present in such compounds of formula V (e.g., on the aromatic ring system [C]), and the particular combination of such substituents present in said compounds of formula IV are each such (and are such combinations) that said compounds of formula IV have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 III (as further described herein), comprising: (i) an aromatic ring system [C], an aliphatic ring [A], and an acidic substituent [D], each of which is further described herein; and (ii) each of the substituents R1, R2, and R4 (if present) present in said compound of formula III, and specific combinations of such substituents R1, R2, and R4; and (iii) m (which may be 0 or 1, as described herein); and (iii) a substituent R1 present in said compound of formula III. A and R B (if present), as well as each such substituent R A and R Band (iv) any further substituents present in such compounds of formula III (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the particular combinations of such substituents present in said compounds of formula III are each such (and are such combinations) that said compounds of formula III have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 VI (as further described herein), comprising: (i) an aromatic ring system [C] and an acidic substituent [D], each of which is further described herein; and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, and preferably at least one Q is a nitrogen atom); and (iii) each of the substituents R1, R2, and R4 (if present) and specific combinations of such substituents R1, R2, and R4 present in the compound of formula VI; and (iv) substituents R5 to R6 present in the compound of formula VI. 12 (if present) and each such substituent R5 to R 12 and (v) m (which may be 0 or 1 as described herein), and (vi) any substituent R present in the compound of formula VI. A and R B (if present), as well as each such substituent R A and R Band (vii) any further substituents present in such compounds of formula VI (e.g., on the aromatic ring system [C]), and the particular combinations of such substituents present in said compounds of formula VI are each such (and are such combinations) that said compounds of formula VI have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0125] It should be noted that for the purposes of the above aspect of the invention and each of the further aspects of the invention described herein, a substituent may be a hydrogen atom (i.e., meaning that the relevant position in the compound of the invention is unsubstituted), where the definition of the substituent, further description of the relevant compound and / or context permits.

[0126] As further described herein, 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 aromatic ring system C are aromatic rings, although this is not critical.

[0127] In general, it will be apparent to those skilled in the art from the present disclosure that the exact nature or structure of the aromatic ring system C is not critical so long as it contains at least one aromatic ring, although it is preferred that the aromatic ring system C is a monocyclic or bicyclic ring system.

[0128] It is also preferred (but not critical) that the aromatic ring system C is suitably linked to the aliphatic ring A (i.e., either directly or via an alkylene linking group as defined herein, particularly a methylene linking group, both as defined herein) at a ring atom that forms part of an aromatic ring present within the aromatic ring system C.

[0129] The ring atoms making up the aromatic ring system C may suitably consist entirely of carbon atoms, or the aromatic ring system C may suitably contain one or more heteroatoms (wherein any heteroatoms present are preferably each independently, but preferably selected from N, S or O). When the aromatic ring system C suitably contains at least one heteroatom, each of the rings making up the aromatic ring system C may suitably contain zero heteroatoms or suitably 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 ring 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 ring 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 in the ring system to share a nitrogen atom. Also, when the aromatic ring system C contains at least one heteroatom and is a monocyclic ring, the total number of heteroatoms in the aromatic ring system C can preferably be 1, 2, or 3. Also, in general, when the aromatic ring system C contains two or more heteroatoms, the heteroatoms may suitably be the same or different (again, as mentioned herein, preferably at least one of the heteroatoms is a nitrogen atom).

[0131] As can be seen from the various formulas provided herein, the aromatic ring system C is linked to one of the atoms Q in the aliphatic ring A. When the atom Q to which the aromatic ring system C is linked is a nitrogen atom, the aromatic ring system C is preferably linked to the aliphatic ring A (i.e., either directly or via an alkylene linking group, particularly a methylene linking group, both as defined herein) not via a nitrogen atom in the aromatic ring system C (i.e., when the aromatic ring system C contains at least one nitrogen atom), but preferably via a carbon atom present in the aromatic ring system C (which carbon atom preferably forms part of an aromatic ring in the aromatic ring system C, as referred to herein, but this is also not critical), since the resulting compound is generally expected to be not sufficiently stable for pharmaceutical use (unless the aromatic ring system C is linked to the rest of the molecule via a carbonyl linking group linked to such a nitrogen atom in the aromatic ring system C).

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

[0133] Examples of aromatic ring systems that may be present 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 the monocyclic, bicyclic and polycyclic aromatic ring systems referred to herein.

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

[0135] Unsubstituted or suitably substituted pyrazolyl groups (e.g. pyrazol-3-yl groups), such as 2,5-dimethylpyrazol-3-yl, - 1-methylpyrazol-3-yl, 2-methylpyrazol-3-yl,

[0136] Unsubstituted or substituted imidazolyl groups (e.g., imidazol-2-yl or imidazol-4-yl groups), such as - 1-methylimidazol-2-yl, - 1-methylimidazol-4-yl, - 3-methylimidazol-4-yl, - 2,3-dimethylimidazol-4-yl,

[0137] Unsubstituted or substituted triazolyl groups (e.g., 1,2,4-triazol-3-yl groups), such as 4-methyl-1,2,4-triazol-3-yl,

[0138] pyrazine group, Unsubstituted or substituted pyrimidine groups (for example 2-pyrimidine or 4-pyrimidine groups), such as - 2-pyrimidine, 4-[2-methyl]-pyrimidine,

[0139] Unsubstituted or substituted pyridazine groups (e.g., 3-pyridazine groups), such as - 6-methyl-3-pyridazine, - 5-methyl-3-pyridazine, - 6-methoxy-3-pyridazine,

[0140] Unsubstituted or substituted pyridyl groups (e.g., 2-pyridyl groups), such as 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 groups, for example: - 1-methyl-indazole,

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

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

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

[0145] Unsubstituted or substituted quinoxaline groups, for example - 2-methyl-3-quinoxaline,

[0146] Unsubstituted or substituted oxazole groups (e.g., 1,4-oxazole groups), such as 1,4-oxazole,

[0147] Unsubstituted or substituted isoxazole groups (e.g., isoxazole groups), such as - 5-methyl-isoxazole,

[0148] Unsubstituted or substituted oxadiazole groups (e.g., 1,2,4-oxadiazole groups), such as - 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 groups (e.g., 1,3-benzoxazole groups), such as - 2-[1,3-benzoxazole],

[0150] Unsubstituted or substituted oxazolopyridine groups (e.g., oxazolo[4,5-b]pyridine groups), such as - oxazolo[4,5-b]pyridine,

[0151] Unsubstituted or substituted thiazole groups (e.g., 2-thiazole or 4-thiazole groups), such as - 5-methyl-4-thiazole, - 5-methyl-2-thiazole, - 2-methyl-thiazole,

[0152] Unsubstituted or substituted benzothiazolyl groups (e.g., 1,3-benzothiazol-2-yl groups), such as 1,3-benzothiazol-2-yl,

[0153] Unsubstituted or substituted pyrimidinone groups (e.g., pyrimidin-4-one groups), such as 2-methyl-1H-pyrimidin-4-one, - 6-methyl-1H-pyrimidin-4-one,

[0154] Unsubstituted or substituted quinazolin-4-one groups (e.g. quinazolin-4-one groups), such as - quinazolin-4-one, - 2-ethyl-3-quinazolin-4-one,

[0155] Unsubstituted or substituted quinolinone groups (e.g., quinolin-2-one groups), such as - 1-methyl-quinolin-2-one,

[0156] Unsubstituted or substituted bicyclic pyrimidinone groups, 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 one skilled in the art based on the disclosure herein, aromatic ring system C may also be suitably substituted (as defined herein) with one or more (e.g., 1, 2, 3, or 4) suitable substituents on one or more (e.g., 1, 2, 3, or 4) suitable positions / ring atoms of aromatic ring system C. Suitable substituents will be apparent to one 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 suitable substituents mentioned herein. In a specific, but non-limiting, embodiment of the present invention, aromatic ring system C does not have a carboxylic acid (COOH) group.

[0158] As generally referred to herein, the total number of suitable substituents on the aromatic ring system C is generally not critical and typically depends on the size of the aromatic ring system C and the number of ring atoms in the aromatic ring system C. Typically, 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 specific, but non-limiting embodiments, each of the one or more substituents on the aromatic ring system C is suitably and independently selected from one or more of methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, cyano / nitrile, halogen atoms (particularly fluorine or chlorine), C1-C4 amines or oxygen atoms (i.e., said oxygen together with the carbon atom to which it is attached forms a carbonyl group, said carbon atom being capable of forming such a carbonyl group).

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

[0161] As already generally described herein for aromatic ring system C, when aromatic ring system C is a monocyclic or bicyclic aromatic ring system composed of one or two five- and / or six-membered rings, respectively, it suitably contains at least one heteroatom (each such heteroatom is preferably independently, but suitably selected from O, N or S, and preferably at least one of the heteroatoms present is a nitrogen atom), the total number of heteroatoms in aromatic ring system C being preferably 1 or 2 for monocyclic ring systems and preferably 1, 2, 3 or 4 for bicyclic ring systems. Also, as exemplified by some of the non-limiting examples of compounds of the present invention set forth in the experimental section below, such aromatic ring systems C, each composed of one or two five- and / or six-membered rings, preferably further comprise an aliphatic ring A linked to a carbon atom in the aromatic ring system C (i.e., either directly via a covalent bond or via an alkylene linking group as further described herein), which carbon atom forms part of an aromatic ring in the aromatic ring system C (which ring essentially forms the aromatic ring system C when the aromatic ring system C is a monocyclic ring), wherein the aromatic ring contains, in addition to the one carbon atom to which the aliphatic ring A is linked, 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 may be present as aromatic ring system C in the compounds of the present invention include the following ((i) where reference is made in Tables A, B, C and D below to atoms "A" or "Q" and groups R, R1, R2, R3 and R4, such atoms A and Q and such groups R, R1, R2, R3 and R4 are as defined in said Tables A-D, and (ii) it should be understood that 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 the tables and not to any other atoms, groups, structures or formulas described herein).

[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 selected from the group consisting of the aromatic rings / ring systems of formulae VII to LXXXIII:

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

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

[0173] Thus, in a further aspect, the present invention relates to: - compounds of the invention (as further described herein) in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, in particular, - compounds of formula I (as further described herein) in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, More specifically, - compounds of formula IV (as further described herein), in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, More specifically, - compounds of formula II (as further described herein), in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, More specifically, - compounds of formula V (as further described herein), in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, More specifically, - compounds of formula III (as further described herein), in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, More specifically, - compounds of formula VI (as further described herein), in which the aromatic ring system C is selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII, wherein such compounds of the invention (i.e., compounds of the invention according to any of the above-mentioned aspects) are preferably further such that such compounds have an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 rest being as further described herein).

[0174] As generally described herein, for each of the aromatic rings / ring systems shown as Formulas VII-LXXXIII, respectively, it is not excluded that when such ring or ring system is present as aromatic ring system C in the compounds of the present invention, such aromatic ring or ring system may be suitably substituted (or, in the case of aromatic rings of Formulas VII-LXXXIII already bearing one or more substituents, be suitably further substituted) with one or more (e.g., one, two, or three) additional substituents (where suitable 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 present invention exemplified in the experimental section below, as well as other suitable substituents described herein). However, for each of the aromatic rings / ring systems shown as Formulas VII-LXXXIII, it is generally preferred that such aromatic ring or ring system be present as aromatic ring system C in the compounds of the present invention without such (additional) substituents, particularly when such aromatic ring or ring system is shown in one of Formulas VII-LXXXIII to already bear one or more substituents. Also, in a specific, but non-limiting, embodiment of the present invention, aromatic ring system C does not bear a carboxylic acid (COOH) group.

[0175] Thus, preferably, the aromatic ring or ring system present as aromatic ring system C in the compounds of the present invention preferably consists of one of the aromatic rings / ring systems having the structure according to formulae VII to LXXXIII, more preferably one of the aromatic rings / ring systems having the structure according to formulae LIX to LXXXIII, and most preferably one of the aromatic rings / ring systems having the structure according to formulae LXXIII to LXXXIII.

[0176] Some specific, but non-limiting examples of compounds of the invention containing the aromatic ring system C 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 are as exemplified in the experimental section below.

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

[0178] The aliphatic ring A is generally a 5-, 6-, 7-, 8-, 9-, or 10-membered ring, preferably a 5-, 6-, or 7-membered ring, and most preferably a 6-membered ring, and the ring consists essentially of carbon atoms and one or more (e.g., 1 or 2) heteroatoms (when present, the heteroatoms are preferably each independently selected from O, S, and N, but most preferably nitrogen atoms as further described herein). It is not excluded that the aliphatic ring A may also suitably contain one or more double bonds (provided that the presence of these bonds does not make the aliphatic ring A an aromatic ring system), but preferably, the ring A is fully saturated (i.e., there are no double bonds in the ring), since compounds containing an unsaturated ring A are usually expected to be insufficiently stable for pharmaceutical use.

[0179] Aliphatic ring A is preferably a monocyclic ring, but may also be a bridged monocyclic ring suitably containing a suitable alkylene bridge (as defined herein) containing 1 or 2 carbon atoms, such that aliphatic ring A forms part of a "bicyclo" type structure containing a total of 7 to 12 atoms (including the alkylene bridge), preferably a total of 7, 8, or 9 atoms (including the alkylene bridge), as further described herein. For example, but not by way of limitation, aliphatic ring A may include a cyclohexane, piperidine, or piperazine ring suitably containing a suitable alkylene bridge (as defined herein) containing 1 or 2 carbon atoms (e.g., suitably bridging positions "2" and "6," "2" and "5," "3" and "6," or "3" and "5" in aliphatic ring A, such as 3,8-diazabicyclo[3.2.1]octane and 2,5-diazabicyclo[2.2.1]heptane (see also Formulas LXXXV and XCII herein)). In the experimental section below, compounds A-189 and A-190 provide some specific, but non-limiting examples of compounds of the present invention that contain a bridged aliphatic ring A. Also, as generally referred to herein, aliphatic 5-, 6-, 7-, 8-, 9-, and 10-membered aliphatic ring systems (such as in the aliphatic ring system of formula XCVIII and the aliphatic ring systems present in compounds A-232 and A-233) that are appropriately "bridged" by a covalent bond to form a system containing two fused rings that share the two "bridge" atoms are also considered to be bridged ring structures for the purposes of this specification and claims. Such bridged or fused ring structures, when present, also include the group R x or R y or R5~R 12 It may be optionally and suitably substituted with one or more substituents, each of which may be independently selected from the substituents mentioned herein for.

[0180] The aliphatic ring A may also be a spiro structure (preferably having any such spiro structure containing a total of 7 to 10 atoms), as exemplified, for example, by the spiro structure shown below as Formula C. Such spiro structures, when present, also contain the group R x or Ry and / or R5 to R 12 It may be optionally and suitably substituted with one or more substituents, each of which may be independently selected from the substituents mentioned herein for.

[0181] As further described herein, the aliphatic ring A is preferably linked to the aromatic ring system C (either directly or via an alkylene linking group as further described herein) and also to the aromatic ring B (again, either directly or via an alkylene linking group as further described herein), either such that the aromatic ring system C is linked to the aliphatic ring A via an alkylene linking group (the aromatic ring B is directly linked to the aliphatic ring A), or such that the aromatic ring B is linked to the aliphatic ring A via an alkylene linking group (the aromatic ring C is directly linked to the aliphatic ring A), more preferably such that the aromatic ring system C is linked to the aliphatic ring A via an alkylene linking group (the aromatic ring B is directly linked to the aliphatic ring A). As described herein, the alkylene linking group, when present, is preferably a methylene linking group (i.e., in Formulas I-VI, respectively, "C (m) R A R B " and "C (n) R C R D 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 linked to aliphatic ring A at atoms in aliphatic ring A (as defined herein) that are opposite each other in said aliphatic ring A.

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

[0184] In specific, but non-limiting, preferred embodiments, the aliphatic ring A described herein consists of carbon atoms and 0, 1 or 2 (preferably 1 or 2, more preferably 2) nitrogen atoms, particularly such that the aliphatic ring A contains a total of 5, 6 or 7 (preferably 6) ring atoms (excluding any carbon atoms present in the alkylene bridge, if present).

[0185] Thus, in general, the aliphatic ring A may have an overall structure that can be represented schematically as follows (Scheme C):

[0186] [ka] During the ceremony, - each C, if present, represents a carbon 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; - v is an integer of 1 to 4, w is an integer of 1 to 4, the sum of (v+w) is 3, 4, 5, 6, 7, or 8 (preferably 3, 4, or 5, and more preferably both v and w are 2), and the difference (vw) is 1, 0, or −1; - each carbon atom C is a group R x and group R y wherein each group R x may independently be hydrogen or a suitable substituent, the substituent preferably being selected from hydrogen, methyl, ethyl, halogen (especially fluorine (F)), CF3, and isopropyl, and each group R present y may independently be hydrogen or a suitable substituent, preferably selected from hydrogen, methyl, ethyl, halogen (especially fluorine (F)), CF3, and isopropyl.

[0187] Also, as described and exemplified herein, Ring A may be a ring that is suitably bridged by an alkylene bridge (as defined herein, but not shown in Scheme C) or a covalent bond (also not shown in Scheme C), where one end of the alkylene bridge or covalent bond is C (v) and the other end of the alkylene bridge or covalent bond is linked to one of the carbon atoms constituting the carbon chain represented by C (w) As will be apparent to 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, and C (w) R on the carbon chain represented by x or R y is substituted by an alkylene bridge, and when ring A is bridged by a covalent bond, C (v) R on the carbon chain represented by x or R y One of the, and C (w) R on the carbon chain represented by x or R yis replaced by the covalent bond.

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

[0189] As noted above, ring A may also be a spiro structure (preferably having any such spiro structure containing a total of 7 to 10 atoms), as exemplified, for example, by the spiro structure shown below as Formula C. Where possible given the number of available (remaining) covalent bonds on each carbon atom present in such a spiro structure, each carbon atom in such a spiro structure may also be bonded to a group R as defined herein. x and / or group R y may suitably have

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

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

[0192] It will be apparent to those skilled in the art that, according to a preferred embodiment of the ring represented by Scheme C, where v is 2 and w is 2, the aliphatic ring A is a six-membered ring. In such a six-membered ring, each carbon atom may be optionally (independently) substituted with one or two suitable substituents, preferably independently selected from hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3, and isopropyl.

[0193] Such six-membered rings can also be represented schematically by the following structure (Scheme D), where the optional substituents are R to R 12 Shown as:

[0194] [ka] During the ceremony, each Q is independently a carbon atom or a nitrogen atom, preferably at least one Q is a nitrogen atom, more preferably both atoms Q are nitrogen atoms; - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are preferably independently selected from hydrogen, methyl, ethyl, halogen (especially fluorine (F)), CF3, and isopropyl.

[0195] According to some preferred, but non-limiting examples, the aliphatic ring A can be, 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, particularly a methylene linking group, both as defined herein) and the aromatic ring B is linked at the "4" position of the cyclohexane ring (i.e., either directly or via an alkylene linking group, particularly a methylene linking group, both as defined herein), which may be a cyclohexane ring; in particular, - an (optionally suitably substituted) piperidine ring, in which aromatic ring system C is linked to the nitrogen atom of the piperidine ring (i.e. either directly or via an alkylene linking group as defined herein) and aromatic ring B is linked at the "4" position of the piperidine ring (i.e. either directly or via an alkylene linking group, in particular a methylene linking group, both as defined herein) (or vice versa, aromatic ring B is linked to the nitrogen atom and aromatic ring system C at the "4" position), which may be a piperidine ring; More specifically, - an (optionally suitably substituted) piperazine ring in which aromatic ring system C is linked to the nitrogen atom at the "1" position (i.e., either directly or through an alkylene linking group, particularly a methylene linking group, both as 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 through an alkylene linking group, particularly a methylene linking group, both as defined herein).

[0196] As an alternative to the structures of Scheme C or D, as described herein, the aliphatic ring A may be a ring system of one of formulas XCIX or C:

[0197] [ka] wherein the ring systems of formula XCIX or formula C, if present, may each be suitably optionally substituted with one or more suitable substituents, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, halogen (particularly fluorine (F)), CF3 and isopropyl.

[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:

[0199] [Table 8]

[0200] [Table 9]

[0201] As will be apparent to one of ordinary skill in the art based on the disclosure herein and the compounds of the invention exemplified in the experimental section below, the aliphatic ring A (in its various embodiments disclosed herein) can be unsubstituted or substituted. As will be apparent to one of ordinary skill in the art, when the aliphatic ring A is unsubstituted, each R in Scheme C can be substituted. x and R y , and each R5 to R in Scheme D 12 is a hydrogen atom.

[0202] Also, as mentioned herein, when the aliphatic ring A is substituted, each substituent present can generally be independently selected from the group consisting of methyl, ethyl, fluoro(F), CF3, 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 x and R y , and each R5 to R in Scheme D 12 may be independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF, and isopropyl (preferably, independently selected from the group consisting of methyl, ethyl, and isopropyl), provided that (i) with respect to Scheme C, the group R x and R y at least one of is selected from the group consisting of methyl, ethyl, fluoro(F), CF3, and isopropyl (preferably selected from the group consisting of methyl, ethyl, and isopropyl); and / or (ii) with respect to Scheme D, groups R5 to R 12 At least one of is selected from the group consisting of methyl, ethyl, fluoro (F), CF3, and isopropyl (preferably selected from the group consisting of methyl, ethyl, and isopropyl).

[0203] When the aliphatic ring A is substituted with two or more substituents as described herein, the substituents may suitably be the same or different. Furthermore, each of the substituents may suitably be present on a different carbon atom in the aliphatic ring A, although one carbon atom in the aliphatic ring A may suitably have two such substituents (although such a carbon atom may suitably have two substituents). It will also be apparent to those skilled in the art that when a carbon atom in the aliphatic ring A has a single substituent, such a carbon atom may also suitably have a hydrogen atom.

[0204] It will also be apparent to one skilled in the art that the maximum number of substituents that may 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 may bear. Thus, by way of example and not limitation, in a 6-membered aliphatic ring A generally represented by Scheme D, the maximum number of substituents that may be present on ring A is 8 (i.e., R5-R 12 where each of is a substituent as described herein.

[0205] Typically, but without limitation, 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. Again, as described herein, such substituents may be the same or different and may be present on different carbon atoms in aliphatic ring A, although one carbon atom in aliphatic ring A may suitably bear two such substituents (although such a carbon atom may suitably bear two substituents).

[0206] According to one specific, but non-limiting, aspect, the total number of substituents on ring A is 0, 1, 2, 3, or 4 (preferably 0, 1, or 2), and any substituents present on aliphatic ring A are preferably independently selected from methyl, ethyl, and isopropyl (preferably methyl). Again, as described herein, such substituents may be the same or different and may be present on different carbon atoms in aliphatic ring A, although one carbon atom in aliphatic ring A may suitably have two such substituents (although such a carbon atom may suitably have two substituents).

[0207] Some preferred, but non-limiting examples of compounds of the present invention in which the aliphatic ring A is substituted are shown in the experimental section below 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 the other compounds of the present invention may be substituted (i.e., have the same substituents on the same carbon atoms) in the same way that the aliphatic ring A is substituted in one of the compounds A-173 to A-188, A-216 to A-218, A-222 to A-224, and A-226 to A-229 (in other words, the other compounds of the present invention may contain the same substituted aliphatic ring A as the substituted aliphatic ring A present in one of the compounds such as Compounds A-173 to A-188, A-216 to A-218, A-222 to A-224, and A-226 to A-229).

[0208] Also, when aliphatic ring A is substituted with one or more substituents as described herein, the substituent may suitably be present on any carbon atom in aliphatic ring A that may suitably bear one or more such substituents. According to one specific, but non-limiting, embodiment, when aliphatic ring A is substituted with one or more substituents as described herein, at least one of these substituents is present on a carbon atom in ring A adjacent to a carbon or nitrogen atom (preferably a nitrogen atom) in aliphatic ring A to which aromatic ring system C is linked. According to an even more specific, but non-limiting, embodiment, when aliphatic ring A has one, two, three, or four such substituents (as described herein), particularly one or two such substituents, all such substituents are suitably present on one or both of the carbon atoms in ring A adjacent to a carbon or nitrogen atom (preferably a nitrogen atom) in aliphatic ring A to which aromatic ring system C is linked. Again, such substituents are preferably independently selected from methyl, ethyl, and isopropyl, and most 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 one or two substituents (preferably one substituent) selected from methyl, ethyl, and isopropyl (preferably methyl), which substituent is located on a carbon atom in the aliphatic ring A adjacent to the carbon or nitrogen atom (preferably a nitrogen atom) in the aliphatic ring A to which the aromatic ring system C is connected.

[0210] A further aspect of the present invention relates to compounds of the present invention (particularly compounds of formula I, II, III, IV, V or VI), wherein the aliphatic ring A is unsubstituted or substituted as described herein (particularly as described in the preceding paragraph), and such compounds of the present invention are preferably further such that such compounds have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of 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 rest being as further described herein).

[0211] Some specific, but non-limiting examples of 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 are as exemplified in the experimental section below.

[0212] As described herein, aromatic ring B is generally a 6-membered aromatic ring comprising carbon atoms and may optionally (and suitably) contain 1, 2 or 3 nitrogen atoms, provided that aromatic ring B may still have an acidic substituent D at least in the ortho position (i.e., as further described herein) relative to aliphatic ring A. Also, when aromatic ring B contains one or more nitrogen atoms, it is preferably such that it may still have one or more substituents or combinations of such substituents described herein as preferably present on aromatic ring B (i.e., at the positions on aromatic ring B described herein as preferred for that substituent), and more preferably such that it may still have one or more substituents or combinations of such substituents described herein as particularly or most preferred, respectively, for being present on aromatic ring B (i.e., at the positions on aromatic ring B described herein as particularly or most preferred for that substituent).

[0213] Some preferred examples of aromatic rings that can form a 6-membered ring within aromatic ring B are phenyl (benzene), pyridin-2-yl and 1,4-pyrimidin-2-yl, with phenyl being most preferred.

[0214] As described herein, aromatic ring B is most preferably a 6-membered ring, although the present invention does not exclude that aromatic ring B, in its broadest sense, may be a 5-membered aromatic ring (which may optionally and appropriately contain 1 or 2 heteroatoms selected from O, N or S), provided that such 5-membered aromatic ring may still preferably bear one or more substituents or combinations of such substituents as described herein as being present on the 6-membered aromatic ring B. More preferably, when such a 5-membered aromatic ring is present in place of a 6-membered aromatic ring, the resulting 5-membered aromatic ring B is preferably a bioisostere of the 6-membered aromatic ring B described herein, more preferably a bioisostere of the 6-membered aromatic ring B represented by Scheme E, even more preferably a bioisostere of the 6-membered aromatic ring B represented by Scheme F, and most preferably a bioisostere of the 6-membered aromatic ring B represented by Scheme G.

[0215] It is most preferred that aromatic ring B be a monocyclic ring, since the use of a bicyclic aromatic ring system as aromatic ring B often results in compounds that cannot adequately contain the preferred substituents described herein for aromatic ring B (such as an isobutyl group at the 5-position and a fluorine at either the 3- or 4-position).

[0216] As further described herein, aromatic ring B has an acidic substituent (i.e., acidic substituent D) on the carbon atom of ring B adjacent to the carbon atom at which aliphatic ring A is connected to aromatic ring B. The acidic substituent D may be any suitable acidic group or substituent (suitable groups / substituents will be apparent to those skilled in the art based on the disclosure herein, optionally after some trial and error), and is preferably selected from the group consisting of a carboxylic acid group (i.e., a -C(=O)-OH group), an acylsulfonamide group (such as, but not limited to, an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (such as, but not limited to, a 4H-(1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole.

[0217] As also further described herein, aromatic ring B preferably has at least one further substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methylcyclopropyl, n-butyl, sec-butyl, isobutyl, cyclobutyl, methylcyclobutyl, vinyl, allyl, isobutenyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, difluoroethoxy, methoxyethyloxy, fluorine, chlorine, cyano, oxirane, cyclopropoxy, cyclobutoxy, cyclopentoxy, N-acetyl, substituted and unsubstituted carbamoyl, which substituent (if present) is most preferably located on a carbon atom in ring B that is para to the position in ring B of the carbon atom to which the acidic substituent D is attached (e.g., the "5" position according to the numbering system used when aromatic ring B is a 6-membered aromatic ring such as a phenyl ring), in which case said substituent forms the substituent R3 as shown in Schemes E and F below and in some of the further schemes and formulas provided herein. The substituent is preferably an isobutyl group, as exemplified by compounds of formulae III and VI.

[0218] As further described herein, in addition to the acidic substituent [D] and the at least one further substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylmethoxy (which substituent, as referred to herein, is preferably isobutyl and is in the para position relative to the acidic substituent D), aromatic ring B may optionally be further suitably substituted with one or more (such as one or two) suitable substituents (as defined herein), which are shown as R1, R2, and R4 in Schemes E-G and Formulas I-VI herein.

[0219] Thus, according to a specific but non-limiting embodiment, aromatic ring B has an overall structure that can be represented schematically as follows (Scheme E):

[0220] [ka] During the ceremony, - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; - X and Y are each either a nitrogen atom or a carbon atom, both of which 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, - R1, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; - R2, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine); R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g., sec-butyl, and especially iso-butyl), fluorine-substituted methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, -NH-heteroalkyl, -N(C is selected from the group consisting of (1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, and is most preferably isobutyl (i.e., as in the compounds of the invention of formula III and / or formula VI), R4, if present, is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl); however, - X, Y and Z are selected (i.e., from carbon atoms or nitrogen atoms, respectively) such that the resulting ring structure forms an aromatic ring (i.e., a planar conjugated ring); Furthermore, however, when X is a nitrogen atom, R1 is absent; Furthermore, however, when Y is a nitrogen atom, R2 is absent; Furthermore, however, When Z is a nitrogen atom, R4 is absent.

[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), and 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 that does not contain a nitrogen atom).

[0222] According to a preferred but non-limiting embodiment, aromatic ring B has an overall structure that can be represented schematically as follows (Scheme F):

[0223] [ka] Thus, it comprises or consists essentially of a phenyl ring substituted with an acidic substituent represented by [D] and with substituents R1, R2, R3 and / or R4, wherein: - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g., sec-butyl, and in particular iso-butyl), for example a fluorine-substituted methyl group (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, -NH-heteroalkyl, -N(C is selected from the group consisting of (1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, and is most preferably isobutyl (i.e., as in the compounds of the invention of formula III and / or formula VI), R4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0224] According to a particularly preferred, but non-limiting embodiment, aromatic ring B has an overall structure that can be represented schematically as follows (Scheme G):

[0225] [ka] During the ceremony, - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), R4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0226] Some specific, but non-limiting examples of compounds of the invention containing the aromatic ring B 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 are as exemplified in the experimental section below.

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

[0228] [ka] 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 bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B - (either via a carbon atom or via a carbon atom) to the remainder of the compound of formula I; (iii) said at least one aromatic ring (i.e. the aromatic ring containing the carbon atom to which the remainder of the compound of formula I is linked) preferably contains at least one (e.g. 1 or 2) heteroatom, which heteroatoms (if present) are preferably each independently selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0, preferably 1 or 0 (when m=0, R A. and R B does not exist, and when n=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 each, when present, is independently selected from hydrogen, methyl and / or trifluoromethyl; or A +R B When present, together with the carbon atom to which they are attached form a carbonyl (C=O) group, or R C +R DWhen present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A +R B are taken together and replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached, or R C +R D are, when present, taken together to form a carbonyl group with the carbon atom to which it is attached, replaced by a single oxygen atom), preferably each a hydrogen atom; [A] is any of the ring systems represented schematically by Scheme C below,

[0229] [ka] wherein each atom 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), v is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), w is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), the sum of (v+w) is 3, 4, 5, 6, 7, or 8 (preferably, 3, 4, or 5, and more preferably, v and w are both 2), the difference (vw) is either 1, 0, or −1, and each R present x and each R y are preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3 and isopropyl, and in particular are ring systems generally represented by Scheme D below:

[0230] [ka] wherein each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), and R, R, R, R, R, R 10 , R 11 and R 12are each preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3 and isopropyl, or a ring system of formula XCIX or C;

[0231] [ka] wherein said ring systems of formula XCIX or formula C, when present, may be suitably optionally substituted with one or more suitable substituents, each preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl; - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; - X and Y are each either a nitrogen atom or a carbon atom, both of which 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, - R1, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; - R2, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine); R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g. sec-butyl, and in particular iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g. cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, is selected from the group consisting of -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, most preferably isobutyl; R4, if present, is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl); however, - X, Y and Z are selected (i.e., from carbon atoms or nitrogen atoms, respectively) such that the resulting ring structure forms an aromatic ring (i.e., a planar conjugated ring); Furthermore, however, when X is a nitrogen atom, R1 is absent; Furthermore, however, when Y is a nitrogen atom, R2 is absent; Furthermore, however, When Z is a nitrogen atom, R4 is absent.

[0232] As further described herein, the present invention relates in certain aspects to such compounds of formula I having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 aspects, the present invention relates to compounds of formula I that are selected from (i) the aromatic ring system [C], the aliphatic ring [A], and the acidic substituent [D], each of which is further described herein, and (ii) each of X, Y, and Z, and specific combinations of atoms X, Y, and Z, present in the compounds of formula I, and (iii) each of the substituents R1, R2, R3, and R4, if present, and specific combinations of such substituents R1, R2, R3, and R4, present in the compounds of formula I, and (iv) m and n (which may each independently be 0 or 1, as described herein), and (v) the substituent R1, R2, R3, and R4, present in the compounds of formula I. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (vi) any further substituents present in such compounds of formula I (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the specific combinations of such substituents present in said compounds of formula I, respectively, are such (and are such combinations) that said compounds of formula I have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0233] In a more specific, but non-limiting embodiment, the present invention relates to compounds of formula II:

[0234] [ka] 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 bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B - (either via a carbon atom or via a carbon atom) to the remainder of the compound of formula II; (iii) said at least one aromatic ring (i.e. the aromatic ring containing the carbon atom to which the remainder of the compound of formula II is linked) preferably contains at least one (e.g. 1 or 2) heteroatom, which heteroatoms (if present) are preferably each independently suitably selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0, preferably 1 or 0 (when m=0, R A. and R B does not exist, and when n=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 are, when present, independently selected from hydrogen, methyl and / or trifluoromethyl; RA +R B When present, together with the carbon atom to which they are attached form a carbonyl (C=O) group, or R C +R D When present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A +R B are taken together and replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached, or R C +R D are, when present, taken together to form a carbonyl group with the carbon atom to which it is attached, replaced by a single oxygen atom), preferably each a hydrogen atom; [A] is any of the ring systems represented schematically by Scheme C below,

[0235] [ka] wherein each atom 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), v is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), w is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), the sum of (v+w) is 3, 4, 5, 6, 7, or 8 (preferably, 3, 4, or 5, and more preferably, v and w are both 2), the difference (vw) is either 1, 0, or −1, and each R present x and each R y are preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3 and isopropyl, and in particular are ring systems generally represented by Scheme D below:

[0236] [ka] wherein each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), and R, R, R, R, R, R 10 , R 11 and R 12 may each independently be a suitable substituent, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3 and isopropyl, or a ring system of formula XCIX or C,

[0237] [ka] wherein said ring systems of formula XCIX or formula C, when present, may be suitably optionally substituted with one or more suitable substituents, each preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl; the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (—COOH) group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is —C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g. sec-butyl, and in particular iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g. cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, is selected from the group consisting of -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, most preferably isobutyl; R4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0238] As further described herein, the present invention relates in certain embodiments to such compounds of formula II having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 present invention relates to compounds of formula II that are characterized by (i) the aromatic ring system [C], the aliphatic ring [A], and the acidic substituent [D], each of which is further described herein, and (ii) each of the substituents R1, R2, R3, and R4 (if present) present in such compounds of formula II, and specific combinations of such substituents R1, R2, R3, and R4, and (iii) m and n (each of which may independently be 0 or 1, as described herein), and (iv) the substituents R1, R2, R3, and R4 present in such compounds of formula II. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (v) any further substituents present in such compounds of formula II (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the specific combinations of such substituents present in said compounds of formula II, respectively, relate to compounds of formula II (further described herein) that are (and are) such that said compounds of formula II have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0239] In a more specific, but non-limiting embodiment, the present invention relates to compounds 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 comprises at least one aromatic ring, and (ii) the aromatic ring system is bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B - (either via a carbon atom or via a carbon atom) to the remainder of the compound of formula III; (iii) said at least one aromatic ring (i.e. the aromatic ring containing the carbon atom to which the remainder of the compound of formula III is linked) preferably contains at least one (e.g. 1 or 2) heteroatom, which heteroatoms (if present) are preferably each independently selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, -R A and R B each, when present, is independently selected from hydrogen, methyl and / or trifluoromethyl, or R A +R B When present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A. +R B are replaced by a single oxygen atom and together form a carbonyl group with the carbon atom to which said oxygen atom is attached), preferably each are a hydrogen atom; [A] is any of the ring systems represented schematically by Scheme C below,

[0241] [ka] wherein each atom 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), v is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), w is an integer from 1 to 4 (i.e., 1, 2, 3, or 4), the sum of (v+w) is 3, 4, 5, 6, 7, or 8 (preferably, 3, 4, or 5, and more preferably, v and w are both 2), the difference (vw) is either 1, 0, or −1, and each R present x and each R y are preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3 and isopropyl, and in particular are ring systems generally represented by Scheme D below:

[0242] [ka] wherein each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), and R, R, R, R, R, R 10 , R 11 and R 12 may each independently be a suitable substituent, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3 and isopropyl, or a ring system of formula XCIX or C,

[0243] [ka] wherein said ring systems of formula XCIX or formula C, when present, may be suitably optionally substituted with one or more suitable substituents, each preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl; - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), R4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0244] As further described herein, the present invention relates in certain embodiments to such compounds of formula III having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 present invention relates to compounds of formula III that are selected from (i) the aromatic ring system [C], the aliphatic ring [A], and the acidic substituent [D], each of which is further described herein, and (ii) each of the substituents R1, R2, and R4 (if present) present in such compounds of formula III, and specific combinations of such substituents R1, R2, and R4, and (iii) m (which may be 0 or 1, as described herein), and (iii) the substituent R1, R2, and R4 present in such compounds of formula III. A and R B (if present), as well as each such substituent R A and R B and (iv) any further substituents present in such compounds of formula III (e.g., on the aromatic ring system [C] and / or the aliphatic ring system [A], as further described herein), and the specific combinations of such substituents present in said compounds of formula III, respectively, are such (and are such combinations) that said compounds of formula III have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

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

[0246] [ka] 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 bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B - (either via a carbon atom) to the remainder of the compound of formula IV; (iii) said 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, which heteroatoms (if present) are preferably each independently selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0, preferably 1 or 0 (when m=0, R A. and R B does not exist, and when n=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 are, when present, independently selected from hydrogen, methyl and / or trifluoromethyl; R A +R B When present, together with the carbon atom to which they are attached form a carbonyl (C=O) group, or R C +R DWhen present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A +R B are taken together and replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached, or R C +R D are, when present, taken together to form a carbonyl group with the carbon atom to which it is attached, replaced by a single oxygen atom), preferably each 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; - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 may each independently be a suitable substituent, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3, and isopropyl; - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; - X and Y are each either a nitrogen atom or a carbon atom, both of which 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, - R1, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; - R2, if present, is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine); R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g. sec-butyl, and in particular iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g. cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, is selected from the group consisting of -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, most preferably isobutyl; R4, if present, is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl); however, - X, Y and Z are selected (i.e., from carbon atoms or nitrogen atoms, respectively) such that the resulting ring structure forms an aromatic ring (i.e., a planar conjugated ring); Furthermore, however, when X is a nitrogen atom, R1 is absent; Furthermore, however, when Y is a nitrogen atom, R2 is absent; Furthermore, however, When Z is a nitrogen atom, R4 is absent.

[0247] As further described herein, the present invention relates in certain aspects to such compounds of formula IV having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 aspects, the present invention relates to (i) an aromatic ring system [C] and acidic substituents [D], each of which are further described herein, and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, and preferably at least one Q is a nitrogen atom), and (iii) each of X, Y, and Z, and specific combinations of atoms X, Y, and Z, present in the compound of formula IV, and (iv) each of the substituents R1, R2, R3, and R4, if present, and specific combinations of such substituents R1, R2, R3, and R4, present in the compound of formula IV, and (v) substituents R5 through R6, present in the compound of formula IV. 12 (if present) and each such substituent R5 to R 12 and (vi) m and n (each of which may independently be 0 or 1, as described herein), and (vii) any substituent R present in the compound of formula IV. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and RD and (viii) any further substituents present in such compounds of formula IV (e.g., on the aromatic ring system [C]), and the specific combinations of such substituents present in said compounds of formula IV, respectively, relate to compounds of formula IV (further described herein) such that (and are such combinations) said compounds of formula IV have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0248] In a more preferred, but non-limiting embodiment, the present invention relates to compounds 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 comprises at least one aromatic ring, and (ii) the aromatic ring system is bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B- (either via a carbon atom) to the remainder of the compound of formula V; (iii) said at least one aromatic ring (i.e. the aromatic ring containing the carbon atom to which the remainder of the compound of formula V is linked) preferably contains at least one (e.g. 1 or 2) heteroatom, which heteroatoms (if present) are preferably each independently suitably selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0, preferably 1 or 0 (when m=0, R A. and R B does not exist, and when n=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 are, when present, independently selected from hydrogen, methyl and / or trifluoromethyl; R A +R B When present, together with the carbon atom to which they are attached form a carbonyl (C=O) group, or R C +R D When present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A +R B are taken together and replaced by a single oxygen atom to form a carbonyl group with the carbon atom to which the oxygen atom is attached, or R C +R Dare, when present, taken together to form a carbonyl group with the carbon atom to which it is attached, replaced by a single oxygen atom), preferably each 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; - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 may each independently be a suitable substituent, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3, and isopropyl; - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl (e.g. sec-butyl, and in particular iso-butyl), for example fluorine-substituted methyl groups (e.g. trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyloxy (-O-(CH2)2-O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g. cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1-C3)-cycloalkyl, is selected from the group consisting of -NH-heteroalkyl, -N(C1-C3)-heteroalkyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., -CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano, most preferably isobutyl; R4 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 relates in certain embodiments to such compounds of formula V having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 present invention relates to (i) an aromatic ring system [C] and acidic substituents [D], each of which are further described herein, and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, and preferably at least one Q is a nitrogen atom), and (iii) each of the substituents R1, R2, R3, and R4, if present, in the compound of formula V, and specific combinations of such substituents R1, R2, R3, and R4, and (v) the substituents R5 through R6, present in the compound of formula V. 12 (if present) and each such substituent R5 to R 12 and (vi) m and n (each of which may independently be 0 or 1, as described herein), and (vi) any substituent R present in the compound of formula V. A , R B , R C and R D (if present), as well as each such substituent R A , R B , R C and R D and (viii) any further substituents present in such compounds of formula V (e.g., on the aromatic ring system [C]), and the particular combinations of such substituents present in said compounds of formula V, respectively, are such (and are such combinations) that said compounds of formula V have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

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

[0252] [ka] 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 bonded to a carbon atom present in the at least one aromatic ring (i.e., directly via a covalent bond or, if an alkylene linking group is present, via the alkylene linking group -C (m) R A R B - (either via a carbon atom) to the remainder of the compound of formula VI; (iii) said at least one aromatic ring (i.e. the aromatic ring containing the carbon atom to which the remainder of the compound of formula VI is linked) preferably contains at least one (e.g. 1 or 2) heteroatom, which heteroatoms (if present) are preferably each independently suitably selected from N, S and O, more preferably at least one of the heteroatoms (if present) is a nitrogen atom; and the aromatic ring system designated as [C] is preferably an aromatic ring or ring system selected from the group consisting of aromatic rings / ring systems of formulae VII to LXXXIII, more preferably from the group consisting of aromatic rings / ring systems of formulae LIX to LXXXIII, and even more preferably from the group consisting of aromatic rings / ring systems of formulae LXXIII to LXXXIII; m is 1 or 0, -R A and R B are each independently selected from hydrogen, methyl and / or trifluoromethyl, or R A +R B When present, they combine with the carbon atom to which they are attached to form a carbonyl (C=O) group (in other words, R A. +R B are replaced by a single oxygen atom and together form a carbonyl group with the carbon atom to which said oxygen atom is attached), preferably each are 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; - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 may each independently be a suitable substituent, preferably independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro (F), CF3, and isopropyl; - the acidic substituent represented by [D] is selected from the group consisting of a carboxylic acid (-COOH) group, an acylsulfonamide group (e.g., an acylsulfonamide group of the general formula CONHSOR or SONHCOR, where R is -C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(heterocyclyl having 1-6 ring atoms), C1-C8 alkoxy, or C1-C8 amine), a tetrazole group, or a group that is a bioisostere (as defined herein) of a tetrazole group (e.g., without limitation, a 4H-1,2,4-oxadiazol-5-one group), more preferably tetrazole or a bioisostere thereof, and most preferably tetrazole; R1 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alkoxy, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine) and cyano; R2 is selected from the group consisting of H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (—NH2) or C1-C2 substituted amine (for example dimethylamine or diethylamine), R4 is selected from the group consisting of H or halogen (F, Cl, Br or I, preferably F or Cl).

[0253] As further described herein, the present invention relates in certain embodiments to such compounds of formula VI having an affinity for AT2R (measured according to the protocol described in Example 2 below) of 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 present invention relates to (i) an aromatic ring system [C] and an acidic substituent [D], each of which is further described herein, and (ii) each atom Q (which may independently be a carbon atom or a nitrogen atom, as described herein, and preferably at least one Q is a nitrogen atom), and (iii) each of the substituents R1, R2, and R4, if present, in the compound of formula VI, and specific combinations of such substituents R1, R2, and R4, and (iv) the substituents R5 through R6, present in the compound of formula VI. 12 (if present) and each such substituent R5 to R 12 and (v) m (which may be 0 or 1 as described herein), and (vi) any substituent R present in the compound of formula VI. A and R B (if present), as well as each such substituent R A and R B and (vii) any further substituents present in such compounds of formula VI (e.g., on the aromatic ring system [C]), and the particular combinations of such substituents present in said compounds of formula VI are each such (and are such combinations) that said compounds of formula VI have an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, preferably better than 1 micromolar, more preferably better than 0.1 micromolar, and even more preferably better than 10 nanomolar.

[0254] Some specific, but non-limiting examples of compounds of the invention according to each of Formulas I-VI (including preferred, more preferred, particularly preferred, and / or most preferred compounds), and / or compounds of the invention according to various and preferred aspects of the invention defined herein with reference to one of Formulas I-VI, will be apparent to the skilled artisan based on the disclosure herein and / or as exemplified in the experimental section below.

[0255] The compounds of the present invention may be used in the prevention, treatment and / or management of pain, in particular chronic pain, such as the chronic pain conditions described herein.

[0256] Thus, in a further aspect, the present invention relates to the use of a compound of the present invention (e.g. a compound of formula I as defined herein, particularly a compound of formula II as defined herein, more particularly 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 VI as defined herein) in the prevention, treatment and / or management of pain, in particular the prevention, treatment and / or management of chronic pain.

[0257] In a further aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of the invention (e.g., a compound of formula I as defined herein, particularly a compound of formula II as defined herein, more particularly 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, and even more preferably a compound of formula VI as defined herein) in the prevention, treatment and / or management of pain, in particular the prevention, treatment and / or management of chronic pain. Such pharmaceutical compositions are generally as further described herein and generally contain a compound of the invention in an amount that allows a pharmaceutically active amount, e.g., a dose of a compound of the invention as described herein, to be administered to a subject using an appropriate dosing regimen (e.g., as single or multiple administrations / doses per day).

[0258] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of pain, in particular 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 invention or a pharmaceutical composition comprising same (e.g., according to an appropriate dosing regimen as further described herein).

[0259] It will be apparent to those skilled in the art that for the treatment of chronic pain (including the additional conditions described herein associated with chronic pain, such as neuropathic pain and inflammatory pain), the compounds or compositions of the present invention should typically be administered or used for an extended period of time (e.g., 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 subsided), e.g., as part of a chronic treatment regimen for the management of chronic pain, or as part of an overall treatment regimen. Such chronic treatment regimens or pain management regimens, and the use of the compounds or compositions of the present invention as part of such regimens, can be determined by the treating physician based on the patient's overall condition, the nature and cause of the pain, and / or the specific pain condition involved, as well as other relevant factors apparent to the clinician. Such treatment regimens and dosing regimens form further aspects of the present invention.

[0260] The compounds and compositions of the present invention can be used in particular for the prevention, treatment and / or management of pain, particularly chronic pain, and such (chronic) pain is neuropathic pain. Such neuropathic pain can be neuropathic pain originating from the peripheral part of the nervous system (e.g., in the case of trigeminal neuralgia or post-herpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or radiculopathy), or neuropathic pain originating from and / or involving the central nervous system (e.g., in the case of chronic neuropathic pain resulting from spinal cord or brain injury, stroke, or multiple sclerosis). Such uses and corresponding / related treatment methods form further aspects of the present invention.

[0261] In a specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of (peripheral) neuropathy. Such uses and corresponding / related methods of treatment 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., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of trigeminal neuralgia. Such uses and corresponding / related methods of treatment 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., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of chronic NP following peripheral nerve injury. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0264] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of painful polyneuropathy. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0265] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of post-herpetic neuralgia. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0266] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of painful radiculopathy. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0267] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of chronic central NP associated with spinal cord injury (SCI). Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0268] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of chronic central NP associated with brain injury. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0269] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of chronic central post-stroke pain. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0270] However, without being limited to any particular mechanism or hypothesis, it is generally noted that, because the compounds of the invention are expected to be more likely to be effective in the prevention, treatment and / or management of types of neuropathic pain generally associated with the peripheral nervous system (i.e., compared to types of neuropathic pain generally associated with the central nervous system), use of the compounds of the invention in the prevention, treatment and / or management of types of neuropathic pain associated with and / or arising from the peripheral nervous system (e.g., caused by disease, dysfunction or injury to peripheral nerves) generally forms a preferred application and aspect of the invention.

[0271] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of chronic central NP associated with multiple sclerosis. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0272] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) can be used in the prevention, treatment and / or management of inflammatory pain. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0273] In the context of the present invention, prevention, treatment and / or management of pain (including the various types of pain referred to herein) also includes reducing, alleviating and / or alleviating pain and / or pain intensity, severity and / or duration, reducing, alleviating and / or alleviating sensitivity or hypersensitivity to pain, reducing, alleviating and / or alleviating hyperalgesia and / or reducing, alleviating and / or allodynia, and delaying the onset of pain.

[0274] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of chronic neuropathic pain arising from peripheral parts of the nervous system in a subject, the method 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 same (e.g., according to an appropriate dosing regimen as further described herein).

[0275] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of chronic neuropathic pain originating from and / or involving the central nervous system arising from peripheral parts of the nervous system in a subject, the method comprising administering to a 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 same (e.g., according to an appropriate dosing regimen as further described herein).

[0276] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of peripheral neuropathy 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 same (e.g., according to a suitable dosing regimen as further described herein).

[0277] In a further aspect, the present invention relates to a method for the treatment and / or management of diabetic neuropathy 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 same (e.g., according to an appropriate dosing regimen as further described herein).

[0278] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of pain, in particular chronic pain, comprising administering to a 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 same (e.g., according to a suitable dosing regimen as further described herein), wherein the (chronic) pain is one of the following pain conditions: trigeminal or post-herpetic neuralgia, chronic neuropathic pain occurring as a result of peripheral nerve injury, painful polyneuropathy, painful radiculopathy, spinal cord or brain injury, stroke or multiple sclerosis, chronic NP after peripheral nerve injury, chronic central NP associated with spinal cord injury (SCI), chronic central NP associated with brain injury, chronic central pain after stroke, chronic central NP associated with multiple sclerosis, and / or chronic pain resulting from tissue injury (including, but not limited to, chronic pain after surgery and phantom limb pain after amputation).

[0279] Again, it will be apparent to those skilled in the art that for the treatment of any of the chronic pain conditions described herein, the compounds or compositions of the invention will typically be administered or used for an extended period of time (e.g., at least one week, e.g., at least one month, e.g., at least three months or more, and / or until pain is reduced or subsided), e.g., as part of a chronic treatment regimen for the management of chronic pain, or as part of an overall treatment regimen. Such chronic treatment regimens or pain management regimens, and the use of the compounds or compositions of the invention as part of such regimens, can be determined by the treating physician based on the patient's overall condition, the nature and cause of the pain, and / or the particular pain condition involved, as well as other relevant factors apparent to the clinician. Such treatment regimens and dosing regimens form further aspects of the invention.

[0280] It is also clear here that in the context of the various pain conditions referred to herein, the prevention, treatment and / or management of these pain conditions pain also includes reducing, alleviating and / or alleviating pain and / or pain intensity, severity and / or duration, reducing, alleviating and / or alleviating sensitivity or hypersensitivity to pain, reducing, alleviating and / or alleviating hyperalgesia and / or reducing, alleviating and / or alleviating allodynia, and delaying the onset of pain.

[0281] In another specific, but non-limiting, aspect, the compounds and compositions of the invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used to reduce, alleviate and / or alleviate hyperalgesia, particularly hyperalgesia associated with chronic pain, more particularly hyperalgesia associated with neuropathic pain and / or inflammatory pain, such as hyperalgesia associated with one of the specific pain conditions mentioned herein. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0282] In another specific, but non-limiting, embodiment, the compounds and compositions of the present invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used to reduce, alleviate, and / or relieve allodynia, particularly allodynia associated with chronic pain, more particularly allodynia associated with neuropathic pain and / or inflammatory pain, such as allodynia associated with one of the specific pain conditions mentioned herein. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0283] In another specific, but non-limiting, aspect, the compounds and compositions of the invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used to reduce, alleviate, and / or alleviate hypersensitivity to inflammatory pain, such as pain that occurs in response to tissue injury and inflammation. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0284] In another specific, but non-limiting, aspect, the compounds and compositions of the invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used to reduce, alleviate and / or relieve pain, particularly inflammatory pain, caused by and / or associated with trauma and / or arthritis. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0285] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of Formula I as defined herein, particularly compounds of Formula II as defined herein, more particularly 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 compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used to reduce, alleviate, and / or relieve post-operative pain. Such uses and corresponding / related methods of treatment form further aspects of the present invention.

[0286] Again, it will be apparent to those skilled in the art that for the prevention, treatment, and / or management of any of the aforementioned pain conditions, the compounds or compositions of the present invention should be administered or used according to an appropriate treatment regimen and / or as an overall treatment regimen for the management of the pain condition involved (e.g., which may be applied until the pain subsides or is alleviated, and / or until the underlying disease or condition is treated or alleviated, or may be chronic in the case of a chronic disease). Such treatment or pain management regimens, and the use of the compounds or compositions of the present invention as part of such regimens, can be determined by the treating physician based on the patient's overall condition, the nature and cause of the pain, and / or the particular pain condition involved, as well as other relevant factors apparent to the clinician. Such treatment and dosing regimens form further aspects of the present invention.

[0287] It will also be apparent to those skilled in the art that, as part of the use of the compounds or compositions of the present invention in the prevention, treatment, and / or management of any type of pain and / or painful condition described herein, the use of the compounds or compositions of the present invention may be appropriately combined with the administration or use of one or more other compounds or active substances known per se for the prevention, treatment, and / or management of pain (such as chronic pain), particularly for the prevention, treatment, and / or management of the particular type of pain or painful condition involved. Such compounds and active substances will be apparent to those skilled in the art based on the disclosure herein, and the use of the compounds of the present invention in combination with such other compounds and active substances as part of such a therapeutic regimen may be determined by the treating physician based on the patient's overall condition, the nature and cause of the pain, and / or the particular painful condition involved, as well as other relevant factors apparent to the clinician. Such therapeutic and dosing regimens form further aspects of the present invention.

[0288] Also, as further described herein, when a compound of the invention (such as a compound of formula I as defined herein, particularly a compound of formula II as defined herein, more particularly 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 VI as defined herein) is present in a pharmaceutical composition (as described herein) and / or used in a therapeutic application (as described further herein) and / or used as part of a method of treatment (as described further herein), such a compound of the invention preferably has an affinity for the AT2R (measured according to the protocol described in Example 2 below) of better than 10 micromolar, more preferably better than 1 micromolar, even more preferably better than 0.1 micromolar, and in particular may have an affinity for the AT2R of better than 10 nanomolar.

[0289] As mentioned herein, it is also expected that the compounds of the present invention can be used in the prevention and treatment of diseases and disorders that can be prevented or treated by modulating the angiotensin II receptor type 2, AT2R-mediated signaling, and / or pathways and / or biological processes involving AT2R and / or AT2R-mediated signaling in a subject in need thereof. Furthermore, it is expected that the compounds and compositions 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.

[0290] Such diseases include, but are not limited to, diseases referred to in the art as being associated with AT2R and / or AT2R-mediated signaling, as well as other diseases and disorders for which the use of known modulators (particularly modulators that compete with ligand binding to AT2R) and / or known inhibitors and / or antagonists of AT2R and / or AT2R-mediated signaling has been described in the art (see, for example, the diseases and disorders listed in WO 2019 / 179515 (listed in more detail below)).

[0291] Thus, in another specific, but non-limiting aspect, the compounds and compositions of the present 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, and even more preferably compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used in the prevention and / or treatment of diseases and disorders that can be prevented or treated by modulating angiotensin II receptor type 2, AT2R-mediated signaling and / or AT2R and / or AT2R-mediated signaling pathways and / or biological processes in a subject in need thereof, in particular by administering to said subject one or more pharmaceutically active amounts (e.g., doses) of a compound of the present invention in accordance with an appropriate treatment or dosing regimen (which may be determined by the treating physician based on the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that may be determined by the treating physician and that may be taken into account as appropriate). Such uses and corresponding / related methods of treatment, and such treatment and dosing regimens, form further aspects of the present invention.

[0292] In another specific, but non-limiting, aspect, the compounds and compositions of the present 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, and even more preferably compounds of Formula VI as defined herein, or pharmaceutical compositions comprising same) are used in the prevention and / or treatment of diseases and disorders that can be prevented or treated by administering to a subject in need thereof a compound capable of competing with the binding of one or more natural ligands to the angiotensin II receptor, in particular by administering to said subject one or more pharmaceutically active amounts (e.g., doses) of a compound of the present invention in accordance with an appropriate treatment or dosing regimen (which may be determined by the treating physician based on the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that may be determined by the treating physician and that may be taken into account as appropriate). Such uses and corresponding / related methods of treatment, as well as such treatment and dosing regimens, form further aspects of the present invention.

[0293] In another specific, but non-limiting, aspect, the compounds and compositions of the present invention (e.g., compounds of formula I as defined herein, particularly compounds of formula II as defined herein, more particularly 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 compounds of formula VI as defined herein, or pharmaceutical compositions comprising same) are used for the prevention and / or treatment of one of the following diseases and disorders (e.g., those referred to in WO 2019 / 179515 as being an AT2R-mediated disorder): - Cerebrovascular disorders (including cerebral vasospasm and cerebral ischemia), cognitive impairment (including amnesia, senile dementia, AIDS-related dementia and Down's syndrome), diseases or conditions of the central nervous system (including addictions such as alcoholism, anxiety, depression or dysthymia, epilepsy, hyperactivity, pain, Parkinson's disease, psychiatric disorders, sleep disorders, autonomic nervous system irregularities and demyelinating diseases such as tardive dyskinesia, schizophrenia, multiple sclerosis and amyotrophic lateral sclerosis), respiratory diseases (including bronchospasm, asthma and chronic obstructive airway disease), neuronal tumors, inflammatory diseases (including inflammatory bowel disease and osteoarthritis) , gastrointestinal (GI) diseases or conditions (including ulcerative colitis, Crohn's disease and incontinence), vasodilation caused by impaired blood flow, allergic diseases (including allergies such as eczema, rhinitis, contact dermatitis), vasospasm (including angina, migraines and Raynaud's disease), fibro- and collagen diseases (including scleroderma and eosinophilic schistosomiasis), reflex sympathetic dystrophies (including shoulder-hand syndrome), stress-related somatic disorders, peripheral neuropathy, neuralgia, autoimmune diseases (including systemic erythema), lupus, rheumatoid arthritis, psoriasis and graft-versus-host disease, and rheumatic diseases including fibromyalgia. - neuropathic diseases (including primary and secondary neuropathy, e.g. peripheral neuropathy) or symptoms associated therewith (including hyperesthesia, hyperalgesia, allodynia, spontaneous burning sensations, numbness, weakness, burning pain), tingling pain and loss of reflexes, preferably neuropathic pain, where secondary neuropathy includes: diabetic neuropathy, shingles-associated neuropathy, uremia-associated neuropathy, amyloidosis neuropathy, neuropathy, hereditary motor and sensory neuropathies, hereditary sensory neuropathies, hereditary sensory and autonomic neuropathies, hereditary neuropathy with ulcer lesions, nitrofurantoin neuropathy, sausage peripheral neuropathy caused by arsenic, mercury, and organophosphate pesticides; peripheral neuropathy associated with infectious processes (e.g., Guillain-Barré syndrome); peripheral neuropathy caused by repetitive movements (such as typing or assembly line work); peripheral neuropathy caused by antiretroviral drugs (e.g., zalcitabine and didanosine); antibiotics (e.g., nitrazole and isoniazid); gold compounds; chemotherapy drugs (e.g., vincristine); alcohol; and lead. - conditions characterized by neuronal hypersensitivity, including hyperalgesic conditions such as fibromyalgia and irritable bowel syndrome, - Disorders associated with abnormal nerve regeneration, including neuronal hypersensitivity, breast pain, interstitial cystitis, vulvodynia, and cancer-induced neuropathy; - inflammatory pain that can result from conditions characterized by inflammation (including burns such as chemical burns, abrasions or scalds, autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and colitis, osteoarthritis, carditis, dermatitis, myositis, neuritis and collagen vascular diseases); - nerve conduction velocity disorders that may be associated with the above-mentioned neuropathies (such as peripheral neuropathy), as well as carpal tunnel syndrome, ulnar neuropathy, Guillain-Barré syndrome, facioscapular muscular dystrophy, and herniated discs; - Cell proliferative disorders such as cancer (including leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, and lung cancer), and non-cancerous hyperplastic conditions (including phlegm, keloids, psoriasis, phlegm disorders, and skin conditions such as scar tissue reduction and cosmetic tissue repair), - Conditions associated with an imbalance between bone resorption and bone formation, including osteoporosis.

[0294] The methods include administering to the subject one or more pharmaceutically active amounts (e.g., doses) of a compound of the invention in accordance with an appropriate treatment or dosing regimen (which may be determined by the treating physician based on the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and other factors that may be determined and appropriately taken into account by the treating physician).

[0295] In a further aspect, the present invention relates to a method for the prevention, treatment and / or management of diabetes, in particular type II diabetes, 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 same (e.g., according to an appropriate dosing regimen as further described herein).

[0296] The compounds of the invention can be prepared in a manner known per se, for example for structurally related compounds using well-known techniques of organic chemistry. Some specific, but non-limiting, methods are described in the experimental section below.

[0297] It will also be apparent that if the desired compound of the invention, and / or the starting materials, precursors, and / or intermediates used in its preparation, contain functional groups that are sensitive to the reaction conditions used in the preparation of the compounds of the invention (i.e., which, if not properly protected, undergo undesired reactions under those conditions), they can be protected during the reaction using a suitable protecting group, which can then be suitably removed after completion of the reaction and / or as a subsequent or final step in the preparation of the compounds of the invention. Suitable protecting groups, and methods and conditions for inserting and removing them, will be apparent to those skilled in the art and can be found in standard handbooks of organic chemistry, e.g., Greene and Wuts, "Protective groups in organic synthesis," 3 rd Edition, Wiley and Sons, 1999. It will also be apparent to those skilled in the art that compounds of the invention in which one or more functional groups are protected with appropriate functional groups may find use as intermediates in the preparation and / or synthesis of compounds of the invention, and as such form a further aspect of the invention.

[0298] For pharmaceutical use, the compounds of the present invention can be used as free acids or free bases, and / or in the form of pharmaceutically acceptable acid and / or base addition salts (e.g., obtained with non-toxic organic or inorganic acids or bases), in the form of hydrates, solvates and / or complexes, and / or in the form of prodrugs or predrugs, such as esters. Such salts, hydrates, solvates, etc. and their preparation will be apparent to those skilled in the art, see, for example, the salts, hydrates, solvates, etc. described in U.S. Patent Nos. 6,372,778(A), 6,369,086(A), 6,369,087(A), and 6,372,733(A).

[0299] Generally, for pharmaceutical use, the compounds of the present invention can be formulated as a pharmaceutical formulation comprising at least one compound of the present invention, at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more additional pharmaceutically active compounds. By way of non-limiting example, such a formulation can be in a form suitable for oral administration, parenteral administration (e.g., by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration, administration by inhalation, administration by a transdermal patch, administration by implant, administration by suppository, etc. Such suitable dosage forms may be solid, semi-solid or liquid, depending on the mode of administration and the methods and carriers, diluents and excipients used in their preparation, as will be apparent to those skilled in the art, again reference being made to standard handbooks such as, for example, U.S. Pat. Nos. 6,372,778(A), 6,369,086(A), 6,369,087(A) and 6,372,733(A), as well as the latest edition of Remington's Pharmaceutical Sciences.

[0300] Some preferred, but non-limiting examples of such formulations include tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders (which are usually reconstituted before use) for administration as a bolus and / or for continuous administration, which may be formulated with carriers, excipients and diluents suitable for such formulations themselves, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations may optionally contain other pharmaceutically active substances (which may or may not have a synergistic effect with the compounds of the invention), as well as other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, extenders, fillers, preservatives, sweeteners, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated to provide rapid, sustained, or delayed release of the active compound contained therein, for example, using liposomes or hydrophilic polymer matrices based on natural gels or synthetic polymers.

[0301] The preparations can be prepared in a manner known per se, which usually involves mixing the active substance used with one or more pharmaceutically acceptable carriers, if necessary under sterile conditions.Here again, reference is made to U.S. Patent Nos. 6,372,778(A), 6,369,086(A), 6,369,087(A) and 6,372,733(A), and the above-mentioned further prior art, as well as to standard handbooks such as the latest edition of Remington's Pharmaceutical Sciences.

[0302] The pharmaceutical formulations of the invention are preferably in unit dosage form and may be suitably packaged, for example, in a box, blister, vial, bottle, sachet, ampule, or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled), optionally with one or more leaflets containing product information and / or instructions for use. Generally, such a unit dose contains 1 to 1000 mg, usually 5 to 500 mg, of at least one compound of the invention, e.g., about 10, 25, 50, 100, 200, 300, or 400 mg per unit dose.

[0303] The compounds can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal, depending primarily on the particular formulation used and the condition to be treated or prevented, with oral and intravenous administration usually being preferred. At least one compound of the present invention is generally administered in an "effective amount," which means any amount of a compound of Formula I or VI above that, upon proper administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to whom it is administered. Typically, depending on the condition to be prevented or treated and the route of administration, such an effective amount will typically be 0.01 to 1000 mg, more often 0.1 to 500 mg, e.g., 1 to 250 mg, e.g., about 5, 10, 20, 50, 100, 150, 200, or 250 mg, per kilogram of patient body weight per day, which may be administered as a single daily dose, divided into one or more daily doses, or essentially continuously, e.g., using intravenous infusion. The amount to be administered, the route of administration and further treatment regimens can be determined by the treating clinician depending on factors such as the age, sex and general condition of the patient, and the nature and severity of the disease / symptom to be treated. Again, reference is made to U.S. Patent Nos. 6,372,778(A), 6,369,086(A), 6,369,087(A) and 6,372,733(A) and the further prior art cited above, as well as standard handbooks such as the latest edition of Remington's Pharmaceutical Sciences.

[0304] Therefore, in a further aspect, the present invention relates to compositions, in particular compositions for pharmaceutical use, containing at least one compound of the present invention and at least one suitable carrier (i.e., a carrier suitable for pharmaceutical use). The present invention also relates to the use of the compounds of the present invention in the preparation of such compositions.

[0305] It is also envisioned that the above compounds and compositions may be valuable in the veterinary field, which for purposes herein includes not only the prevention and / or treatment of diseases in animals, but also for economically important animals such as cattle, pigs, sheep, chickens, fish, etc., to improve animal growth and / or weight and / or the quantity and / or quality of meat or other products obtained from the animal. Thus, in a further aspect, the present invention relates to compositions for veterinary use containing at least one compound of the present invention and at least one suitable carrier (i.e., a carrier suitable for veterinary use). The present invention also relates to the use of the compounds of the present invention in the preparation of such compositions. [Brief explanation of the drawings]

[0306] [Figure 1] 1 is a graph showing the results obtained in the CCI model of Example 3. [Figure 2] 1 is a graph showing the results obtained in the CCI model of Example 3.

[0307] The present invention will now be illustrated by the experimental part below, as well as by Figures 1 and 2, which are graphs showing the results obtained in the CCI model used in Example 3), which are not intended to limit the scope of the present invention in any way. Experimental Section: Example 1: Synthetic Procedure Synthesis of intermediates Intermediate 1

[0308] [ka]

[0309] Step (i): 4-Bromo-2-(piperazin-1-yl)benzonitrile Piperazine (107.5 g, 1250.0 mmol) was added to a stirred solution of 4-bromo-2-fluorobenzonitrile (50 g, 250.0 mmol) in acetonitrile (500 mL), and the reaction was continued at 80 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude gummy solid (57.0 g, crude) was used in the next step without purification.

[0310] Step (ii): 4-(2-methylprop-1-en-1-yl)-2-(piperazin-1-yl)benzonitrile To a stirred solution of 4-bromo-2-(piperazin-1-yl)benzonitrile (57.0 g, 214.2 mmol) in 1,4-dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (46.76 g, 257.0 mmol), followed by K2CO3 (73.89 g, 535.4 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (15.7 g, 21.4 mmol) was then added, after which the reaction was heated to 100 °C for 10 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-(2-methylprop-1-en-1-yl)-2-(piperazin-1-yl)benzonitrile (47.0 g), which was used in the next step without further purification.

[0311] Step (iii): tert-butyl 4-(2-cyano-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate To a stirred solution of 4-(2-methylprop-1-en-1-yl)-2-(piperazin-1-yl)benzonitrile (47 g, 194.8 mmol) in CHCl (300 mL) at 0 °C was added EtN (81.0 mL, 584.3 mmol). The solution was stirred at 0 °C for 10 minutes, after which Boc-anhydride (63.8 g, 292.5 mmol) was added and the reaction was continued to stir at room temperature for an additional 3 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was diluted with cold water and extracted with CHCl (3 × 300 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (20-30% EtOAc in hexanes) to give tert-butyl 4-(2-cyano-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate as a white solid (53.2 g, 80%).

[0312] Step (iv): tert-butyl 4-(2-cyano-5-isobutylphenyl)piperazine-1-carboxylate A stirred solution of tert-butyl 4-(2-cyano-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (52 g, 19.4 mmol) in MeOH (200 mL) was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 The mixture was hydrogenated over 10% Pd / C (5.2 g) under H pressure at ambient temperature for 5 hours. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a Celite® bed and evaporated in vacuo. The crude residue (47.5 g) was used in the next step without further purification.

[0313] Step (v): 4-Isobutyl-2-(piperazin-1-yl)benzonitrile hydrochloride To a stirred solution of tert-butyl 4-(2-cyano-5-isobutylphenyl)piperazine-1-carboxylate (47.5 g, 138.5 mmol) in 1,4-dioxane (50 mL) was added HCl (g) in dioxane (150 mL) at 0 °C, and the solution was then slowly warmed to room temperature and continued stirring at room temperature for 3 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with hexane to give 4-isobutyl-2-(piperazin-1-yl)benzonitrile hydrochloride (35.0 g).

[0314] Intermediate 2

[0315] [ka]

[0316] Step (i): 2,6-Difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 4-bromo-2,6-difluorobenzonitrile (5.0 g, 22.93 mmol) in 1,4-dioxane (100 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (5.01 g, 27.52 mmol), followed by K2CO3 (7.92 g, 57.34 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.935 g, 1.156 mmol) was then added, after which the reaction was heated to 80 °C for 6 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated under reduced pressure to remove volatiles. The residue was dissolved in ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue. The crude compound thus obtained was purified by column chromatography on silica gel eluting with 15-20% EtOAc in hexane to give 2,6-difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile as a colorless gum (4.0 g, 90%).

[0317] Step (ii): 2,6-difluoro-4-isobutylbenzonitrile A stirred solution of 2,6-difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile (4 g, 20.72 mmol) in MeOH was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 The mixture was hydrogenated over 10% Pd / C (0.4 g) under H pressure at ambient temperature for 3 hours. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a Celite® bed and evaporated in vacuo. The crude residue was purified by silica chromatography using 20-25% EtOAc in hexane to give 2,6-difluoro-4-isobutylbenzonitrile as a colorless gum (3.3 g, 82%).

[0318] Step (iii): 2-fluoro-4-isobutyl-6-(piperazin-1-yl)benzonitrile To a stirred solution of 2,6-difluoro-4-isobutylbenzonitrile (2 g, 10.25 mmol) in acetonitrile (25 mL) was added piperazine (2.20 g, 25.64 mmol), and the reaction was then maintained at 80 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude residue obtained as an off-white solid (2.40 g, 95%) was used directly in the following step.

[0319] Intermediate 3

[0320] [ka]

[0321] Step (i): Methyl 4-bromo-2-fluorobenzoate To a stirred solution of 4-bromo-2-fluorobenzoic acid (5.0 g, 22.83 mmol) in MeOH (50 mL) was added HSO (25 mL) at 0 °C, after which the reaction was brought to 80 °C and continued stirring for 5 h. After TLC showed the reaction was complete, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was treated with saturated NaHCO and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave the crude residue (4.93 g, crude), which was used in the next step without further purification.

[0322] Step (ii): Methyl 4-bromo-2-(piperazin-1-yl)benzoate To a stirred solution of methyl 4-bromo-2-fluorobenzoate (4.8 g, 20.6 mmol) in acetonitrile (50 mL) was added piperazine (8.86 g, 103.0 mmol), and the resulting solution was then stirred at 80° C. for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give methyl 4-bromo-2-(piperazin-1-yl)benzoate (5.33 g, crude), which was used directly in the next step.

[0323] Step (iii): Methyl 2-(4-(benzo[d]thiazol-2-ylmethyl)piperazin-1-yl)-4-bromobenzoate To a stirred solution of methyl 4-bromo-2-(piperazin-1-yl)benzoate (5.0 g, 16.72 mmol) in 1,4-dioxane (50 mL) was added EtN (6.95 mL, 50.15 mmol) at 0 °C, followed 10 min later by the addition of 2-(chloromethyl)benzo[d]thiazole (3.65 g, 20.06 mmol). The resulting reaction mixture was stirred at 100 °C for 10 h. After completion of the reaction was confirmed by TLC, cold water was added to the reaction mixture, which was then extracted with CHCl (3 × 100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude residue, which was further purified by column chromatography on silica gel (35-45% EtOAc in hexanes) to give the expected compound, methyl 2-(4-(benzo[d]thiazol-2-ylmethyl)piperazin-1-yl)-4-bromobenzoate (5.17 g, 69%).

[0324] Intermediate 4 (alternative route to intermediate 2)

[0325] [ka]

[0326] Step (i): 4-Bromo-2-fluoro-6-(piperazin-1-yl)benzonitrile Piperazine (0.986 g, 11.4 mmol) was added to a stirred solution of 4-bromo-2,6-difluorobenzonitrile (0.5 g, 2.29 mmol) in acetonitrile (20 mL), and the reaction was continued at 80 °C for 14 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness. The crude residue was then purified by column chromatography on silica gel eluting with 2-4% MeOH in CHCl to give 4-bromo-2-fluoro-6-(piperazin-1-yl)benzonitrile as a gummy liquid (0.51 g, 78%).

[0327] Step (ii): 2-fluoro-4-(2-methylprop-1-en-1-yl)-6-(piperazin-1-yl)benzonitrile To a stirred solution of 4-bromo-2-fluoro-6-(piperazin-1-yl)benzonitrile (0.5 g, 1.76 mmol) in 1,4-dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (0.385 g, 2.1 mmol), followed by K2CO3 (0.608 g, 4.4 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.065 g, 0.088 mmol) was then added, after which the reaction was heated to 80 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2-fluoro-4-(2-methylprop-1-en-1-yl)-6-(piperazin-1-yl)benzonitrile, which was used in the next step without further purification.

[0328] Step (iii): tert-butyl 4-(2-cyano-3-fluoro-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate To an ice-cold solution of 2-fluoro-4-(2-methylprop-1-en-1-yl)-6-(piperazin-1-yl)benzonitrile in CHCl (25 mL) was added EtN (0.62 mL, 4.4 mmol). The solution was stirred at 0 °C for 10 minutes, after which Boc-anhydride (0.575 g, 2.64 mmol) was added, and the reaction was continued at room temperature for another 14 hours. After completion of the reaction was confirmed by TLC, cold water was added to the reaction mixture, which was extracted with CHCl (3 × 300 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (20-30% EtOAc in hexanes) to give tert-butyl 4-(2-cyano-3-fluoro-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate as a colorless gum (0.41 g, 65% over two steps).

[0329] Step (iv): tert-butyl 4-(2-cyano-3-fluoro-5-isobutylphenyl)piperazine-1-carboxylate A stirred solution of tert-butyl 4-(2-cyano-3-fluoro-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.4 g, 1.11 mmol) in MeOH (20 mL) was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 Hydrogenation was carried out over 10% Pd / C (0.1 g) under H pressure at ambient temperature for 2 hours. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a bed of Celite® and concentrated in vacuo to give the desired compound as a colorless gum (0.36 g, 90%).

[0330] Step (v): 2-fluoro-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-3-fluoro-5-isobutylphenyl)piperazine-1-carboxylate (0.35 g, 0.97 mmol) was dissolved in 4 M HCl in 1,4-dioxane (20 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 2-fluoro-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.25 g, 89%).

[0331] Intermediate 5

[0332] [ka]

[0333] Step (i): 2-chloro-6-methyl-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 2,4-dichloro-6-methylbenzonitrile (0.25 g, 1.34 mmol) in 1,4-dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (0.27 g, 1.47 mmol), followed by K2CO3 (0.46 g, 3.35 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.049 g, 0.067 mmol) was then added, after which the reaction was heated to 100 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10-15% EtOAc in hexanes) afforded 2-chloro-6-methyl-4-(2-methylprop-1-en-1-yl)benzonitrile as an off-white solid (0.21 g, 77%).

[0334] Step (ii): tert-butyl 4-(2-cyano-3-methyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate To a stirred solution of 2-chloro-6-methyl-4-(2-methylprop-1-en-1-yl)benzonitrile (0.21 g, 1.02 mmol) in 1,4-dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (0.228 g, 1.23 mmol), followed by KPO (0.541 g, 2.55 mmol) and BINAP (0.025 g, 0.041 mmol). Argon was bubbled through the resulting mixture for 20 minutes. Next, P(tBu)BF (0.012 g, 0.041 mmol) was added, followed by Pd(dba) (0.030 g, 0.051 mmol), and the reaction was then heated to 100 °C for 14 hours. After TLC showed the reaction was complete, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Drying over anhydrous sodium sulfate and concentration in vacuo, followed by column chromatography on silica gel (25-30% EtOAc in hexanes) afforded the desired compound as a pale yellow gum (0.15 g, 41%).

[0335] Step (iii): tert-butyl 4-(2-cyano-5-isobutyl-3-methylphenyl)piperazine-1-carboxylate A stirred solution of tert-butyl 4-(2-cyano-3-methyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.15 g, 0.42 mmol) in MeOH (20 mL) was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 Hydrogenation was carried out over 10% Pd / C (40 mg) under H pressure at ambient temperature for 2 h. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a bed of Celite® and concentrated in vacuo to give the expected hydrogenated compound as a colorless gum (0.12 g, 80%).

[0336] Step (iv): 4-Isobutyl-2-methyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-5-isobutyl-3-methylphenyl)piperazine-1-carboxylate (0.12 g, 0.336 mmol) was dissolved in 4 M HCl in 1,4-dioxane (10 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 4-isobutyl-2-methyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.08 g, 81%). Intermediate 6

[0337] [ka]

[0338] Step (i): 2-chloro-4-cyclopropyl-6-methylbenzonitrile To a stirred solution of 2,4-dichloro-6-methylbenzonitrile (0.3 g, 1.61 mmol) in 1,4-dioxane (10 mL) was added cyclopropylboronic acid (0.152 g, 1.77 mmol), followed by K2CO3 (0.555 g, 4.025 mmol), and the resulting mixture was sparged with argon for 20 min. Pd(dppf)Cl2 (0.058 g, 0.0805 mmol) was then added, after which the reaction was heated to 100 °C for 12 h. After TLC showed the reaction was complete, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10–13% EtOAc in hexanes) afforded 2-chloro-4-cyclopropyl-6-methylbenzonitrile as a gummy liquid (0.21 g, 68%).

[0339] Step (ii): tert-butyl 4-(2-cyano-5-cyclopropyl-3-methylphenyl)piperazine-1-carboxylate To a stirred solution of 2-chloro-4-cyclopropyl-6-methylbenzonitrile (0.2 g, 1.047 mmol) in 1,4-dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (0.232 g, 1.25 mmol), followed by KPO (0.555 g, 2.617 mmol) and BINAP (0.026 g, 0.0418 mmol). Argon was bubbled through the resulting mixture for 20 minutes. P(tBu)BF (0.012 g, 0.0418 mmol) was then added, followed by Pd(dba) (0.030 g, 0.0523 mmol), and the reaction was then heated to 100 °C for 14 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Drying over anhydrous sodium sulfate and concentration in vacuo followed by column chromatography on silica gel (25-30% EtOAc in hexanes) afforded the desired compound as a pale yellow gum (0.18 g, 51%).

[0340] Step (iii): 4-Cyclopropyl-2-methyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-5-cyclopropyl-3-methylphenyl)piperazine-1-carboxylate (0.18 g, 0.527 mmol) was dissolved in 4 M HCl in 1,4-dioxane (10 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 4-cyclopropyl-2-methyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.12 g, 82%).

[0341] Intermediate 7

[0342] [ka]

[0343] Step (i): 2,6-Dichloro-4-cyclopropylbenzonitrile To a stirred solution of 4-bromo-2,6-dichlorobenzonitrile (1 g, 3.985 mmol) in 1,4-dioxane (25 mL) was added cyclopropylboronic acid (0.411 g, 4.78 mmol), followed by K2CO3 (1.354 g, 9.963 mmol), and the resulting mixture was sparged with argon for 20 min. Pd(dppf)Cl2 (0.146 g, 0.1992 mmol) was then added, after which the reaction was heated to 80 °C for 12 h. After TLC showed the reaction was complete, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10–12% EtOAc in hexanes) afforded 2,6-dichloro-4-cyclopropylbenzonitrile as a gummy liquid (0.74 g, 88%).

[0344] Step (ii): 2-chloro-4,6-dicyclopropylbenzonitrile To a stirred solution of 2,6-dichloro-4-cyclopropylbenzonitrile (0.37 g, 1.745 mmol) in 1,4-dioxane (20 mL) was added cyclopropylboronic acid (0.18 g, 2.06 mmol), followed by K2CO3 (0.593 g, 4.36 mmol), and the resulting mixture was sparged with argon for 20 min. Pd(dppf)Cl2 (0.064 g, 0.0873 mmol) was then added, after which the reaction was heated to 100 °C for 12 h. After TLC showed the reaction was complete, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (15–18% EtOAc in hexanes) afforded 2-chloro-4,6-dicyclopropylbenzonitrile as a gummy liquid (0.3 g, 79%).

[0345] Step (iii): tert-butyl 4-(2-cyano-3,5-dicyclopropylphenyl)piperazine-1-carboxylate To a stirred solution of 2-chloro-4,6-dicyclopropylbenzonitrile (0.3 g, 1.38 mmol) in 1,4-dioxane (20 mL) was added tert-butyl piperazine-1-carboxylate (0.308 g, 1.66 mmol), followed by KPO (0.731 g, 3.45 mmol) and BINAP (0.034 g, 0.0552 mmol). Argon was bubbled through the resulting mixture for 20 minutes. P(tBu)BF (0.016 g, 0.0552 mmol) was then added, followed by Pd(dba) (0.040 g, 0.069 mmol), after which the reaction was heated to 100 °C for 14 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Drying over anhydrous sodium sulfate and concentration in vacuo followed by column chromatography on silica gel (30-35% EtOAc in hexanes) afforded the desired compound as a pale yellow gum (0.31 g, 60%).

[0346] Step (iv): 2,4-Dicyclopropyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-3,5-dicyclopropylphenyl)piperazine-1-carboxylate (0.3 g, 0.817 mmol) was dissolved in 4 M HCl in 1,4-dioxane (10 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 2,4-dicyclopropyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.21 g, 82%).

[0347] Intermediate 8

[0348] [ka]

[0349] Step (i): 2,6-dichloro-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 4-bromo-2,6-dichlorobenzonitrile (0.5 g, 2.0 mmol) in 1,4-dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (0.436 g, 2.4 mmol), followed by K2CO3 (0.69 g, 5 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.074 g, 0.10 mmol) was then added, after which the reaction was heated to 80 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10-12% EtOAc in hexanes) afforded 2,6-dichloro-4-(2-methylprop-1-en-1-yl)benzonitrile as a gummy liquid (0.4 g, 88%).

[0350] Step (ii): 2-chloro-6-cyclopropyl-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 2,6-dichloro-4-(2-methylprop-1-en-1-yl)benzonitrile (0.2 g, 0.885 mmol) in 1,4-dioxane (10 mL) was added cyclopropylboronic acid (0.091 g, 1.06 mmol), followed by K2CO3 (0.305 g, 2.21 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.033 g, 0.044 mmol) was then added, after which the reaction was heated to 100 °C for 12 hours. After completion of the reaction was confirmed by LC-MS, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10-15% EtOAc in hexanes) afforded 2-chloro-6-cyclopropyl-4-(2-methylprop-1-en-1-yl)benzonitrile as a gummy liquid (0.175 g, 87%).

[0351] Step (iii): tert-butyl 4-(2-cyano-3-cyclopropyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate To a stirred solution of 2-chloro-6-cyclopropyl-4-(2-methylprop-1-en-1-yl)benzonitrile (0.17 g, 0.735 mmol) in 1,4-dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (0.164 g, 0.883 mmol), followed by KPO (0.390 g, 1.837 mmol) and BINAP (0.018 g, 0.029 mmol). Argon was bubbled through the resulting mixture for 20 minutes. Next, P(tBu)BF (0.009 g, 0.029 mmol) was added, followed by Pd(dba) (0.021 g, 0.368 mmol), and the reaction was then heated to 100 °C for 14 hours. After completion of the reaction was confirmed by LC-MS, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Drying over anhydrous sodium sulfate and concentration in vacuo, followed by column chromatography on silica gel (20-25% EtOAc in hexanes) afforded the desired compound as a pale yellow gum (0.16 g, 57%).

[0352] Step (iv): tert-butyl 4-(2-cyano-5-isobutyl-3-methylphenyl)piperazine-1-carboxylate A stirred solution of tert-butyl 4-(2-cyano-3-cyclopropyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.13 g, 0.341 mmol) in MeOH (20 mL) was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 Hydrogenation was carried out over 10% Pd / C (30 mg) under H pressure at ambient temperature for 2 h. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a bed of Celite® and concentrated in vacuo to give the expected hydrogenated compound as a colorless gum (0.11 g, 84%).

[0353] Step (v): 2-Cyclopropyl-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-5-isobutyl-3-methylphenyl)piperazine-1-carboxylate (0.10 g, 0.26 mmol) was dissolved in 4 M HCl in 1,4-dioxane (5 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 2-cyclopropyl-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.06 g, 72%).

[0354] Intermediate 9

[0355] [ka]

[0356] Step (i): 2-chloro-6-ethyl-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 2,6-dichloro-4-(2-methylprop-1-en-1-yl)benzonitrile (0.2 g, 0.885 mmol) in 1,4-dioxane (10 mL) was added ethylboronic acid (0.078 g, 1.06 mmol), followed by K2CO3 (0.305 g, 2.21 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.033 g, 0.044 mmol) was then added, after which the reaction was heated to 100 °C for 12 hours. After completion of the reaction was confirmed by LC-MS, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (10-15% EtOAc in hexanes) afforded 2-chloro-6-ethyl-4-(2-methylprop-1-en-1-yl)benzonitrile as a gummy liquid (0.169 g, 87%).

[0357] Step (ii): tert-butyl 4-(2-cyano-3-ethyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate To a stirred solution of 2-chloro-6-ethyl-4-(2-methylprop-1-en-1-yl)benzonitrile (0.17 g, 0.735 mmol) in 1,4-dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (0.164 g, 0.883 mmol), followed by KPO (0.390 g, 1.837 mmol) and BINAP (0.018 g, 0.029 mmol). Argon was bubbled through the resulting mixture for 20 minutes. Next, P(tBu)BF (0.009 g, 0.029 mmol) was added, followed by Pd(dba) (0.021 g, 0.368 mmol), and the reaction was then heated to 100 °C for 14 hours. After completion of the reaction was confirmed by LC-MS, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Drying over anhydrous sodium sulfate and concentration in vacuo, followed by column chromatography on silica gel (20-25% EtOAc in hexanes) afforded the desired compound as a pale yellow gum (0.155 g, 57%).

[0358] Step (iii): tert-butyl 4-(2-cyano-3-ethyl-5-isobutylphenyl)piperazine-1-carboxylate A stirred solution of tert-butyl 4-(2-cyano-3-ethyl-5-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.155 g, 0.419 mmol) in MeOH (20 mL) was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 Hydrogenation was carried out over 10% Pd / C (40 mg) under H pressure at ambient temperature for 2 h. After LC-MS showed the reaction was complete, the reaction mixture was filtered through a bed of Celite® and concentrated in vacuo to give the expected hydrogenated compound as a colorless gum (0.145 g, 93%).

[0359] Step (iv): 2-Ethyl-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride tert-Butyl 4-(2-cyano-3-ethyl-5-isobutylphenyl)piperazine-1-carboxylate (0.145 g, 0.390 mmol) was dissolved in 4 M HCl in 1,4-dioxane (5 mL) at 0 °C. The solution was then slowly warmed to room temperature and stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness under reduced pressure. The crude residue was further triturated with diethyl ether to give 2-ethyl-4-isobutyl-6-(piperazin-1-yl)benzonitrile hydrochloride as an off-white solid (0.097 g, 92%).

[0360] Intermediate 10

[0361] [ka]

[0362] Step (i): 2,6-Difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile To a stirred solution of 4-bromo-2,6-dichlorobenzonitrile (10 g, 45.87 mmol) in 1,4-dioxane was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (10.01 g, 55.05 mmol), followed by K2CO3 (15.82 g, 114.68 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (3.37 g, 4.58 mmol) was then added, after which the reaction was heated to 80 °C for 6 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. Subsequent drying over anhydrous sodium sulfate and evaporation under reduced pressure followed by column chromatography on silica gel (15-20% EtOAc in hexanes) afforded 2,6-difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile as a colorless gum (7.10 g, 80%).

[0363] Step (ii): 2,6-difluoro-4-isobutylbenzonitrile A stirred solution of 2,6-difluoro-4-(2-methylprop-1-en-1-yl)benzonitrile (7.0 g, 36.2 mmol) in MeOH was hydrogenated at 5 Kg / cm using a Parr hydrogenation apparatus. 2 Hydrogenation was carried out over 10% Pd / C (1.4 g) under H pressure at ambient temperature for 3 h. After completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered through a bed of Celite® and concentrated in vacuo to give the expected hydrogenated compound as a viscous liquid (5.81 g, 83%).

[0364] Intermediate 11

[0365] [ka]

[0366] Step (i): 4-Bromo-2-(piperazin-1-yl)benzonitrile Piperazine (431 mg, 5.0 mmol) was added to a stirred solution of 4-bromo-2-fluorobenzonitrile (200 mg, 1.0 mmol) in acetonitrile (5 mL), and the reaction was continued at 85° C. for 8 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude gummy colorless liquid was used in the next step without purification.

[0367] Step (ii): 2-(piperazin-1-yl)-4-(prop-1-en-1-yl)benzonitrile To a stirred solution of 4-bromo-2-(piperazin-1-yl)benzonitrile (0.25 g, 0.94 mmol) in 1,4-dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane (0.19 g, 1.1 mmol), followed by K2CO3 (0.39 g, 2.81 mmol), and the resulting mixture was sparged with argon for 20 minutes. Pd(dppf)Cl2 (0.068 g, 0.09 mmol) was then added, after which the reaction was heated to 80 °C for 6 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated in vacuo to remove volatiles, and the residue was redissolved in ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 2-(piperazin-1-yl)-4-(prop-1-en-1-yl)benzonitrile (47.0 g), which was used in the next step without further purification (Method L, used in Step 2).

[0368] Intermediate 12

[0369] [ka]

[0370] Step (i): Substituted methyl 2-fluorobenzoates To a stirred solution of substituted 2-fluorobenzoic acid (3.5 mmol) in MeOH (25 mL) was added SOCl (0.8 mL, 10.7 mmol) at 0 °C, after which the reaction was brought to 80 °C and continued to stir at this temperature for 3 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, diluted with water, washed with saturated NaHCO, and extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave the crude product, which was used in the next step without further purification.

[0371] Step (ii): Substituted methyl 2-(piperazin-1-yl)benzoates To a stirred solution of the desired substituted methyl 2-fluorobenzoate (3.2 mmol) in 1,4-dioxane (50 mL) was added piperazine (1.4 g, 16.2 mmol). Upon completion of the addition, the reaction was continued to stir at 100 °C for 8 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the crude residue, which was subjected to column chromatography (SiO, 3–10% MeOH in CHCl) to afford the desired substituted methyl 2-(piperazin-1-yl)benzoate.

[0372] Intermediate 13

[0373] [ka]

[0374] Step (i): Methyl 2-fluoro-4-hydroxybenzoate To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (1.0 g, 6.4 mmol) in MeOH (30 mL) was added H2SO4 (10 mL, 64.0 mmol) at 0 °C, and then the reaction was heated to 80 °C for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, diluted with water, washed with saturated NaHCO3, and extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave the crude residue (1.08 g, crude), which was used in the next step without purification.

[0375] Step (ii): Methyl 4-alkoxy 2-fluoro-benzoate To a stirred solution of methyl 2-fluoro-4-hydroxybenzoate (1.0 g, 5.9 mmol) in DMF (25 mL) was added K2CO3 (1.62 g, 11.75 mmol) at 0 °C, and the solution was then warmed to room temperature. After stirring at room temperature for 10 min, the desired alkyl halide (8.81 mmol) was added, and the reaction mixture was then heated to 80 °C and stirred at this temperature for 3–4 h. After confirming the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue. The resulting residue was purified by column chromatography on silica gel eluting with 10–15% EtOAc in hexane to give the expected methyl 4-alkoxy 2-fluorobenzoate.

[0376] Step (iii): Methyl 4-alkoxy-2-(piperazin-1-yl)benzoate To a stirred solution of methyl 4-alkoxy-2-fluorobenzoate (4.71 mmol) in acetonitrile (30 mL) was added piperazine (23.5 mmol), and the resulting solution was then stirred at 100° C. for 6 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the desired methyl 4-alkoxy-2-(piperazin-1-yl)benzoate. The crude compound was used in the next step without further purification.

[0377] Intermediate 14

[0378] [ka]

[0379] Step (i): 4-alkoxy-2-fluorobenzonitrile To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1.0 mmol) in DMF, K2CO3 (3.0 mmol) was added at 0 °C, and the solution was then warmed to room temperature. After stirring at room temperature for 10 minutes, the desired alkyl halide (1.2 mmol) was added, and the reaction mixture was then brought to 80 °C and stirred at this temperature for 3–4 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was extracted with water and ethyl acetate. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue. The resulting residue was purified by column chromatography on silica gel eluting with EtOAc in hexane to give 4-alkoxy-2-fluorobenzonitrile.

[0380] Step (ii): 4-alkoxy-2-(piperazin-1-yl)benzonitrile To a stirred solution of 4-alkoxy-2-fluorobenzonitrile (1 equivalent) in acetonitrile was added piperazine (5 equivalents), and the resulting solution was then stirred at 85°C for 11-15 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 4-alkoxy-2-(piperazin-1-yl)benzonitrile as a colorless oil. The crude compound was used in the next step without further purification (Method L, used in Step 2).

[0381] Intermediate 15

[0382] [ka]

[0383] Step (i): 4-alkoxy-1-bromo-2-methylbenzene To a stirred solution of 4-bromo-3-methylphenol (1.0 g, 5.3 mmol) in DMF (25 mL) was added K2CO3 (1.44 g, 10.7 mmol) at 0 °C, and the solution was then warmed to room temperature. After stirring at room temperature for 10 min, the desired alkyl halide (8.02 mmol) was added, and the reaction mixture was then heated to 80 °C and stirred at this temperature for 3–4 h. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, which was then extracted with EtOAc. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue. The resulting residue was purified by column chromatography on silica gel eluting with EtOAc in hexane to give 4-alkoxy-1-bromo-2-methylbenzene.

[0384] Step (ii): 4-alkoxy-2-methylbenzonitrile To a stirred solution of 4-alkoxy-1-bromo-2-methylbenzene (4.36 mmol) in DMF (30 mL) was added Zn(CN) (0.77 g, 6.54 mmol), followed by a catalytic amount of dppf (0.024 g, 0.043 mmol). The resulting reaction mixture was sparged with argon for 20 minutes, after which Pd(dba) (0.039 g, 0.043 mmol) was added and the reaction was brought to 60 °C. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, which was then extracted with EtOAc. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting crude compound was purified by column chromatography on silica gel eluting with EtOAc in hexane to give the desired 4-alkoxy-2-methylbenzonitrile.

[0385] Step (iii): 4-alkoxy-2-(bromomethyl)benzonitrile To a stirred solution of 4-alkoxy-2-methylbenzonitrile (1.99 mmol) in CCl4 (25 mL) was added NBS (0.71 g, 3.99 mmol), followed by AIBN (0.032 g, 0.2 mmol). Upon completion of the addition, the resulting reaction mixture was heated to 60 °C for 6 h. After completion of the reaction was confirmed by TLC, the reaction mixture was cooled and cold water was added. After extraction with ethyl acetate, the combined organic layers were washed successively with water and saturated brine. Drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure gave the crude residue, which was further purified by column chromatography on silica gel (10–15% EtOAc in hexanes).

[0386] Intermediate 16

[0387] [ka]

[0388] Step (i): Methyl 4-hydroxy-2-methylbenzoate To a stirred solution of 4-hydroxy-2-methylbenzoic acid (1.0 g, 6.57 mmol) in MeOH (30 mL) was added H2SO4 (10 mL) at 0 °C, and then the reaction was heated to 80 °C for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added to the reaction mixture, which was treated with saturated NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave the crude residue (1.12 g, crude), which was used in the next step without further purification.

[0389] Step (ii): Methyl 4-alkoxy-2-methylbenzoate To a stirred solution of methyl 4-hydroxy-2-methylbenzoate (1.0 g, 6.01 mmol) in DMF (30 mL) was added K2CO3 (1.66 g, 12.03 mmol) at 0 °C, and the solution was then warmed to room temperature. After stirring at room temperature for 10 min, the desired alkyl halide (9.02 mmol) was added, and the reaction mixture was then heated to 80 °C and stirred at this temperature for 3–4 h. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, followed by extraction with EtOAc. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue. The resulting residue was purified by column chromatography on silica gel eluting with EtOAc in hexane to give methyl 4-alkoxy-2-methylbenzoate.

[0390] Step (iii): Methyl 4-alkoxy-2-(bromomethyl)benzoate To a stirred solution of methyl 4-alkoxy-2-methylbenzoate (2.40 mmol) in CCl4 (30 mL) was added NBS (0.85 g, 4.80 mmol), followed by AIBN (0.035 g, 0.24 mmol). Upon completion of the addition, the resulting reaction mixture was heated to 60 °C for 6 h. After completion of the reaction was confirmed by TLC, the reaction mixture was cooled and cold water was added. After extraction with ethyl acetate, the combined organic layers were washed successively with water and saturated brine. Drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure gave the crude residue, which was further purified by column chromatography on silica gel (10–20% EtOAc in hexanes).

[0391] Intermediate 17

[0392] [ka]

[0393] Step (i): 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole To a stirred solution of 2-(chloromethyl)-1H-benzo[d]imidazole (5 g, 30.0 mmol) in anhydrous toluene (50 mL), dimethyl sulfate (4.26 mL, 45.0 mmol) was added, and the solution was then stirred at 100 °C for 8 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added to the solution, which was then extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the expected methylated heterocycle as a pale yellow solid (5.6 g, crude). The crude compound was used in the next step without further purification.

[0394] Intermediate 18

[0395] [ka]

[0396] Step (i): Methyl 2-fluoro-4-hydroxybenzoate To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (5.0 g, 32.03 mmol) in MeOH (50 mL) was added HSO (25 mL) at 0 °C, and then the reaction was heated to 80 °C for 4 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, followed by treatment with saturated NaHCO and extraction with ethyl acetate. The combined organic layers were washed with water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave the crude residue (5.11 g, crude), which was used in the next step without further purification.

[0397] Step (ii): Methyl 2-fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate To a stirred solution of methyl 2-fluoro-4-hydroxybenzoate (5.0 g, 29.4 mmol) in anhydrous CHCl (75 mL) at room temperature was added PPTS (804 mg, 2.94 mmol). After stirring for 10 min, 3,4-dihydro-2H-pyran (4.94 g, 58.79 mmol) was added, and the reaction mixture was then stirred at room temperature for 12 h. After completion of the reaction was confirmed by TLC, the reaction mixture was diluted with water and extracted with CHCl. ​​The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude residue. The resulting residue was purified by column chromatography on silica gel eluting with 10–15% EtOAc in hexane to give methyl 2-fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate (6.81 g, 91%).

[0398] Step (iii): Methyl 2-(piperazin-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate To a stirred solution of methyl 2-fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate (6.0 g, 23.60 mmol) in acetonitrile (100 mL) was added piperazine (10.15 g, 118.02 mmol), and the resulting solution was then stirred at 80° C. for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude residue (6.8 g, crude), which was used in the next step without further purification.

[0399] Step (iv): Methyl 2-(4-(benzo[d]thiazol-2-ylmethyl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate To a stirred solution of methyl 2-(piperazin-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate (6.5 g, 20.29 mmol) in 1,4-dioxane (60 mL) was added EtN (8.43 mL, 60.86 mmol) at 0 °C, followed 10 min later by the addition of 2-(chloromethyl)benzo[d]thiazole (5.54 g, 30.43 mmol). The resulting reaction mixture was stirred at 100 °C for 12 h. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the crude residue. The crude compound was further purified by column chromatography on silica gel (30–40% EtOAc in hexanes) to give the desired compound (6.3 g, 78%).

[0400] Step (v): Methyl 2-(4-(benzo[d]thiazol-2-ylmethyl)piperazin-1-yl)-4-hydroxybenzoate To a stirred solution of methyl 2-(4-(benzo[d]thiazol-2-ylmethyl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)benzoate (6.0 g, 12.83 mmol) in MeOH (50 mL) was added PPTS (322 mg, 1.28 mmol), and the resulting solution was then stirred at 50 °C for 8 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude residue, which was purified by column chromatography (SiO, 40–50% EtOAc in hexanes) to give the expected product (3.42 g, 70%).

[0401] Intermediate 19

[0402] [ka]

[0403] Step (i): 4-Bromo-2-(piperazin-1-yl)benzonitrile To a stirred solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in acetonitrile (100 mL) was added piperazine (21.5 g, 250.0 mmol), and the resulting solution was then stirred at 80° C. for 12 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness, water was added, and the resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to...

Claims

1. the below described: 【Chemistry 6】 A compound, or a pharma- ceutically acceptable salt thereof.

2. the below described: 【Chemistry 7】 2. The compound of claim 1, wherein:

3. the below described: 【Chemistry 8】 2. The compound of claim 1, wherein:

4. 13. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

5. 5. The pharmaceutical composition according to claim 4 for use in the prevention, treatment and / or management of pain.

6. The pharmaceutical composition according to claim 5 , wherein the pain is diabetic peripheral neuropathic pain.

7. 13. A medicament comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof for use in treating or preventing chronic pain.

8. The pharmaceutical composition according to claim 7, wherein the pain is diabetic peripheral neuropathic pain.

9. A pharmaceutical composition comprising the compound of claim 2 or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

10. The pharmaceutical composition described in claim 9, for use in the prevention, treatment and / or management of pain.

11. The pharmaceutical composition described in claim 10, wherein the pain is diabetic peripheral neuropathic pain.

12. A medicine comprising the compound of claim 2 or a pharma- ceutically acceptable salt thereof, for use in treating or preventing chronic pain.

13. The pharmaceutical composition described in claim 12, wherein the pain is diabetic peripheral neuropathic pain.

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