Compounds for the treatment of pain, particularly neuropathic pain, and / or other diseases or disorders related to AT2R and / or AT2R-mediated signaling.

Abstract

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

Description

[Technical Field]

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

[0002] Pain can occur in many forms and may have various causes and underlying pathophysiological mechanisms. Pain can be spontaneous, chronic, or acute, and may be caused by, for example, physical injury to the body or latent pain. Damage to the somatic nervous system (so-called "nociceptive pain"), or damage to the somatosensory nervous system pain / or disease (so-called "neuropathic pain"), for example, "peripheral neuropathy" or abbreviated as " Also known as "neuropathy," this refers to damage to peripheral nerves (i.e., nerves beyond the brain and spinal cord) or It can be caused by pain resulting from a disease.

[0003] Pain conditions can also manifest as a form of hypersensitivity to pain, such as in so-called "inflammatory pain." This term may be used in some cases, and generally refers to tissue damage and inflammation (e.g., postoperative pain, trauma, It is used to describe spontaneous hypersensitivity to pain that arises in response to arthritis. A state of dysalgia is characterized by hyperalgesia (increased pain induced by noxious stimuli and a decrease in the pain threshold). ) and / or allodynia (sensitivity to stimuli at levels that were previously non-noxious) Although often associated with the onset of (increase), the term hyperalgesia is used for hyperalgesia and allodini. It is also used in literature to collectively refer to both A and B (for example, Guindon and Hohmann,British Journal of Pharmaco See logy (2008) 153, 319-334).

[0004] The prevention, treatment, and / or management of chronic and severe pain in patients is the responsibility of Guindon A. In the explanation by nd Hohmann (above), the phrase "burden on clinicians" is used.

[0005] Characteristic symptoms induced by tissue damage, inflammation, neurological trauma, chemotherapy agents, and metabolic problems. To experimentally evaluate the pathophysiological mechanisms underlying clinical pain states, various animal models are used. Dell has developed a model that also performs preclinical evaluation and validation of the therapeutic effects of candidate analgesics. This makes it possible. For example, Dubner and Ren, "Assessing Tra nsient and persistent pain in animals",I n:Textbook of Pain, 4 th edition(Wall and Melzack, Eds.), pp. 359-369, Churchill Livin. gstone,1999,53,319-334(Guindon and Hohma (The above is also cited) is referenced.

[0006] Furthermore, various molecular targets for the prevention, treatment, and / or management of pain are being developed in this technology. This has been suggested. These include cannabinoid CB2 receptors (e.g., Guindon and Hohmann (see above again), NMDA receptor (e.g., Parson s,European Journal of Pharmacology,429 Z See 2001, 71-78), various ion channels (e.g., Dib-Hajj et al.) al.,Brain Research Reviews,Volume 60,Is Sue 1, April 2009, Pages 65-83, and Markman a nd Dworkin,The Journal of Pain,Volume 7, Issue 1,Supplement,January 2006,Pages S3 See 8-S47), sphingosine-1-phosphate receptor (e.g., Welch et al.) l.,Biochemical Pharmacology,Volume 84,Is sue 12,15 December 2012, Pages 1551-1562 (Likely referring to) and monoacylglycerol lipase (MAGL) (e.g., International Publication No. 2020 / (See issue 112905) is one example.

[0007] Neuropathic pain is generally characterized by hyperalgesia and / or allodynia. It is a chronic secondary pain condition caused by damage and / or disease of the somatosensory nervous system. Neuropathic pain affects approximately 7-10% of the population and significantly impacts their quality of life. It is possible. For example, Szok et al., Behav. Neurol., 2019: 8685954, Colloca et al., Nat. Rev. Dis. Prime rs,2017 Feb 16,3:17002, Alles and Smith,P harmacol. Rev.70:315-347, April 2018, and Cav alli et al.,Int.J.Immunopathol.Pharmacol ., 2019 Jan-Dec, 33, and further references cited herein. Please refer to the references.

[0008] As mentioned in these references, neuropathic pain (also abbreviated as "NP") (This refers to a disease of the somatosensory system, including peripheral fibers (Aβ, Aδ, and C fibers) and central neurons.) Caused by a disorder or disease. Several causes of neuropathic pain have been described, for example. For example, metabolic diseases such as diabetes, cancer and cancer treatment, such as chemotherapy, neurological conditions, etc. This includes conditions caused by autoimmune diseases (e.g., multiple sclerosis) and Parkinson's disease. Neurodegenerative conditions such as stroke, nerve damage caused by viral infections, for example, Conditions caused by the rupes virus (e.g., shingles), leprosy, Guillain's disease • Barre syndrome, HIV infection, vascular diseases and vascular malformations, autoimmune conditions, and neurological or Damage to the nervous system is one example.

[0009] Therefore, chronic neuropathic pain can originate from the peripheral parts of the nervous system (e.g., trigeminal nerve). Menstrual pain or postherpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or nerve root injury. (In the case of) or may originate from or be involved with the central nervous system (for example, Chronic neuropathic disease that develops as a result of spinal cord injury or brain injury, stroke, or multiple sclerosis. (In the case of pain). As mentioned, if it originates from nerves beyond the brain and central nervous system, it is called "peripheral." It is also called "neurological disorder" or simply "neurological disorder."

[0010] As mentioned by Szok et al. (above), in 2019, Int ernational Association for the Study of Pain (IASP) published a classification of these different pain syndromes, and the following subtypes Ip is recognized. - Subtypes of chronic peripheral neuropathy: trigeminal neuralgia (TN), chronic neuropathy after peripheral nerve injury, Painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. - Subtypes of chronic central NP: Chronic central NP associated with spinal cord injury (SCI), brain Chronic central neuropathies (NPs) associated with injury, chronic central pain after stroke, and conditions associated with multiple sclerosis. Chronic central NP.

[0011] As stated by Szok et al., "Generally, the NP state is recognized "Awareness is insufficient, diagnosis is insufficient, and treatment is insufficient."

[0012] Angiotensin II receptor type 2 (also referred to herein as "AT2R") is It has been proposed as a target for the treatment of neuropathic pain. For example, Shepherd et al. al., PNAS, vol. 115, no. 34, E8057-E8066 and Kepp El Hesselink and Schatman, Journal of Pai n Research, 2017, 10:439-443, and Matavelli a nd Siragy,J.Cardiovasc.Pharmacol.,2015;6 See 5(3):226-232 and International Publication No. 2015 / 003223. Several known AT2R modulators have been proposed or studied for the treatment of neuropathic pain. In addition, compounds EMA200 (also known as PD-123319) and EMA300 , EMA400 (also known as PD-126055) and EMA401 / oloda nrigan (for example, Smith et al., Pain Medicine 20) 13,14:692-705, Anand et al.,Mol.Pain 2015 (See 11:38, and International Publication No. 2006 / 066361), compound PD-123 177 (For example, Singh and Karnik, J. Cell. Signal., See 2016 June, 1(111), and compounds known as C-38 (e.g.) For example, Wallinder et al.,ACS Med.Chem.Lett.,2 015,6,2,178-182, and Isaksson et al., Chemis This includes (see try Open 2019, 8(1), 114-125).

[0013] The analgesic properties of AT2R antagonists (e.g., EMA-401, mentioned below) The underlying mechanism remains unexplained. Some researchers have suggested that it may be related to preclinical studies. The analgesic properties of AT2R antagonists regulate macrophage-mediated neuroimmune interactions. It has been reported that there is a suggestion that this can be explained by a mechanism involving (Shepher d et al.,J.Neurosci.,2018,38(32):7032-70 57 and Shepherd et al., Proc. Natl. Acad. Sci. U SA, 2018 Aug 21;115(34):E8057-E8066) is another research The researchers found that AT2R is located in the same place as TRPV1 in the human dorsal root ganglion (DRG). Based on the finding that AT2R is involved in nociception by capsaicin-sensitive sensory neurons, In this context, AT2R antagonists play a role in pain response and in such cells. This suggests that it may inhibit neurite growth (Anand et al., Eur. J.Pain,17,(2013),1012-1026).

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

[0015] As described in these references, AT2R is related to the renin-angiotensin system. (RAS) is a G protein-coupled receptor that forms part of the system, and this system consists of multiple enzymes, It includes ptidohormones and receptors, and among its various biological functions, it is particularly important for the cardiovascular and renal systems. It is known to be a major regulatory element in the control of cognitive function.

[0016] Some of the main receptors in the RAS are angiotensin II receptor type 1 (AT1R). Angiotensin II receptor type 2 (AT2R), Ang IV receptor (also known as AT4R) It is known to be involved in the RAS (Renin-Abstract Syndrome). Some of the natural peptide ligands that have been identified are those of the angiotensin and pro(renin) receptor. It is a ligand (such as renin and prorenin) and a ligand for the MAS receptor.

[0017] Angiotensin contains the octapeptide Ang II and its natural degradation product A ng III (both known to be ligands for AT1R and AT2R), Ang(1-7), a hexapeptide, is known to be an endogenous ligand for the MAS receptor. (It is said that Ang IV (the natural degradation product of Ang II, the main ligand of AT4R) is produced when Ang II is broken down. Ang I (a decapeptide precursor of Ang II) and Ang II are themselves major known (It appears that it does not have direct biological activity.)

[0018] Ang II is described as a central peptide hormone of the RAS, and is a potent stimulant. Aldosterone is a blood pressure hormone produced by the adrenal cortex that promotes sodium retention in the kidneys. It is known to be a major regulator of secretion. Therefore, it is important for blood pressure and the cardiovascular system. It is an important effector that controls blood volume. Ang II also has vasodilatory properties. It is also a medicine for the treatment of cu (marketed under the trademark name GIAPREZA(trademark)). It will be used.

[0019] Ang II and its natural degradation product, Ang III, are (mainly) AT1R and A They are known to act via T2R, and both of them have approximately 34% of the sequence relative to each other. They are identical G protein-coupled receptors. The actions of AT1R and AT2R are generally It is assumed that they are in opposition to each other. Activation of AT1R is not limited to cells. Dedifferentiation and proliferation of , vasoconstriction, antinatriuretic, aldosterone secretion, and ultimately It is explained that it induces biological effects such as sympathetic nerve activation, which leads to high blood pressure. Activation of 2R has, among other biological effects, particularly inhibition of cell differentiation and proliferation / application. It induces cis, vasodilation, and natriuresis, potentially lowering blood pressure in kidney disease. It has a blood pressure-lowering effect and also provides protective functions for various tissues and organs. It is described as something that does.

[0020] AT2R is used to analyze fetal tissues, such as the fetal aorta, gastrointestinal mesenchyme, connective tissue, skeletal system, brain, and paraplegia. It is known to be highly expressed in the renal medulla and fetal kidney tissue. AT2R expression is Generally, levels decrease after birth, and in adults, they are most pronounced in the uterine muscle layer, as well as in the adrenal glands and f(x). The levels are lower in the Alopius tube. Otherwise, in the tissues of healthy adults. Although AT2R expression levels are generally low, AT2R is involved in tissue damage and injury (vascular damage, etc.). To be strongly upregulated in pathological conditions (including neuron injury, myocardial infarction, and cerebral ischemia). It is known that AT2R primarily antagonizes AT1R, thereby reducing inflammation and oxidation. It is also thought to provide endogenous protection against the apoptotic process.

[0021] In particular, as explained by Anand (mentioned above), "AngII and AT2R are, It is co-expressed in human nociceptive sensory neurons and is a major endogenous factor in human peripheral nerves. The level of the sex ligand AngII is preserved after injury. [...] Therefore, AngII / AT2R signaling in DRG neurons secondary to peripheral nerve injury The increase may play a significant role in chronic pain mechanisms, including neuropathic pain. - Anan d also states that the mechanism of action of the known AT2R antagonist EMA401 is "enhanced An Inhibition of gII / AT2R-induced p38 and p42 / p44 MAPK activation, and consequently D It appears to be involved in the hyperexcitability of RG neurons and the inhibition of DRG neuron budding." This is an assumption. Similarly, Smith et al. (2013) (above), regarding the analgesic dose A T2R antagonist EMA300 enhances angiotensin I in the dorsal root ganglia. Blocking I / AT2R signaling subsequently occurs in the ipsilateral lumbar DRG of nerve-injured rats. It explains that this inhibits the activation of p38 MAPK and p44 / p42 MAPK. .

[0022] AT2R antagonists such as EMA401 have shown improvement in postherpetic neuralgia in humans. In the treatment of (for example, Rice et al., The Lancet, Vol. e 383, P1637-1647, May 10, 2014, see also herpes zoster, In preclinical pain models of diabetes, osteoarthritis, HIV, and chemotherapy (e.g., international Publication No. 2006 / 066361 and Anand et al. (see above) for the effect Despite this, known AT2R antagonists so far have been ( Success in clinical development appears to be limited.

[0023] Rice et al., Pain, 2021, March, 1: Postherpetic nerve Regarding the analgesic effect and safety of EMA401 in patients with painful and painful diabetic neuropathy. The results of two multicenter, randomized, double-blind, phase 2b treatment trials are described. (Rice et al.) Therefore, as mentioned, "The primary outcome in both trials was from baseline to 12 weeks." The weekly average change in 24-hour average pain scores using a numerical rating scale (NRS) up to the eye. It was a transformation. Although not observed in these trials, both trials showed preclinical effects during long-term administration. The trial was terminated early due to hepatotoxicity. Rice et al. further stated, "[...] The trial was terminated early." Although we were unable to reach a definitive conclusion because the study was not completed, these findings in two different groups "The consistent clinical improvement in pain intensity reduction observed in these two trials is noteworthy," he stated. He is eating.

[0024] As is clear from the above, prevention and / or prevention of pain, especially chronic pain such as neuropathic pain There is a constant need in this field for compounds that can be used for therapeutic purposes. (According to Rice et al.) In the case of leaves, "the effectiveness of existing treatments for peripheral neuropathic pain (PNP) is minimal." Furthermore, these treatments are often not well tolerated, and improvements in these common chronic pain conditions are not always effective. The development of treatments is recognized as a critical, unmet need.

[0025] In particular, targeting AT2R and / or AT2R and its ligand (such as AngII) It can be used to modulate interactions with one or more factors, and for various forms of chronic pain, for example , due to damage and / or disease of the somatosensory nervous system (especially damage and / or disease of the peripheral nerves) Responding to chronic pain conditions, tissue damage, and / or inflammation caused by and / or associated with them. A chronic pain condition caused and / or associated with hypersensitivity to pain. More generally, AT2R-mediated signaling, AngII-mediated activation of AT2R, and Ang For use in the prevention and / or treatment of chronic pain conditions associated with II-mediated activated signaling pathways. A new class of molecules is needed. [Overview of the project]

[0026] explanation The present invention generally provides compounds that can interact with AT2R, thereby addressing this requirement. The objective is to satisfy the requirements. In particular, the present invention generally refers to AT2R and AT2R-mediated Signal transduction, for example, AT2R ligands (e.g., Ang II and other natural AT2R molecules). Regulates AT2R-mediated signaling related to the binding of ligands to AT2R (as specified herein). The objective is to provide compounds that can be (as defined by...).

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

[0028] Without being limited to any specific description, hypothesis, or mechanism of action, the compounds of the present invention are Regarding the binding of a compound to AT2R, one or more ligands of AT2R (in particular, Ang In a manner that allows competition with one or more natural ligands of AT2R (such as II), A It is generally assumed that it can bind to T2R.

[0029] Furthermore, generally speaking, the compounds of the present invention are compared to AT2R (for example, compared to AT1R) It has favorable selectivity.

[0030] Furthermore, generally speaking, based on their overall chemical structure, the compounds of the present invention are suitable for human and other It is assumed to contain pharmacophores that are favorable for clinical and therapeutic use in mammals. The compounds of the present invention are known AT2R modules described in the art. It may also have certain advantages in terms of safety and tolerability compared to some other devices. It is thought that...

[0031] Furthermore, without being limited to any specific explanation, hypothesis, or mechanism of action, the chemicals of the present invention These substances generally interact with angiotensin receptors, particularly angiotensin II receptor type 2. It will be clear from this specification that it is considered possible to operate in this manner.

[0032] In particular, the compounds of the present invention affect angiotensin II receptor type 2, AT2R-mediated signaling Transmission and / or pathways involving AT2R and / or AT2R-mediated signaling to regulate (as defined herein) a biological process, in particular to regulate it specifically. It is assumed that it can do (as defined herein), for example, inhibit. More details As referred to herein, the compounds of the present invention have a bond to AT2R. It is assumed that it can compete with one or more natural ligands of AT2R.

[0033] Therefore, this compound and its composition are angiotensin II receptor type 2, AT2R AT2R-mediated signaling and / or AT2R-mediated signaling To regulate the pathways and / or biological processes involved in the target population that requires them. By doing so, in particular, an appropriate treatment or medication regimen can be provided to the subject (depending on the patient's condition and involvement). The nature of the disease, the severity of the disease and / or its symptoms, and the treatment physician's assessment (and may be determined by the treating physician based on other factors that may be appropriately considered) By administering one or more pharmaceutically active amounts (e.g., doses) of the compounds of the present invention, It is expected that it can also be used for the prevention and treatment of preventable or treatable diseases and disorders.

[0034] Therefore, this compound and composition target one or more angiotensin II receptor type 2 receptors. By administering compounds that can compete with the binding of natural ligands to subjects that require them... In particular, appropriate treatment or medication regimen for the subject (patient's condition, nature of the disease involved) The severity of the disease and / or its symptoms, as well as the treatment physician's determination and appropriate consideration. One or more (which may be determined by the doctor treating based on other possible factors) By administering a pharmaceutically active amount (e.g., dose) of the compound of the present invention, prevention or It is further anticipated that it will be used for the prevention and treatment of treatable diseases and disorders. Not limited to explanations, hypotheses, or mechanisms of action, usually angiotensin II receptor The binding of one or more natural ligands to type 2 and the administration of a compound that can compete with them to a target ligament Reduction of AT2R-mediated signaling related to the binding of the nucleotide to AT2R, and / or The pathways and / or pathways that are induced and / or activated by the binding of the ligand to AT2R It will be obvious to those skilled in the art that this will result in the inhibition and / or antagonism of biological processes. Ro.

[0035] AT2R, AT2R-mediated signaling, AT2R and / or AT2R-mediated signaling Pathways and / or biological processes in which 1 AT2R is involved, and / or 1 Examples of such diseases and disorders associated with the binding of one or more natural ligands are obvious to those skilled in the art. (For example, from the prior art cited herein), known modulators (especially , use of modulators that compete for ligand binding to AT2R and / or AT Known inhibitors and / or antagonists of 2R and / or AT2R-mediated signaling The use of nistrone includes other diseases and disorders described in the art. For example, , AT2R-mediated diseases and disorders described in International Publication No. 2019 / 179515 See also the list. Also, Bonas-Guarch et al., Nat.Co. mmun., 2018 Jan 22;9(1):321 and Dominguez-Cr See also uz et al.,Gene,2018 Nov 30;677:324-331 These findings indicate the following regarding the involvement of AT2R in diabetes, particularly type II diabetes: It states: "This rare variant identified on chromosome Xq23 is AGTR2 Located near the gene, it approximately doubles the risk of T2D in men, which is, To our knowledge, the largest effect size identified in Europeans to date, and other It represents a similar scale to other variants with significant effects identified in the population. Using binding and gene reporter analysis, the functional role of this variant was demonstrated. We propose a possible mechanism underlying the pathophysiology of T2D in T risk allele carriers. However, this rare variant had previously been associated with insulin resistance. This supported the acquisition of TR2 function. Therefore, AGTR2 is a potential treatment for this disease. It appears that blockade of the renin-angiotensin system in mice and humans is a target, and it is associated with the development of T2D. This would be consistent with previous studies showing that it can prevent the disease and restore normal blood sugar levels. This gene helps angiotensin II (Ang II) mediate its action. Encoding a receptor bound to a G protein (Harrison-Bernard, 2020) 09). Furthermore, the AGTR2 gene is an insulin sensitivity modulator, and until now The study showed blockade of the renin-angiotensin system in mice (Fran (tz et al., 2013; Leung, 2007), in humans, the onset of T2D is predicted. It prevents and restores normal blood glucose levels (Geng et al., 2013). Therefore, this The compound is expected to be useful in the prevention and treatment of diabetes, particularly type II diabetes. .

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

[0037] The present invention particularly concerns pain, especially chronic pain, in various forms, such as those further described herein. Neuropathic pain and / or inflammatory pain of the state, and AT2R and / or AT2R-mediated pain The use of the compounds and compositions of the present invention in the prevention, treatment and / or management of other diseases or disorders related to cannabinoid signaling (further described herein). / or management.

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

[0039] WO 2020 / 112905 describes compounds and methods for treating diseases using inhibitors of monoacylglycerol lipase (MAGL ), and the compounds have the following formula, where R1 is a -C(O)OR group (R 15 is hydrogen or C1-C6 alkyl) or a -C(O)NR 15 R group (R 10 R 11 and R 10 and R 11 are each independently hydrogen or C1-C6 alkyl).

[0040]

Chemical formula

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

[0042] Among various MAGL inhibitors for which detailed chemical structures are listed, in International Publication No. 2020 / 112905, page 53, paragraph

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

[0043] [Chemical formula]

[0044] Neither the activity against AT2R is described nor suggested. Also, as can be seen from Formula B, the said MAGL inhibitor has a substituent (i.e., a CF3 group) at the meta position with respect to the tetrazole group, and there are linking groups both between the piperazine ring and the tetrazole-substituted phenyl ring (i.e., a methylene linking group), 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 through a nitrogen atom rather than a carbon atom in the pyrazole ring.

[0045] In this specification and the claims, - When a term is not specifically defined in this specification, it has its ordinary meaning that would be apparent to a person skilled in the art. For example, standard reference books in the fields of organic chemistry and / or pharmaceutical chemistry, such as Karrer, Organic Chemist ry, 3 Ed, 1947, Vogel, Practical Organic C hemistry, 3 rd Ed, 1964, Roberts and Caserio Ed, 1964, Roberts and Caserio rd Ed, 1964, Roberts and Caserio <000,Basic Principles of Organic Chemistry,1 st Ed, 1965, Carey and Sundberg, Advanced O. Physic Chemistry, 2 nd Ed, 1985, Michael BS mith,March's Advanced Organic Chemistry: Reactions,Mechanisms,and Structure,1 st E d,2020, Jonathan Clayden, Nick Greeves, Stu art Warren,Organic Chemistry,2 nd Ed, 2012 ,D.Sriram,Medical Chemistry,2 nd Ed, 201 0;and Camille Georges Wermuth,David Aldo us,Pierre Raboisson,The Practice of Medi Cinal Chemistry, 4 th Ed. 2015, and "Glossar y of terms used in medicinal chemistry(I UPAC Recommendations 1998) by Wermuth et al. al.,Pure and Applied Chemistry,70(5):11 See 29-1143 (1998). - A particular embodiment is preferred (for example, a particular part or structural element of the compound of the present invention, (and / or the presence of a particular preferred substituent or combination of substituents is preferred.) If indicated as such, such an embodiment is preferred (for example, another part of the compound of the present invention or with respect to the presence of structural elements and / or another preferred substituent or combination of substituents can be appropriately combined with another embodiment which is described as being "preferred", and such a combination of preferred embodiments forms another preferred embodiment of the present invention. The same also applies mutatis mutandis to the embodiments described herein by expressions such as "more preferred", "particularly preferred", "even more preferred", "most preferred" or similar / equivalent expressions. - When a structural formula is used to schematically illustrate or define a compound, embodiment or implementation form of the present invention, and such a structural formula represents an atom where not all (necessary or possible) bonds / groups / substituents are shown, the bonds / groups / substituents not explicitly shown can follow the further description of such a compound / embodiment / implementation form in this specification. In the absence of such further description, they can be hydrogen, or optionally and independently selected appropriately from suitable substituents (defined herein), but are usually understood to be hydrogen atoms. - When referring to "suitable substituents", or when it is stated that an atom or position in a compound of the present invention can be "appropriately substituted", each of these substituents (and their combinations) can be preferably selected by those skilled in the art, possibly after some trial and error. Suitable substituents are obvious to those skilled in the art based on the disclosure of this specification (optionally, after some trial and error), and include, for example, substituents or combinations of substituents present in the compounds of the present invention described herein and / or shown in the following experimental section (see compounds A-01 to A-251 in Table 1). Other suitable substituents are as described in this As will be apparent to those skilled in the art based on the disclosure, for example, halogens (i.e., F, Cl, B) r and I), C1-C8 alkyl (especially C1-C4 alkyl), C1-C8 alkoxy (especially C1-C4 alkoxys), C1-C8 amines (especially C1-C4 amines), cyclamines Ropropyl, cyclobutyl, trifluoromethyl (CF3), and cyanopropyl, as well as, for example, acids Examples of elements (i.e., those that form a carbonyl group) include (but are not limited to) For example, one or more substituents present in the compound of the present invention as exemplified in the following experimental section May contain (related substituents present in compounds A-01 to A-251 in Table 1) (See combinations.) - Specific positions in the compound of the present invention (in particular, carbon atoms or nitrogen atoms present at such positions) When an atom is said to be "optionally substituted," the atom at that position is not substituted. None, or appropriately and independently, one or more appropriate substituents (as defined herein) Selected from (), 1, 2 and up to 3 (in the case of carbon atoms) or 1 or 2 The compound may be appropriately substituted with a substituent (in the case of a nitrogen atom). The maximum number of such suitable substituents that may be present at that position is, and the suitable substitutions present at that position. Water supported by atoms that can be appropriately substituted by a group (as defined herein) Depending on the number of elementary atoms, other atoms in the compound of the present invention to which the atom at that position is bonded may also be a factor. Children should also be taken into consideration. Furthermore, as is clear, the compound of the present invention (or any structural part thereof) The total number of substituents that may be present in or on the substituent is generally available for such substitution. It is capable of (for example, supporting hydrogen atoms that can be appropriately substituted by such substituents). It depends on the number of atoms in such a compound. - Each compound of the present invention may, if necessary, be a suitable salt or ester (further described herein). Forms of (that which are used), in particular pharmaceutically acceptable salts or esters (which are also described further herein). It may be in the form of (being made). Examples of suitable salts will be obvious to those skilled in the art, and further details herein This includes, but is not limited to, the items mentioned in the explanation. - The compounds of the present invention (including any salt or ester thereof) are generally suitable for any appropriate or This is the desired physical form, for example, a suitable crystalline form (including cocrystal form or cocrystal salt form), A suitable amorphous form, and / or an anhydrous or a suitable hydrate or solvate (hydrate or This can be in the form of hemihydrates, but is not limited to these. - The compounds of the present invention (including their salts or esters) are generally used in solution, for example Alternatively, it may be present in a suitable solvent or solvent mixture, such as a suitable aqueous solvent or buffer solution. For pharmaceutical use, the compounds of the present invention are particularly useful when present in pharmaceutically acceptable solutions. This may typically be (sterile) water or a pharmaceutically acceptable aqueous buffer or solution. Suitable examples of such pharmaceutically acceptable aqueous buffers or solutions will be obvious to those skilled in the art. This includes, but is not limited to, those mentioned in further descriptions herein. stomach. - The compounds of the present invention (or their salts or esters) are generally pure or essential. In a pure form, isolated or essentially isolated form, or in combination with one or more other compounds It could be a bitter mixture. - If the compound of the present invention contains one or more chiral atoms or centers, one or more different The optical form, for example, the form of different enantiomers or different stereoisomers (for example) , in the form of two or more enantiomers or two or more diastereomers, term Diastereomers or diastereoisomers are generally not enantiomers. (as used herein to refer to any stereoisomer) may be. In general, otherwise explicitly stated Unless otherwise indicated or the specific context implies otherwise, the present invention may refer to one or more compounds. If such an optical form may exist, the “compound of the present invention” as used herein The term refers to all such conceivable optical forms (e.g., each of all conceivable This refers to and includes enantiomers or stereoisomers. Furthermore, if one or more compounds of the present invention are present, When such optical forms can exist as described above, the term "compound of the present invention" is essentially Each of such optical forms in its pure form (and / or essentially isolated form), as well as race A mixture of two or more possible optical forms, including but not limited to a mixture of any two or more such mixtures (any) It includes (in proportion to). - The compounds of the present invention may also be used as appropriate prodrugs, for example, when administered to a subject and / or Under physiological conditions, the compound is converted into the compound of the present invention (by administration or use) For example, IYAKUHIN no KAIHATSU (Development o f Pharmaceuticals),Vol.7,Design of Molec ules, p.163-198, Published by HIROKAWA SHO See TEN (1990). - The compounds of the present invention are appropriately labeled (for example, under appropriate conditions, a detectable signal is provided) It can be appropriately labeled with atoms, groups, parts, or entities that can be generated (or used to generate). Some specific but non-limiting aspects of appropriate labeling include radioactive isotopes (e.g., 2 H, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) and fluorescent or phosphorescent labeling included Such labeled compounds are detected using appropriate techniques for detecting the label. For purposes known to the public, for example, for tissue distribution / permeation studies, and for PK and other pharmacological studies. It can be used for academic testing and in fields such as medical diagnosis. For example, the present invention Radiolabeled compounds are used as tracers in positron emission tomography (PET) technology. can. - As will become apparent to those skilled in the art from further description herein, in some cases As further shown herein, different parts or structural elements of the compounds of the present invention are directly linked. They are connected (i.e., via covalent bonds) or via appropriate linking or bridging groups. They may be linked or otherwise. Such linking groups (referred to herein as "alkylene linking") If a group (also called a "group") is present, it is generally a C1 or C2 alkylene group (preferably) The group is a methylene group, also referred to as a "methylene linking group" in this specification, and the aluminum Each carbon atom in the chilen linkage can be independently and appropriately optionally substituted, but (carbon atoms) (For example, one or two methyl groups per molecule), preferably unsubstituted (i.e., -CH 2-linking group). Alternatively, such alkylene linking groups are further described herein. It may also be a carbonyl group (i.e., a -(C=O)-) group. - If an atom is substituted with a fluorine atom, the substituent is "fluorine" or "fluoro Also called substituents (where a carbon atom is substituted with another halogen such as chlorine or bromine) (The same terminology applies to combinations as well.) - The term "biological equivalent" is used in relation to a compound, group, or part, respectively. In such cases, it has the ordinary meaning of the term in the art and possesses similar physical or chemical properties. As a result, compounds, groups, or moieties having broadly similar biological activity to the compound, group, or moiety in question. This refers to a part (Friedman HL (1951), NASNR 206:295- 358). Usually, this is done by substituting an atom or group of atoms with another broadly similar atom or group of atoms. The resulting biological equivalent exhibits one or more enhancements compared to the original compound, group, or part. Modified properties (e.g., reduced toxicity, improved bioavailability, modified or improved) It may have increased activity or an improved metabolic profile. For example, Meanwell, T actics in Contemporary Drug Design pp.28 3-380,Topics in Medicinal Chemistry,Volu See me 9,2014. - The term "pharmacophore" is usually defined according to the commonly used IUPAC definition. In other words, "to ensure optimal supramolecular interactions with specific biological targets and their biological responses It refers to "a collection of three-dimensional and electronic features necessary to elicit (or block) an answer." For example, ``Glossary of terms used in medicinal che mistry(IUPAC Recommendations 1998)” by We rmuth et al.,Pure and Applied Chemistry, See 70(5):1129-1143(1998). - The term "alkyl" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group consists of 1 to 12 carbon atoms, particularly 1 to 8 carbon atoms. ("C1-8 alkyl" or "C1-C8 alkyl"), for example, 1-6 carbon atoms (" "C1-C6 alkyl" or "C1-C6 alkyl", for example, 1-4 carbon atoms ("C1 ~4 "Alkyl" or "C1-C4 alkyl"), more specifically 1, 2, 3, 4, 5, 6 It has 7 or 8 carbon atoms. For example, as used herein, the term "C1~ "8 alkyl" and / or "C1-C8 alkyl" refers to a linear or branched chain of 1 to 8 carbon atoms. Chain groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) Sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl These are 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 4-methyl -2-Pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl (e.g., 2-butyl methylbutyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl) These refer to ions that have one or more (e.g., 1 to 3) suitable substituents such as halogens. It is optionally substituted (also called "haloalkyl," e.g., CH2F, CHF) 2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or CH2C (e.g., H2CF3). The terms "C1-C4 alkyl" and "C1-C4 alkyl" are 1 ~A linear or branched aliphatic hydrocarbon chain of 4 carbon atoms (i.e., methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl This refers to (Ru). - The term "C1-C8 alkoxy" refers to the C1-C8 alkyl group as defined herein. This refers to the alkoxy group contained herein. Similarly, the term "C1-C6 alkoxy" is used herein. This refers to an alkoxy group containing a defined C1-C6 alkyl group, and is also known as "C1-C4 alkoxy". The term refers to alkoxy groups, including C1-C4 alkyl groups. - The term "C1-C8 amine" refers to the amine group NR F R G It refers to, and in the formula, R F and R G of Each is independently hydrogen or a C1-C8 alkyl group as defined herein (however, R F and R G (Neither of them is hydrogen). Similarly, the term "C1-C6 amine" is an amine. base NR F R G It refers to, and in the formula, R F and R G Each of these independently refers to hydrogen or as defined herein. It is a C1-C6 alkyl group (however, R F and R G (Neither of them are hydrogen), The term "C1-C4 amine" refers to the amine group NR F R G It refers to, and in the formula, R F and R G Each of them is independent Furthermore, hydrogen or a C1-C4 alkyl group as defined herein (however, R F and R G (Neither of them is hydrogen.) - The term "cycloalkyl" refers to saturated cycloalkyl compounds having 3 to 6 carbon atoms. A cyclopropyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) Preferably, it may be non-substituted or substituted (as described herein), but substituted If present, most preferably a C1 or C2 alkyl group (preferably one or two methyl groups) It is properly replaced only by ). - The term "heterocyclyl" means "3 to 10 ring atoms, preferably 3, 4, 5 Alternatively, it refers to a non-aromatic ring having six ring atoms, preferably a carbon atom and one or two heteroatomic atoms. It contains an atom (each preferably selected from N, O, or S), and such heteroatoms Each of them is most preferably bonded to two carbon atoms in the ring (and most preferably The non-aromatic ring is unsubstituted or appropriately substituted (it is not bonded to another heteroatom in the ring). It may be (as described herein), but if substituted, most preferably C1 or C It is appropriately substituted with only two alkyl groups (preferably one or two methyl groups). Typical but non-specific examples include pyrroline, pyrrolidine, pyrazolidine, and imi. Examples include dazoline, tetrahydrofuran, piperidine, piperazine, and morpholine. Each of these heterocyclyl groups, if present, may be unsubstituted or appropriately substituted. If substituted as described herein, most preferably C1 or C2 ammonium compounds are used. It is appropriately substituted with only kill groups (preferably one or two methyl groups). If the heterocyclyl group contains one or more nitrogen atoms, each such nitrogen atom is It may be unsubstituted, or it may be appropriately substituted with a C1-C3 alkyl group (preferably a methyl group). It is possible. - The terms “adjust,” “modulate,” “modulator,” and “target” are used in reference to the technique. They have their usual meanings in the field of art, and in this regard, in particular, International Publication No. 98 / See definition in Patent No. 06737. Generally, in the context of this invention, "to adjust" Or, "to regulate" generally refers to appropriate in vitro, cell, or in vivo assays (honmei When measured using methods such as those described in the detailed manual, GPCR activity may be reduced or inhibited. It means either to do something or to increase the activity of GPCRs. In particular, "to adjust To "control" or "regulate" is to use an appropriate in vitro, cell, or in vivo assay (honmei When measured using (as mentioned in the detailed document, etc.), the activity of GPCRs under the same conditions However, if the compound, amino acid sequence, or polypeptide (if applicable) of the present invention does not exist Compared to the activity of GPCRs in the same assay, at least 1%, preferably less Both 5%, for example at least 10% or at least 25%, for example at least 50%, less Reduce by at least 60%, at least 70%, at least 80%, or 90% or more. This could mean either inhibiting or increasing the activity of GPCRs. As is clear to the reader, “modulate” also means one of its targets, ligands, or substrates. Changes in affinity, binding activity, specificity and / or selectivity of GPCRs for one or more targets (increases or changes in specific targets). This may result in either a decrease or a reduction, and / or, under the same conditions, this Compared to the case where the compound, amino acid sequence, or polypeptide (if applicable) of the invention does not exist. In comparison, one or more conditions in the medium or environment where GPCRs are present (e.g., pH, iodine) Changes in the sensitivity of GPCRs to (such as ion strength and the presence of cofactors) (either an increase or a decrease). This may include bringing about (which may be). As will be obvious to those skilled in the art, this is also optional. In an appropriate manner, and / or any appropriate assay known in itself, e.g., as specified herein Using the assay described herein or the assay described in the prior art referenced herein , can be determined. "Regulate" also refers to one or more biological or physiological processes involving GPCRs. Scientific mechanism, effect, response, function, pathway or activity (or substrate, ligand or pathway of GPCR) For example, the signaling pathway or metabolic pathway and their related biological or Regarding physiological effects, changes (i.e., GPCR and desired biological or physiological effects) Depending on the effect, they can be agonists, antagonists, reverse agonists and / or This could also mean that it will result in activity as an allosteric modulator. As is clear to the industry, such actions as an agonist or antagonist are In any appropriate manner, and / or in any appropriate manner known by itself (in vitro and usually fine Cellular or in vivo assays, for example, the assays described herein or referenced herein. This can be determined using assays described in prior art. In particular, agonists Alternatively, the antagonistic action may have an unintended biological or physiological effect (e.g., limited Although not definitively established, receptor-mediated signaling (such as) is under the same conditions, but related to the present invention In the same assay in which no compound, amino acid sequence, or polypeptide exists, biological or Compared to physiological activity, each is at least 1%, preferably at least 5%, for example then at least 10% or at least 25%, for example at least 50%, at least 60% , any increase or decrease of at least 70%, at least 80%, or 90% or more. It is possible. Generally, in the context of this specification and the claims, the present invention and disclosures are subject to the law. The compound, amino acid sequence, or polypeptide of the invention modulates any specific mechanism that modulates its target. Not limited to (as long as the target is modified as described herein), and therefore the modification is For example, non-limitingly, binding or allosteric regulation at orthosteric sites (i.e.) , binding at allosteric sites, for example, George et al., Nat. Rev. .Drug Discov.1:808-820(2002);Kenakin,Tre nds Pharmacol. Sci. 25:186-192 (2002) and Ri See os et al., Pharmacol. Ther. 92:71-87 (2001). (Reflecting), reduction or inhibition of GPCR binding to one of its substrates or ligands, and / or may involve competition with natural ligands or substrates for binding to GPCRs. This should be understood. Regulation also involves GPCRs or the mechanisms or pathways in which they are involved. This may include activation. The regulation may be reversible or irreversible, but for pharmaceutical and pharmacological purposes For the purpose, it is usually a reversible mode. Also, generally speaking, a "modulator" is a GPC. A compound or factor that can regulate R, which is physiological as described herein. Under the conditions and / or conditions used in related assays or models, biological Functional properties of activity or process (e.g., of the target, and / or the system in which the target is involved) The biological activity of signal transduction and / or biological pathways, or the target or signal. Enhance, inhibit / reduce, or otherwise alter biological readouts related to signal transduction. It means that it can exert or influence something. In this regard, modulo The device can be used in vitro (e.g., as part of an assay or screening) and / or In vivo (for example, modulators are used in animals (for example, for veterinary purposes, or in vivo) (As part of the model), the subject (i.e., the therapeutic purpose, i.e., the use of the modulator) (For the prevention or treatment of one or more diseases in the subject that can be prevented or treated by use.) It can be used to modulate the target when administered to a modulator or modulo Candidate targets are, for example, those that undergo primary screening (e.g., those with unknown activity regarding the target). Screen used to identify target modulators from a set or library of test chemicals. Leaning) and / or secondary assays (e.g., verifying hits in primary screening) Used to optimize the hit molecules, for example, when optimizing the hit to Assays used as part of the code, and / or one or more related parameters (i.e., A cell or animal model that allows testing / determination of the parameters to be regulated. Which relevant targets can be identified, tested, and / or identified by in vitro screening or assays including the relevant targets? Or it may be further characterized. For example, such an assay or screening is an invisible It can be configured as a troassay or screening, and generally involves (candidate) modules to a target. This includes the coupling of latents, and the signal generated by this coupling is measured. Appropriate methods for in vitro screening are obvious to those skilled in the art, for example, Eld efrawi et al.,(1987).FASEB J.,Vol.1,page s 262-271 and Rauh et al.,(1990),Trends in Pharmacol.Sci., vol.11, pages 325-329. It is listed. For example, such assays or screenings are binding assays or screenings. It may be configured as cleaning, where the (candidate) modulator is detectable from the target. It is used to replace ligands (for example, radioactive ligands or fluorescent ligands), Based on this, the amount of ligand substituted from the target by the modulator is determined. Generally, compounds exhibit biological activity or process (i.e., related assays or models). The functional characteristics of the signal or readout in the same assay or model (candidate) ) Compared to the value obtained when performed in the absence of a modulator, at least 1 percent -Centimeters, for example, at least 5 percent or more, when modifying or altering, modulator —is considered to be the case. - The term "affinity" refers to the strength or stability of molecular interactions. Affinity is, Generally, K D Alternatively, it is given by the dissociation constant and has units of mol / liter (or M). Affinity is also the binding constant K. A It can also be expressed as, which is 1 / K D Equivalent to, ( (mol / liter) -1 (or M -1 ) has units. Affinity is a method known in itself. This can be determined. - In this specification and claims, the term "monocyclic" means that this term refers to a ring system. When referring to (aliphatic ring systems or aromatic ring systems, etc.), it includes or essentially consists of a monocycle. This refers to a ring system, where the ring consists of a carbon atom and, optionally, one or more (one or two, etc.) heterozygotes. Atoms (heteroatoms are preferably each independently and appropriately selected, more preferably O, It is also clear that it appropriately includes or essentially consists of (selected from N and / or S). It is likely that, depending on the atoms present in the ring, the monocyclic ring preferably contains 3 to 10 ring atoms. For example, 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, especially 4, 5, or 6 ring atoms It may include or essentially consist of them.

[0046] Similarly, in this specification and in the claims, the term “bi-ring” means that this term When referring to a cyclic system (such as an aliphatic or aromatic cyclic system), it includes two rings that are appropriately fused to each other. It refers to a ring system that is essentially composed of such a ring (usually two fused rings sharing two ring atoms). Each of the rings forming the bicyclic ring system contains a carbon atom and, optionally, one or more (one or two) (The heteroatoms are preferably each independently and appropriately selected, and more preferably It appropriately includes or essentially consists of (which is selected from O, N, and / or S). ). Generally, depending on the number of atoms present in each ring, a bicyclic ring can have 8 to 12 atoms, for example. , appropriately containing 8, 9, 10, 11 or 12 ring atoms, or essentially consisting of them. It is possible. In bicyclic ring systems, fused rings usually share two carbon atoms, but in this case As is clear to the user, when nitrogen atoms are present in appropriate quantities, the fused ring consists of one carbon atom and It is also possible to share a single nitrogen atom.

[0047] A bicyclic ring system consists of two aliphatic rings (in this case, usually the two fused rings share two atoms). (so that they are properly condensed), two aromatic rings (in this case too, usually two condensed The rings share two atoms, and the two rings in the bicyclic ring system form a conjugated planar ring system. It appropriately contains (and is appropriately condensed) or may essentially contain, or one an aromatic ring and one aliphatic ring (in this case, usually two fused rings share two atoms) It may also appropriately include (and essentially consist of) those that are appropriately condensed. This will be obvious to those skilled in the art. In this specification, for convenience only, and in accordance with the present disclosure or the Patent Publication. Without limiting the scope of the claims, a bicyclic ring system comprising at least one aromatic ring is a ring system Regardless of whether the second ring in the middle is aromatic or aliphatic, in general terms as used herein, aromatic These are called group ring systems. Similarly, as will be apparent to those skilled in the art, biring ring systems are also appropriate to each other. It is condensed (that is, in a bicyclic ring system, the two fused rings are at least two ring progenitors) (To share children) appropriately include two of the monocyclic ring systems referred to herein. It is possible.

[0048] Similarly, in this specification and the claims, the term “polycyclic” means that this term is When referring to a cyclic system (such as an aliphatic or aromatic cyclic system), it can mean two or more rings (two, three, four, or five rings). This refers to a ring system that includes, or essentially consists of, such as, a ring within the ring system, and each ring within the ring system is a ring system with a small number of rings within the ring system. At most, it is appropriately and independently condensed with one other ring (usually, the two rings are condensed with each other). (So ​​that two rings share two ring atoms). In this case as well, in a polycyclic ring system, the ring system forms Each of the rings contains a suitable number of carbon atoms, or is essentially composed of them, and optionally 1 One or more heteroatoms (one or two, etc.) (preferably each heteroatom is independently It may also include (appropriately selected, more preferably selected from O, N, and / or S). As will be apparent to those skilled in the art, the total number of ring atoms in a polycyclic ring system is equal to the number of ring atoms in the ring system. It depends on the total number, the number of ring atoms in each ring, and the number of ring atoms shared between different rings. In polycyclic and bicyclic ring systems, fused rings usually share two carbon atoms, but as will be apparent to those skilled in the art... As such, when nitrogen atoms are present in appropriate amounts, the fused ring consists of one carbon atom and one nitrogen atom. It is also possible to share elementary atoms.

[0049] Polycyclic ring systems appropriately contain only aliphatic rings, or may essentially contain only aromatic rings. It appropriately contains or may essentially contain, or one or more aliphatic rings and one or more It is also obvious to those skilled in the art that it can be appropriately constructed from aromatic rings (in this case, too, simply convenient Accordingly, and without limiting the scope of this disclosure or claims, at least one aromatic ring Polycyclic ring systems, whether the other rings in the system are aromatic and / or aliphatic or not (These are generally referred to as aromatic ring systems in this specification). Similarly, as will be apparent to those skilled in the art, cyclic ring systems are also appropriately condensed with each other (i.e., in polycyclic ring systems, they are appropriately condensed with each other). (Such as the two joined rings share at least two ring atoms) as referred to herein. It can appropriately include two or more monocyclic ring systems.

[0050] In the context of this specification and the claims, the term “tri-ring type” means that this term is equivalent to When referring to a polycyclic ring system described in the specification, it refers to a polycyclic ring system that essentially consists of three rings. That should also be clear.

[0051] Furthermore, in this specification and the claims, the term "heterocyclic ring" means that this term is a ring. When referring to a system (such as an aliphatic or aromatic ring system), one or more heteroatoms (preferably each This refers to a ring system that appropriately contains (independently selected from N, O, or S), and is called "heteroaromatic." The term "a" refers to one or more heteroatoms (preferably) when this term refers to an aromatic ring system. This refers to an aromatic ring system that appropriately contains (each independently selected from N, O, or S).

[0052] In the compounds of the present invention that include the cyclic systems described herein, the following should be noted: That is the case. - The ring system also applies to any other structural element present in or on the ring system, for example, the ring For any heteroatom present in the system, and / or for any substituent present on the ring system In contrast, other parts of the compound of the present invention may be covalently bonded or linked at any suitable position in the ring system. Furthermore, if the ring system contains one or more nitrogen atoms, the ring system is connected to the main body via those nitrogen atoms. The compound of the invention may be covalently bonded or linked to one or more other parts and / or structural elements. or, - Is it acceptable for each atom constituting the ring system to be independent and not have any substituents? , or may be appropriately substituted (as defined herein), possible positions on a given ring atom The number of substitutions is formed in addition to the bonds that a given ring atom has with other ring atoms. The number of further bonds that can be formed (for example, appropriately substituted by appropriate substituents on the ring atom) It depends on the number of hydrogen atoms that can be present. Generally, one or more such suitable substituents exist. If so, they may be located at any suitable position in the ring system, and may also be located at any other structure in the ring system. For elements, for example, for any heteroatom present in a ring system, and / or for the ring system It may also be present at positions where it is covalently bonded to other parts of the compound of the present invention. If it contains one or more nitrogen atoms, each of those nitrogen atoms is independently substituted. It may be absent or appropriately replaced (as defined herein), and in this case as well Further bonds that can be formed in addition to the bonds that the nitrogen ring atom has with other ring atoms The number of bonds (for example, the number of water molecules that the nitrogen atom possesses can be appropriately substituted by appropriate substituents) It depends on the number of elementary atoms. and / or - If the ring system contains one or more heteroatoms, each of those one or more heteroatoms is For any other structural element present in or on the ring system, for example, in the ring system For any further heteroatoms that may be present, for any substituents present on the ring system , and / or relative to the position where the ring system is covalently bonded to other parts of the compound of the present invention, They may be in any suitable position (i.e., relative to carbon atoms in the ring system). One or more It is desirable or intended that one or more rings in the ring system containing the heteroatom be aromatic rings. If this occurs, one or more heteroatoms present in the ring constitute a conjugated planar ring system in the resulting ring. The positions of the carbon atoms in the ring and any other heteroatoms in the ring to form It should be in [location]. Also, if the ring system contains one or more nitrogen atoms, each of those nitrogen atoms In this case as well, these are formed in addition to the bonds that the nitrogen ring atom has with other ring atoms. Depending on the number of further bonds that can be formed, they can be independently and appropriately substituted (as defined herein). (To be justified).

[0053] Furthermore, in this specification and the claims, the terms “aliphatic ring” and “aliphatic ring system” are used as follows: They have the usual meaning in the art, and generally refer to one or more rings (single ring or two or more rings). It is clear that this refers to aliphatic compounds that include (such as the fused rings mentioned above) or that are essentially composed of them. It should be so. As used herein and as is customary in the art, an aliphatic ring The term "system" means one or more double bonds unless the ring is an aromatic ring (as defined herein). This also includes rings and ring systems containing a bond or triple bond.

[0054] Furthermore, the term "alicyclic" refers to a non-aromatic cyclic system containing only carbon atoms, as specified in this document. Used in calligraphy.

[0055] Generally, as will be apparent to those skilled in the art, such aliphatic ring systems are monocyclic, bicyclic, It may be tricyclic or polycyclic (all as described herein) and may contain only carbon atoms. , or a preferred number independently selected from carbon atoms and N, S, or O (aliphatic ring system) Depending on the total number of rings inside, it may suitably contain one, two, three or more heteroatoms. Each atom in such an aliphatic ring system can be appropriately substituted (as defined herein). Please note that aliphatic ring systems also have one or more double bonds (such as carbon-carbon double bonds). It may be contained, but for convenience only, this does not limit the scope of this disclosure or claims. Without requiring the use of at least one aromatic ring, a ring system containing at least one aromatic ring is, in this specification, generally referred to as an aromatic ring. It is called a system.

[0056] The aliphatic ring systems described herein may also be crosslinked ring systems, and "crosslinked" or " The term "crosslinking" has its usual meaning in the art (i.e., Such a bridging aliphatic ring system includes two rings sharing three or more atoms, and at least one Atomic crosslinking, for example, by alkylene crosslinking as described herein, two bridgehead atoms This means separating the elements. Such a bridging aliphatic ring system also contains one or more heteroatoms It may appropriately contain. Some specific but non-limiting examples of crosslinked aliphatic ring systems include , bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane, and the following Crosslinked ring systems present in the compounds of the present invention as exemplified in the experimental department (for example, compound A-1 (See 89, A-190, A-232 and A-233). This specification and patent application For the purpose of the desired range, a direct covalent bond exists between two carbon atoms in the ring, and as a result, The resulting ring system essentially contains two fused rings that share the two connected ring atoms. A 7-membered ring, an 8-membered ring, a 9-membered ring, or a 10-membered ring (for example, decalin or formula XC as specified herein) (As in the bicyclic diaza structure of VIII) can also be considered a "bridged" ring system. However, in such a structure, the "bridge" consists of covalent bonds.

[0057] Some specific but non-exclusive examples of aliphatic ring systems include the following: This is not limited to these. - Monocyclic aliphatic ring systems containing only carbon atoms: cyclopropyl, cyclobutyl, cyclopropyl Cycloalkanes such as lopentyl, cyclohexyl, cycloheptyl, and cyclooctyl , as well as cycloalkenes such as cyclopentene and cyclohexene, - Monocyclic aliphatic ring systems containing carbon and nitrogen atoms: azetidine, pyrrolidine, 2 -Pyrroline, 3-Pyrroline, Pyrazolidine, Imidazolidine, 2-Pyrazolline, 2-Imi Dazoline, piperidine, piperazine, - Monocyclic aliphatic ring systems containing carbon and oxygen atoms: oxetanes, tetrahydroph Lan, 1,3-Dioxolane, Tetrahydropyran, 1,4-Dioxane, 2H-Pyran , 4H-pyran, 1,4-dioxin, - Monocyclic aliphatic ring system containing carbon atoms and sulfur atoms: tetrahydrothiophene (C) Oran), 1,2-oxothiolane, 1,3-oxothiolane, - Monocyclic aliphatic ring system containing a carbon atom and two different heteroatoms: 1,2-oxy Satiolane, 1,3-oxathiolane, morpholine, thiomorpholine, 1,2-thiazine , 1,4-thiaidine, - Bicyclic aliphatic ring systems containing carbon and nitrogen atoms: pyrrolizidine, decahydroid Soquinoline, Decahydroquinoline, - Bicyclic aliphatic ring system containing carbon atoms and sulfur atoms, - A bicyclic aliphatic ring system containing a carbon atom and two or more different heteroatoms.

[0058] Some other examples of aliphatic rings / ring systems are based on further disclosures herein, and The compounds of the present invention, as exemplified in the following experimental section, contain such aliphatic rings / cyclic systems. This should be obvious to those skilled in the art.

[0059] In this case as well, if present in the compound of the present invention, such aliphatic ring system is optional to the ring system. Appropriately covalently bonded to another part (or two or more other parts) of the compound of the present invention at the appropriate location. Alternatively, they may be linked (again, atoms present at that position are shared with other parts of the compound of the present invention). (It depends on whether a bond can be formed.) Also, in this case as well, an aliphatic ring system is formed. Each of the constituent atoms may independently have no substituents, or may be optionally substituted. There may be (as defined herein) the number of possible substituents on a given ring atom, which is the ring atom The number of covalent bonds that the child can form in addition to the bonds it has with other ring atoms depends on the number of covalent bonds it can form. To exist.

[0060] In this specification and in the claims, the terms "aromatic ring" or "aromatic ring system" are used in accordance with the Technical Standards of the Patent Act. These terms have their usual meaning in the field of art and generally refer to rings that form a conjugated planar ring system. This should also be clear.

[0061] Generally, as will be apparent to those skilled in the art, such aromatic ring systems are monocyclic, bicyclic, It may be tricyclic or polycyclic (all as described herein) and may contain only carbon atoms. or a suitable number of heterogens (1, 2, 3 or more, depending on the total number of rings in the aromatic ring system) It may suitably contain the following (preferably each independently selected from N, S, or O). Each atom in an aromatic ring system like the one described herein can be appropriately substituted (as defined herein). This should also be noted. Furthermore, as described herein, for convenience only, one or more fragrances Polycyclic ring systems containing one or more aliphatic rings in addition to a phatic ring (e.g., xanthenes) are aromatic. It is considered a group-ring system.

[0062] Some specific but non-exclusive examples of such aromatic ring systems include the following: These are possible, but are not limited to these. - Monocyclic aromatic ring systems containing only carbon atoms: phenyl, - Monocyclic aromatic ring systems containing carbon atoms and one or more nitrogen atoms: pyrrole, pyrazo Imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole Pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3 ,5-triazine, azepine, 1,4-diazepine, - Monocyclic aromatic ring systems containing carbon and oxygen atoms: furan, - Monocyclic aromatic ring systems containing carbon atoms and sulfur atoms: thiophene, - Monocyclic aromatic ring systems containing a carbon atom and two different heteroatoms: thiazoles, Oxazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1, 2,4-Oxadiazole, 1,2,5-Oxadiazole, 1,3,5-Oxadiazole Ru, - Bicyclic aromatic ring systems containing only carbon atoms: naphthalene, indene, 2,3-dihydroxy Draw-Inden, - Bicyclic aromatic ring systems containing carbon and nitrogen atoms: indole, isoindole Indoline, quinoline, isoquinoline, indidine, indazole, benzimidazoline 1,8-naphtheria dine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido [3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, 4-azaidin 5-Azaindol, 6-Azaindol, 7-Azaindol, Pudding, Tetra Hydroquinoline, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline, - Bicyclic aromatic ring systems containing carbon atoms and oxygen atoms: benzofurans, isobenzofurans run, - Bicyclic aromatic ring systems containing carbon atoms and sulfur atoms: benzo[c]thiophene, benzo[c]thiophene nzio[b]thiophene, - Bicyclic aromatic ring systems containing a carbon atom 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, ben Zo[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, fe Nothiazine.

[0063] Several other examples of aromatic rings / ring systems are based on further disclosures herein, and this From the compounds of the present invention exemplified in the following experimental section, which include aromatic rings / ring systems, it will be clear to those skilled in the art. It will be easy.

[0064] In this case as well, if present in the compound of the present invention, such aromatic ring systems are optional of the ring system. Appropriately covalently bonded to another part (or two or more other parts) of the compound of the present invention at the appropriate location. Or they can be linked (again, the ring atom can be linked to other ring atoms in addition to the bond connecting it to other ring atoms). (It depends on whether a bond can be formed.) Also in this case, the aromatic ring system Each of the constituent atoms may independently be unsubstituted or optionally substituted. It is also possible (as defined herein) that the ring atom connects it to other ring atoms. In addition to the bonds that form, it depends on whether such substituents can also form covalent bonds. To exist.

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

[0066] Other examples of cyclic systems that may be present in the compounds of the present invention are available to those skilled in the art based on the disclosures herein. It has become clear that the compound of the present invention contains the ring system present in the following experimental section.

[0067] Some of the compounds of the present invention, as further described herein and illustrated in the following experimental section, As illustrated, a compound may have two or more rings or ring systems (these rings may be condensed into a single ring system). If it includes (but is not), the ring can appropriately be directly linked via covalent bonds. or (unsubstituted or appropriately substituted) methylene linking groups and other appropriate (unsubstituted or appropriately Indirectly linked via alkylene linking groups (as further defined herein) that have been substituted for (In this case, each of such alkylene linking groups as referred to herein) These can be substituted with carbonyl groups.

[0068] As further described herein, as part of their overall structure, the compounds of the present invention Generally, a covalent bond is formed to an aromatic ring (aromatic rings are further described herein) (i.e., Either directly or via alkylene linking groups, particularly methylene linking groups, both as described in this specification. It includes an aliphatic ring (as defined in this book) (aliphatic rings are further described herein), and the aromatic ring is Furthermore, adjacent to the carbon atom of the ring to which the aliphatic ring is bonded (i.e., orthogonal to it) Acidic substituents on carbon atoms (located at the specified position) (acidic substituents are further described herein and any hypothetical Without being limited to the theory or explanation, when the compound of the present invention binds to AT2R, in particular, It is thought that the AT2R is located in the presumed binding pocket / binding site on / in the AT2R. It is thought that this enables interaction with one or more amino acids in the 2R sequence, or an improved interaction. It has at least (which can be obtained). This is outlined in the following scheme (Scheme A) Here, aliphatic rings are schematically illustrated using six-membered rings, and aromatic rings are... A schematic example is given using a six-membered ring (the aromaticity of the ring is schematically shown using a dashed circle). (It is being done.)

[0069] [ka]

[0070] Scheme A above also includes numbering of atoms in the aliphatic ring and the aromatic ring. The term "Tem" is also shown, and this is for convenience only and does not limit the scope of this disclosure or claims. It shall be used herein and in the claims without any further action. For the purposes of this disclosure or claims only, the aliphatic ring is, In this specification, it is also referred to as "aliphatic ring A" or "ring A," and is also indicated as "[A]." In this specification, the aromatic ring is also referred to as "aromatic ring B" or "ring B," etc. [B] is also indicated as "acidic substituent" or "substituted" in this specification. It is also called "base D" and is sometimes denoted as "[D]".

[0071] Refer to Scheme A above for further explanation and claims, - In scheme A above, the position / atom in aromatic ring B indicated as "3" is generally, Also known as "the position / atom in the ortho position relative to an acidic substituent." - In scheme A above, the position / atom in aromatic ring B indicated as "4" is generally, Also known as "the position / atom at the meta position relative to an acidic substituent." - In scheme A above, the position / atom in aromatic ring B indicated as "5" is generally, It is also called the "para position / atom relative to an acidic substituent."

[0072] In this specification and in the claims, "position / atom at the meta position relative to an acidic substituent" The expression " " refers to the position / atom on aromatic ring B indicated as "4" in scheme A above. Used solely for the purpose of indicating (also referred to herein as "other ortho positions on the aromatic ring") (and not the position / atom on aromatic ring B indicated as "6" in scheme A above) This should be noted.

[0073] With respect to aliphatic ring A, as further described herein, aliphatic ring A is unsubstituted or The following are substituted (as further described herein): crosslinking ring systems (as further described herein): , or a fused ring system that is unsubstituted or may be substituted (as further described herein), Spiro-type ring systems that are unsubstituted or potentially substituted (as further described herein), essentially It should also be noted that some of these fused ring systems or spiro-type ring systems can become... Specific but non-limiting examples of these are given herein by formulas LXXXV and XCII, respectively. These are shown as equations XCVIII and C.

[0074] More generally, the aliphatic ring A is the ring structure of scheme C herein, in particular the scheme herein. It may be a biological equivalent (as defined herein) of the ring structure of 'D'. The scientific equivalents will be apparent to those skilled in the art based on the disclosure herein.

[0075] With respect to aromatic ring B, if ring B is a 5-membered ring, the same numbering system is used. The position / atom where aromatic ring B is bonded to aliphatic ring A is also indicated as position "1". It should be noted that there is no position / atom indicated as "6" in scheme A above.

[0076] Similarly, with respect to an aliphatic ring A, if ring A is a 5-membered ring, then as shown in scheme A The same numbering system is used, and the position / atom of the aromatic ring system C linked to the aliphatic ring A. This is again indicated as position "1", but is the same position / atom indicated as "6" in scheme A above. It should be noted that this does not apply. Also, regarding aliphatic ring A, if ring A is a 7-membered ring... In addition, the same numbering system shown in scheme A is used, and aromatic ring system C is aliphatic. The position / atom linked to ring A is indicated as position "1", and the aliphatic ring A has position / atom Between "1" and position / atom "6", there is a further position / atom referred to herein as "7". There exists a position / atom (similarly, if ring A is an 8-membered ring, as shown in scheme A) (Further positions / atoms "7" and "8" exist between positions "1" and "6").

[0077] Furthermore, referring to Scheme A above, this is also for convenience only, and is not subject to the present disclosure or patent. Without limiting the scope of the claims, in further explanation and claims, Scheme A The positions / atoms on aliphatic ring A, indicated as "1" and "4" respectively, are "opposite" to each other. This is also called the position / atom in ring A. Similarly, if aliphatic ring A is a 5-membered ring, Each of the positions / atoms "3" and "4" is opposite to the position / atom of position "1" in ring A. If aliphatic ring A is considered to be a 7-membered ring, then positions / atoms "4" and "5" are, Position "1" in ring A is considered to be the opposite of the position / atom of position "1".

[0078] If the aliphatic ring A is an 8-membered ring, then positions "4", "5", and "6" (especially position "5") are , is considered opposite to position "1" in the ring, and if aliphatic ring A is a 9-membered ring, position "5 " and "6" are considered to be opposite to position "1" in ring A, and aliphatic ring A is a 10-membered ring In some cases, positions "5", "6", and "7" (especially position "6") are the same as position "1" in ring A. Conversely, (as further described herein, aromatic ring B is at position "1") The position in ring A opposite to the atom of / one of the atoms, i.e., the atom to which the aromatic ring system C is bonded. (At the child / position, such as bonded to an 8, 9, or 10-membered aliphatic ring A). Based on the diagram, if ring A is a bridging ring system or a spiro ring system, which position / atom is in ring A? The same considerations apply to whether something should be considered "opposite" to the position "1". Therefore, it is obvious to those skilled in the art.

[0079] Further description herein indicates that the compounds of the present invention generally, preferably, are second aromatic compounds. It includes a ring system (different from aromatic ring B), and this second aromatic ring system is "1" in the above formula. The position / atom on the aliphatic ring A shown as (i.e., the position / atom to which the aromatic ring B is attached) In the "opposite" position / atom, directly or in alkylene linking groups, especially methylene linking groups (both and (which may also be a carbonyl group as defined herein and referred to herein) via It will also be obvious to those skilled in the art that they are covalently bonded. Generally, here too for convenience This is merely and does not limit the scope of the present disclosure or claims, but the second aromatic ring A system (as further described herein) is referred to herein as "aromatic ring system C" or "ring system" Also called "C," and represented as "[C]," the aromatic ring system C is attached to the aliphatic ring A. The positions / atoms are schematically shown in scheme A above and further explained in the preceding paragraphs. For the purpose of applying the numbering system, the position of aliphatic ring A is considered to be "1".

[0080] Therefore, generally speaking, the compounds of the present invention have the following overall structure. It can be represented. Scheme B: [Aromatic ring system C]-[Aliphatic ring A]-[Aromatic ring B] During the ceremony, - Aromatic ring system C, aliphatic ring A, and aromatic ring B are each described further herein. That is correct, and - Aromatic ring system C is either directly covalently bonded to aliphatic ring A, or an alkylene linking group ( (May be a carbonyl group as defined and referred to herein), in particular Either it is linked to aliphatic ring A via a methylene linking group (as defined herein) It is, and - -Aliphatic ring A is directly covalently bonded to aromatic ring B, or an alkylene linking group ( (May be a carbonyl group as defined and referred to herein), in particular Either it is linked to aromatic ring B via a methylene linking group (as defined herein) It is, and - Aromatic ring system C and aromatic ring B are opposite ring atoms within aliphatic ring A (as specified herein) It is linked to the aliphatic ring A (as further defined).

[0081] In particular, the compound of the present invention has the following overall structure as shown in scheme B above. It can be roughly expressed as follows, in the formula, - Aromatic ring system C is a ring system containing one or more rings, where at least one of the rings is an aromatic ring. (The entire ring may be an aromatic ring at most), and this ring system is further described herein. As stated herein, (as further described herein, appropriately substituted at the discretion of the party) (possible). and - The aliphatic ring A has an overall structure schematically represented by the following scheme C,

[0082] [ka] In the formula, each C is a carbon atom, and each atom Q is independently a carbon atom or a nitrogen atom (preferably) Alternatively, at least one of the atoms Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen (Elementary atoms), v and w are as further defined herein, and present R x Reference Each R that exists y The base is independently defined further herein (wherein C (v) R bonded to the carbon chain x or R y one of the following, and C (w) R bonded to the carbon chain x or R y One of them combines to form an alkylene bridge or covalent bond, and as a result, The structures are either crosslinked ring systems or fused ring systems, both of which are further described herein. (This is the overall structure, more specifically, which is roughly represented by the following scheme D.) the law of nature,

[0083] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably, at least one atom Q). (Each atom is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms), R5~ R 12 Each of these is independently defined further herein (wherein R5 or R8 1 and R9 or R 12 One of them combines to form an alkylene bridge or covalent bond. As a result, the resulting structures are either a cross-linked ring system or a condensed ring system, both of which are described herein. As further described, or in the formula, the aliphatic ring A is the same as in formula XCIX or C. It is a single ring system,

[0084] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. From hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl It may also be optionally and appropriately substituted with one or more appropriate substituents selected from the group. , and - Aromatic ring B has an overall structure schematically represented by the following scheme E,

[0085] [ka] In the formula, [D] represents the acidic substituent [D] (as further described herein), and X, Y and Each of Z and each of R1, R2, R3 and R4 (if any) are further described herein. As described, and in particular the overall structure schematically represented by the following scheme F And,

[0086] [ka] In the formula, [D] represents an acidic substituent [D] (as further described herein), R1, R 2. Each of R3 and R4 is as further described herein, and in particular, the following: This is the overall structure, roughly represented by scheme G,

[0087] [ka] In the formula, [D] represents an acidic substituent [D] (as further described herein), R1, R Each of 2 and R4 is as further described herein, and - Aromatic ring system C is either directly covalently bonded to aliphatic ring A, or an alkylene linking group ( (May be a carbonyl group as defined and referred to herein), in particular Either it is linked to aliphatic ring A via a methylene linking group (as defined herein) It is, and - -Aliphatic ring A is directly covalently bonded to aromatic ring B, or an alkylene linking group ( (May be a carbonyl group as defined and referred to herein), in particular Either it is linked to aromatic ring B via a methylene linking group (as defined herein) It is, and - Aromatic ring system C and aromatic ring B are opposite ring atoms within aliphatic ring A (as specified herein) It is linked to the aliphatic ring A (as further defined).

[0088] As will be apparent to those skilled in the art from further disclosure herein, a preferred embodiment is an aromatic ring System C, aliphatic ring A, aromatic ring B and / or substituent D and / or any substituent or substitution If any combination of bases is referenced or described herein, this preferred state The configuration preferably consists of an aromatic ring system C, an aliphatic ring A, an aromatic ring B, a substituent D, and / or any Other substituents or combinations of substituents are cited or described herein as preferred. It should also be understood that the manner in which it is performed is appropriately combined (the same applies to fragrance) A cyclic system C, an aliphatic ring A, an aromatic ring B, a substituent D and / or a combination of such substituents For each combination, we will categorize them as "more preferable," "particularly preferable," and "most preferable." (Applied to the embodiments referenced or described herein with necessary modifications.)

[0089] Here too, each of the aromatic ring system C, aliphatic ring A, aromatic ring B, and acidic substituent D, and A Lukilen linking group C (m) R A R B and C (n) R C R D (if present) and substituent R 1~R 12 Each of (if any) is generally as further described herein. Preferably, they are obtained in a preferred embodiment as described herein for each of them. They will obey.

[0090] Therefore, as further described herein, the first specific but non-limiting state In this case, the compound of the present invention has the following structure (Formula I):

[0091] [ka] During the ceremony, - Aromatic ring system represented by [C], acidic substituent represented by [D], and each of X, Y, and Z , R1, R2, R3 and R4 (if any), R A , R B , R C and R D Each of , and m and n are as further defined herein (P.S. (and, for each of these, according to the preferred embodiments described herein), During the ceremony, - [A] represents a ring system that can be roughly represented by the following scheme C,

[0092] [ka] In the formula, each atom Q and each group R x and R y , and each of v and w is further specified herein. As described, and in particular, in the ring system schematically represented by scheme D below can be,

[0093] [ka] In the formula, each Q and R5~R 12 Each of these is as further described herein, i is, [A] is one of the ring systems of formula XCIX or C,

[0094] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. From hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl They may be optionally and appropriately substituted with one or more suitable substituents selected from the group. .

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

[0096] [ka] During the ceremony, - Aromatic ring system represented by [C], acidic substituent represented by [D], R1, R2, R3 and Each of R4, A , R B , R C and R D Each of these, as well as m and n, respectively, in this specification As further defined in the book (in particular, each of these is described herein) (According to the preferred configuration described), During the ceremony, - [A] represents a ring system that can be roughly represented by the following scheme C,

[0097] [ka] In the formula, each atom Q and each group R x and R y , and each of v and w is further specified herein. As described, and in particular, in the ring system schematically represented by scheme D below can be,

[0098] [ka] In the formula, each Q and R5~R 12 Each of these is as further described herein, i is, [A] is one of the ring systems of formula XCIX or C,

[0099] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. From hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl They may be optionally and appropriately substituted with one or more suitable substituents selected from the group. .

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

[0101] [ka] During the ceremony, - Aromatic ring system represented by [C], acidic substituent represented by [D], R1, R2 and R4 Each of R A and R B Each of the above, and Each of m is further defined herein. As such (in particular, preferred embodiments described herein for each of these) (according to), During the ceremony, - [A] represents a ring system that can be roughly represented by the following scheme C,

[0102] [ka] In the formula, each atom Q and each group R x and R y , and each of v and w is further specified herein. As described, and in particular, in the ring system schematically represented by scheme D below can be,

[0103] [ka] In the formula, each Q and R5~R 12 Each of these is as further described herein, i is, [A] is one of the ring systems of formula XCIX or C,

[0104] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. From hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl optionally and appropriately substituted with one or more suitable substituents selected from the group consisting of .

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

[0106]

Chemical formula

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

[0108]

Chemical formula

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

[0110]

Chemical formula

[0111] In a specific but non - limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of Formula I, Formula II, Formula III, Formula IV, Formula V and / or Formula VI), - The group 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 xy, amine (-NH2) or C1 - C2 substituted amine (e.g., dimethylamine or diethyl amine) and cyano.

[0112] In another specific but non - limiting embodiment of the present invention, in the compounds of the present invention (in particular, the compounds of the present invention of Formula I, Formula I In the compounds of the present invention (formulas I, III, IV, V and / or VI), - The base R2 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) or consisting of a C1-C2 substituted amine (e.g., dimethylamine or diethylamine) Selected from the group.

[0113] In another specific but non-limiting aspect of the present invention, the compounds of the present invention (in particular, formula I, formula I) In the compounds of the present invention (formula I, formula IV and / or formula V), - Base R3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-8 alkyl (e.g., sec-butyl and especially isobutyl), e.g., f methyl groups substituted with methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy, -O-CF3, methoxyethyl oxy(-O-(CH2)2- O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (e.g.) For example, cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cyclo Lukil, -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl -N(C1~C3)-cycloalkyl, -NH-heteroalkyl, -N(C1~C3 )-heteroalkyl, heterocyclyl (e.g., oxiran), -CH2-heterocyclyl -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-hete Rocyclyl, -NH-heterocyclyl, -N(C1~C3)-heterocyclyl, vinyl or These are methyl-substituted vinyls (e.g., -CH=CHCH3, -CH=C(CH3)2, or -CH =CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), Sobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano Selected from the group.

[0114] In a particularly preferred embodiment of the present invention, group R3 is isobutyl (i.e., formula III and (or as in the compounds of the present invention of formula VI)

[0115] In a more specific but non-limiting aspect of the present invention, the compounds of the present invention (in particular, formula I, formula I) In the compounds of the present invention (formula I, formula IV and / or formula V), - Base R1 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 Lucoxyamine (-NH2) or C1-C2 substituted amine (e.g., dimethylamine) Selected from the group consisting of (or diethylamine) and cyano, and / or - The base R2 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) From C1-C2 substituted amines (e.g., dimethylamine or diethylamine) Selected from the group and / or - Base R3 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-8 alkyl (e.g., sec-butyl and especially isobutyl), e.g., f methyl substituted groups (e.g., trifluoromethyl and CHF2) C1-C8 alkoxy, -O-CF3, methoxyethyl oxy(-O-(CH2)2- O-CH3) or difluoroethoxy (-O-CH2-CHF2), cycloalkyl (For example, cyclopropoxy, cyclobutoxy or cyclopentoxy), -CH2-cyclo -O-CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl Lukyl, -N(C1~C3)-cycloalkyl, -NH-heteroalkyl, -N(C1~ C3)-heteroalkyl, heterocyclyl (e.g., oxiran), -CH2-heterocyclyl krill, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O- Heterocyclyl, -NH-heterocyclyl, -N(C1~C3)-heterocyclyl, vinyl 2 or methyl-substituted vinyl (for example, -CH=CHCH3, -CH=C(CH3)2 or (-CH=CH2), or allyl or methyl-substituted allyl (for example, -CH2CH= CH2), isobutenyl or methyl-substituted isobutenyl (e.g., =C(CH3)2) and Selected from the group consisting of cyano compounds, most preferably isobutyl (i.e., formula I (As in the compounds of the present invention of formula II and / or formula VI)

[0116] In particular, the compounds of the present invention (especially the compounds of formulas I, II, IV and / or V) According to the last aspect of ), - Base R1 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alcohol Xyamine (-NH2) or C1-C2 substituted amines (e.g., dimethylamine or diene) Selected from the group consisting of ethylamine and cyano, - The base R2 is preferably H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) or consisting of a C1-C2 substituted amine (e.g., dimethylamine or diethylamine) Selected from the group, - The base R3 is preferably H, halogen (F, Cl, Br or I), and 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., cyclo (propoxy, cyclobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O -CH2-cycloalkyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C) 1~C3)-cycloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl Lukyl, heterocyclyl (e.g., oxirane), -CH2-heterocyclyl, -OC H2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl, -N(C1-C3)-heterocyclyl, vinyl or methyl substitution Vinyl (for example, -CH=CHCH3, -CH=C(CH3)2, or -CH=CH2), or allyl or methyl-substituted allyl (e.g., -CH2CH=CH2), isobutenyl or Selected from the group consisting of methyl-substituted isobutenyl (e.g., =C(CH3)2) and cyano Most preferably isobutyl (i.e., the present invention of formula III and / or formula VI). (As in the compound)

[0117] In the compounds of the present invention described herein, when referring to an atom represented by the letter Q, In compounds (for example, in compounds of formulas IV, V, and VI), such atoms Q are each independent. They may be carbon atoms or nitrogen atoms, preferably in aliphatic ring A as described herein. If there are two such atoms Q, then at least one such atom Q is a nitrogen atom. They are children, and more preferably, both such atoms Q in the aliphatic ring A are nitrogen atoms. It is an atom.

[0118] In the compounds of the present invention described herein, when group R4 is present (for example, formula I, I As in the compounds described in I, III, IV, V, and VI, the group R4 is If present, preferably H or halogen (F, Cl, Br or I, preferably F or Selected from the group consisting of Cl).

[0119] In the compounds of the present invention described herein, groups R5, R6, R7, R8, R9, R 10 , R 11 and / or R 12 If such a condition exists (for example, as described by formulas IV, V and VI) (As in the listed compounds) such groups R5, R6, R7, R8, R9, R 10 , R 11 and / or R 12 If present, each of them preferably independently contains hydrogen, methyl, Selected from the group consisting of ethyl, fluorine (F), CF3, or isopropyl.

[0120] In the compounds of the present invention described herein, the group R A , R B , R C and / or R D but If present (for example, the compounds described by formulas I, II, III, IV, V and VI) As in the substance, compounds of formulas III and IV have the group RC or R D It is understood that it does not contain (and such a basis R) A. , R B , R C and / or R D Each of these is in a place where A compound, hydrogen, methyl and / or trifluoromethyl, independently selected from, R A +R B If present, it forms a carbonyl group with the carbon atom it is bonded to. (C=O) group is formed and / or R C +R D If they exist, they are combined Together with the carbon atom, it forms a carbonyl (C=O) group (in other words, R A +R B These are substituted together by a single oxygen atom, and the carbon to which the oxygen atom is bonded. It forms a carbonyl group with an elementary atom, and / or R C +R D If they exist, together It is replaced by a single oxygen atom, along with the carbon atom to which that oxygen atom is bonded. These atoms form a carbonyl group, preferably hydrogen atoms.

[0121] Generally, the compounds of the present invention are used with respect to AT2R (the protocol described in Example 2 below) (When measured according to the method), 1.0 × 10 -5 Better than M (i.e., 10 micrometers) Better than , preferably 1.0 × 10 -6 Better than M (i.e., 1 micro Better than moles), more comfortably 1.0 × 10 -7 Better than M (i.e., 0. Better than 1 micromol), and even more preferably 1.0 × 10 -8 Better than M That is, it will have an affinity (better than 10 nanomoles) [in this respect, (i )In this specification, in accordance with generally accepted scientific practice, 10 -5 is "E It is also written as "-05", 10 -6 It is also written as "E-06", and (ii) For illustrative purposes of this specification and the claims, for example, 1.0× 10 -8 The affinity of M(10 nanomoles) is, for example, 1.0 × 10 -6 M (1 micromol) It is considered to be "better" than the affinity of ), and similarly, for example, the affinity of 5 nanomoles is For example, please note that this is considered to be better than the affinity of 10 nanomoles.

[0122] Therefore, in a more specific but non-limiting embodiment, the present invention relates to the following: - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. The compounds of the present invention (further described herein) also exhibit excellent properties. in particular, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula I (further described herein) also exhibit good results. More specifically, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula IV (further described herein) also exhibit good results. More specifically, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula II (further described herein) also exhibit good results. More specifically, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula V (further described herein) also exhibit good results. More specifically, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula III (further described herein) also exhibit good results. More specifically, - Affinity for AT2R (measured according to the protocol described in Example 2 below) , better than 10 micromoles, preferably better than 1 micromoles, Preferably, it is better than 0.1 micromoles, and even more preferably 10 nanomoles. Compounds of formula VI (further described herein) also exhibit good results.

[0123] In more specific but non-limiting aspects, the present invention may be further described herein by (i) each of the following Aromatic ring system [C], aliphatic ring [A], aromatic ring [B] and acidic substituent [D], (i i) Substituents present in such compounds of the present invention (each such substituent is independent) (The specific substituents involved may be as further described herein.) Furthermore, specific combinations of such substituents present in the compound of the present invention, and ( iii) m and n (as described herein, independently of each other, 0 or 1) (This may be done) Each of these means that the compound of the present invention is present in an amount of 10 micromoles relative to AT2R. Better than, preferably better than 1 micromol, more preferably 0.1 micromol Affinity better than moles, and even more preferably better than 10 nanomoles (see the following examples) (and) such that it has (and is measured according to the protocol described in 2) Such combinations, relating to the compounds of the present invention (further described herein). In particular, the present invention relates to each of the substituents R1, R2, R3 and R4 on the aromatic ring [B] (such If the substituent is located on the aromatic ring [B], then according to the further definitions given herein, (and) and such substituents R1, R2, R3 and R4 present on the aromatic ring [B] Each of the specific combinations is preferably one in which the compound of the present invention is present in a quantity of 10 micromoles or less. Or better than 1 micromol, more preferably better than 0.1 micromol, further More preferably, affinity for AT2R is better than 10 nanomoles (as described in Example 2 below). (and such a set) is such that it has (measured according to the protocol) The present invention relates to such compounds (combinations).

[0124] In more specific but non-limiting embodiments, the present invention relates to the following: - Compounds of formula I (as further described herein), where (i) each is further described herein Aromatic ring systems [C], aliphatic rings [A] and acidic substituents [D] as described above, and (ii) Each of X, Y, and Z present in the compound of formula I, and specific pairs of atoms X, Y, and Z (iii) substituents R1, R2, R3 and Each of R4 (if present), and the identification of such substituents R1, R2, R3, and R4. The combination of (iv) m and n (each independently as described herein) (v) substituents R present in the compound of formula I (v) which may be 0 or 1, and (v) substituents R present in the compound of formula I A , R B , R C and R D Each of (if any), and such substituent R A , R B , R C Reach biR D (vi) Any combination of the above, as well as any compound of formula I present in such compound Further substituents (e.g., aromatic ring systems [C] and / or as further described herein) Aliphatic ring system [A](above), and specific substituents present in the compound of formula I Each combination involves the compound of formula I being present in 10 micromoles relative to AT2R. Better than 1 micromol, preferably better than 1 micromol, more preferably 0.1 micromol Better affinity than 10 nanomoles, and more preferably better affinity than 10 nanomoles (see Example 2 below) (and such) are measured according to the protocol described in (and so A compound (a combination of such things). More specifically, - Compounds of formula IV (as further described herein), wherein each of the following is described herein Furthermore, the aromatic ring system [C] and acidic substituent [D] described, and (ii) each atom Q (Honmei As described in the details, these may be independently carbon atoms or nitrogen atoms, preferably (iii) at least one Q is a nitrogen atom, and (iii) present in the compound of formula IV Each of X, Y, and Z, as well as specific combinations of atoms X, Y, and Z, and (iv) Each of the substituents R1, R2, R3, and R4 present in the compound of formula IV (if any) ) and specific combinations of such substituents R1, R2, R3 and R4, and (v) substituents R5 to R present in the compound of formula IV. 12 Each of (if any) and its Such substituents R5~R 12 Specific combinations of (vi)m and n (as specified herein) As shown, each may be independently 0 or 1), and (vii) the said formula I Substituent R present in compound V A , R B , R C and R D Each of them (if any), in order such substituent R A , R B , R C and R D Specific combinations of, as well as (viii) Any further substituents present in such a compound of formula IV (e.g., aromatic ring system [C]) (above), and specific combinations of such substituents present in the compound of formula IV are, Each of the compounds in formula IV is better than 10 micromoles relative to AT2R. Preferably better than 1 micromol, more preferably better than 0.1 micromol Furthermore, even more preferably, an affinity better than 10 nanomoles (as described in Example 2 below) (and such combinations are measured according to the protocol) A compound (that is). More specifically, - Compounds of formula II (as further described herein), wherein each of the following is described herein Further described aromatic ring systems [C], aliphatic rings [A] and acidic substituents [D], and (ii ) Substituents R1, R2, R3, and R4 (if present) present in the compound of formula II Each of these, as well as specific combinations of such substituents R1, R2, R3, and R4, and ( iii) m and n (as described herein, each independently being 0 or 1) (i) and (iv) substituents R present in the compound of formula II A , R B , R C and R D Each of (if any), and such substituent R A , R B , R C and R D specific pair (v) combinations, and any further substituents present in such compounds of formula II (e.g.) For example, aromatic ring systems [C] and / or aliphatic ring systems [A] as further described herein. (above), and certain combinations of such substituents present in the compound of formula II are, Each of the compounds in formula II is better than 10 micromoles relative to AT2R. Preferably better than 1 micromol, more preferably better than 0.1 micromol Furthermore, even more preferably, an affinity better than 10 nanomoles (as described in Example 2 below) (and such combinations are measured according to the protocol) A compound (that is). More specifically, - Compounds of formula V (as further described herein), wherein each of the following is further described herein The aromatic ring system [C] and acidic substituent [D] described herein, and (ii) each atom Q (in this specification As described in the document, these may be carbon atoms or nitrogen atoms, preferably in small numbers. (iii) at least one Q is a nitrogen atom, and (iii) present in the compound of formula V Each of substituents R1, R2, R3, and R4 (if any) and such substituent R1, (v) specific combinations of R2, R3 and R4, and (v) the presence of the compound of formula V Substituent R5~R 12 Each of (if any) and such substituents R5~R 12 specific Combinations, and (vi) m and n (each independently as described herein) (which may be 0 or 1), and (vi) substituent R present in the compound of formula V A , R B , R C and R D Each of (if any), and such substituent R A , R B , R C Reach biR D Certain combinations of, as well as the presence of in such compounds of formula (viii) V Further substituents (e.g., on the aromatic ring system [C]) and those present in the compound of formula IV The specific combinations of such substituents are such that the compound of formula IV is AT2 With respect to R, better than 10 micromoles, preferably better than 1 micromoles, More preferably than 0.1 micromoles, and even more preferably than 10 nanomoles. It also has good affinity (measured according to the protocol described in Example 2 below). A compound that is (or is a combination of) such a compound. More specifically, - Compounds of formula III (as further described herein), wherein (i) each is as described herein Further described are aromatic ring systems [C], aliphatic rings [A] and acidic substituents [D], and (i i) Each of the substituents R1, R2, and R4 (if present) in the compound of formula III (iii) m (which may be 0 or 1 as described herein), and (iii) the formula I Substituent R present in compound II A and R B Each of the (if any), and such substituent R A and R B Specific combinations of, as well as such compounds of formula III (iv) Any further substituent present therein (e.g., aromatic rings as further described herein) (on system [C] and / or aliphatic ring system [A]), and the compound of formula III present in the compound Certain combinations of substituents, such as those shown, mean that the compound of formula III in question is AT2R. In contrast, better than 10 micromoles, preferably better than 1 micromoles, Preferably better than 0.1 micromoles, and more preferably better than 10 nanomoles. It has good affinity (measured according to the protocol described in Example 2 below). A compound that is (or is a combination thereof). More specifically, - Compounds of formula VI (as further described herein), wherein (i) each is as described herein Furthermore, the aromatic ring system [C] and acidic substituent [D] described, and (ii) each atom Q (Honmei As described in the details, these may be independently carbon atoms or nitrogen atoms, preferably (iii) at least one Q is a nitrogen atom, and (iii) present in the compound of formula VI Each of the substituents R1, R2, and R4 (if any) and such substituents R1, R (iv) specific combinations of 2 and R4, and substituents present in the compound of formula VI. R5~R 12 Each of (if any) and such substituents R5~R 12 specific combination (v)m (which may be 0 or 1 as described herein), and (vi) substituent R present in the compound of formula VI A and R B Each of (if any) , as well as such substituent R A and R B Specific combinations of, as well as (vii) expression VI Any further substituents present in such compounds (e.g., on the aromatic ring system [C]), The specific combinations of such substituents present in the compound of formula VI are, respectively The compound of formula VI is preferably better than 10 micromoles relative to AT2R. is better than 1 micromol, more preferably better than 0.1 micromol, and further More preferably, affinity better than 10 nanomoles (as described in Example 2 below) It is such that (and such combinations are measured according to the rule) ), compound.

[0125] For the purposes of each of the above embodiments of the present invention and the further embodiments of the present invention described herein, The substituent is defined as a hydrogen atom, to the extent permitted by the definition of the substituent, further description of the related compound and / or context. It may be a child (i.e., the relevant position in the compound of the present invention is not substituted). It should be noted that (it tastes good).

[0126] As further described herein, aromatic ring system C comprises at least one ring present in the ring system. The ring system can be monocyclic, bicyclic, or polycyclic, provided that one of the rings is aromatic. According to one embodiment, all rings present in the aromatic ring system C are essentially aromatic rings (however (This is not important.)

[0127] In general, as long as aromatic ring system C contains at least one aromatic ring, the positive of aromatic ring system C It will be apparent to those skilled in the art from the description herein that the exact properties or structure are not important, The aromatic ring system C is preferably a monocyclic or bicyclic ring system.

[0128] In aromatic ring system C, the ring atoms that form part of the aromatic ring present within aromatic ring system C , appropriately linked to the aliphatic ring A (i.e., directly, or as defined herein) via either a kylene linking group, particularly a methylene linking group, both as defined herein. It is also desirable (but not important).

[0129] The ring atoms constituting the aromatic ring system C can preferably consist entirely of carbon atoms, The aromatic ring system C preferably contains one or more heteroatoms (where, Any heteroatoms are preferably independent of each other, but preferably N, S, or O. (Selected from). Preferably, the aromatic ring system C contains at least one heteroatom, Each ring constituting the aromatic ring system C preferably does not contain a heteroatom, or preferably does It may contain one or more heteroatoms, provided that the heteroatoms in the entire aromatic ring system C are present. The total number of terrorist atoms is at least 1.

[0130] As will be apparent to those skilled in the art, the aromatic ring system C contains at least one heteroatom In this case, the number of heteroatoms in the aromatic ring system C is usually the total number of rings in the aromatic ring system C and the number of heteroatoms in each ring It depends on the number of atoms. Generally, aromatic ring systems contain at least one heteroatom. In this case, the number of five-membered rings forming part of the aromatic ring system C is preferably up to three (for example, 0, 1, 2). It can contain heteroatoms (or 3), and the 6-membered ring that forms part of the aromatic ring system C is preferred. It may contain up to three heteroatoms (for example, 0, 1, 2, or 3), however Furthermore, the total number of heteroatoms in the entire aromatic ring system C is at least 1. If it is a bicyclic or polycyclic ring system, it is possible for two rings within the ring system to share a nitrogen atom. Furthermore, if the aromatic ring system C contains at least one heteroatom and is a monocyclic ring, In total, the total number of heteroatoms in the aromatic ring system C may preferably be 1, 2, or 3. Generally, when an aromatic ring system C contains two or more heteroatoms, the heteroatoms are preferably They may be the same or different (and here again, as referred to herein, preferred (where at least one of the heteroatoms is a nitrogen atom).

[0131] As can be seen from the various formulas given herein, aromatic ring system C is the original aliphatic ring A It is linked to one of the children Q. The atom Q to which the aromatic ring system C is linked is a nitrogen atom. In some cases, the aromatic ring system C is not via the nitrogen atom in the aromatic ring system C (i.e., aromatic (When the aromatic ring system C contains at least one nitrogen atom), preferably, in the aromatic ring system C Carbon atoms present (these carbon atoms are preferably aromatic, as referred to herein) (It forms part of the aromatic ring within the aliphatic ring system C, but this is also not important) and on the aliphatic ring A Linked (i.e., directly or by alkylene linking groups as defined herein, in particular) via a methylene linking group (both as defined herein), but this is obtained Compounds that can be formed are generally those in which the aromatic ring system C is connected to such nitrogen atoms in the aromatic ring system C. (Unless linked to the rest of the molecule via a carbonyl linking group) For pharmaceutical use This is because it is assumed that the situation is not sufficiently stable.

[0132] In a preferred but non-limiting embodiment, this embodiment relates to the compounds of the present invention shown in the following experimental section. As also explained by some non-restrictive examples, the aromatic ring system C is (i) at least one It contains a heteroatom (preferably at least one of the heteroatoms is a nitrogen atom). ), (ii) forming part of the aromatic ring in aromatic ring system C (if aromatic ring system C is a monocyclic ring) In this case, this ring essentially forms an aromatic ring system C. , linked to the aliphatic ring A (i.e., directly via covalent bonds, or as further described herein) (iii) In addition, a lipid The aromatic ring to which the aliphatic ring A is linked (that is, the carbon atom to which the aliphatic ring A is linked) (In addition to the offspring) at least one heterozygous (e.g., 1 or 2) selected from N, S, and O A compound containing an atom (preferably at least one of the heteroatoms is a nitrogen atom) It is.

[0133] Examples of aromatic ring systems that may exist as aromatic ring system C in the compounds of the present invention are disclosed herein. As will be apparent to those skilled in the art, generally speaking, monocyclic, bicyclic and Includes polycyclic aromatic ring systems.

[0134] Several preferred aromatic ring systems that may exist as aromatic ring system C in the compound of the present invention are Non-limiting examples will be apparent to those skilled in the art based on further disclosures herein, including the following: include.

[0135] Unsubstituted or appropriately substituted pyrazolyl groups (e.g., pyrazole-3-yl groups), for example Ba, - 2,5-dimethylpyrazole-3-yl, - 1-methylpyrazole-3-yl, - 2-methylpyrazole-3-yl,

[0136] Unsubstituted or substituted imidazolyl group (e.g., imidazole-2-yl group or imidazole) -4-yl group), for example - 1-methylimidazole-2-yl, - 1-methylimidazole-4-yl, - 3-methylimidazole-4-yl, - 2,3-dimethylimidazole-4-yl,

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

[0138] pyrazine group, Unsubstituted or substituted pyrimidine groups (e.g., 2-pyrimidine or 4-pyrimidine groups), for example Ba, - 2-pyrimidine, - 4-[2-methyl]-pyrimidine,

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

[0140] Unsubstituted or substituted pyridyl groups (e.g., 2-pyridyl groups), for example, - 4-chloro-2-pyridyl, - 5-chloro-2-pyridyl, - 3-chloro-2-pyridyl, - 4-methoxy-2-pyridyl, - 5-methoxy-2-pyridyl, - 4-fluoro-2-pyridyl, - 5-fluoro-2-pyridyl, - 4-methoxy-3,5-dimethyl-2-pyridyl, - 3,5-dimethyl-2-pyridyl, - 3-methoxy-2-pyridyl, - 5-methyl-2-pyridyl, - 4-(trifluoromethyl)-2-pyridyl, - 3-methyl-2-pyridyl, - 4-methyl-2-pyridyl, - 5-chloro-3-fluoro-2-pyridyl, - 4-Methoxy-3-methyl-2-pyridyl, - 3-chloro-5-fluoro-2-pyridyl, - 4,5-dimethoxy-2-pyridyl, - 4-chloro-5-fluoro-2-pyridyl, - 3,5-difluoro-2-pyridyl,

[0141] Unsubstituted or substituted indazole 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 group), for example, - 1,4-oxazole,

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

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

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

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

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

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

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

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

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

[0156] Unsubstituted or substituted bicyclic pyrimidinone groups, for example, - 1-methyl-7H-pyrazolo[3,4-d]pyrimidine-4-one, - 8-methylpyrido[1,2-a]pyrimidine-4-one, - 1-methyl-pyrazolo[1,5-a]pyrimidine-7-one, - Pyrido[1,2-a]pyrimidine-4-one, - 6-methylpyrido[1,2-a]pyrimidine-4-one, - 3-methyl-thiazolo[3,2-a]pyrimidine-5-one.

[0157] As will be apparent to those skilled in the art based on the disclosure herein, aromatic ring system C is also aromatic One or more (e.g., 1, 2, 3, or 4) appropriate positions on the ring system C / One or more on the ring atoms ( For example, appropriately substituted by appropriate substituents (as defined herein) (1, 2, 3, or 4) (This may be done.) Suitable substituents are obvious to those skilled in the art and are, for example, explained in the following experimental section. The substituents present on the aromatic ring system C in the compound of the present invention, as well as those referred to herein. Other suitable substituents include: The C ring group does not contain a carboxylic acid (COOH) group.

[0158] As generally referred to herein, the total number of suitable substituents on the aromatic ring system C is one Generally unimportant and usually depends on the size of the aromatic ring system C and the number of ring atoms in the aromatic ring system C. It exists. Typically, the total number of substituents is as follows: - When the aromatic ring system C is a monocyclic 5-membered ring, the numbers are 0, 1, 2 or 3, preferably 0, 1 or It is 2, - When the aromatic ring system C is a monocyclic 6-membered ring, the values ​​are 0, 1, 2 or 3, preferably 0, 1 or It is 2, - If the aromatic ring system C is a bicyclic ring system, then 0, 1, 2, 3, 4 or 5, preferably 0 It is 1, 2, or 3.

[0159] In a specific but non-limiting manner, each of one or more substituents on the aromatic ring system C is Methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, cyano / nitrile , one or more of the following: halogen atoms (especially fluorine or chlorine), C1-C4 amines, or oxygen atoms Each is appropriately and independently selected from above (i.e., the carbon to which the oxygen is linked). Together with an atom, it forms a carbonyl group, and the carbon atom forms such a carbonyl group (It is possible to do so.)

[0160] In one non-limiting aspect of the present invention, the aromatic ring system C is one of the following: - Monocyclic 5- or 6-membered aromatic ring system, preferably containing at least one nitrogen atom Monocyclic 5- or 6-membered aromatic ring system, or - Each ring is a 5-membered and / or 6-membered aromatic ring (i.e., the entire bicyclic ring system is conjugated). A bicyclic aromatic ring system (as defined herein) that forms a planar ring system, preferably, Each ring is a 5-membered or 6-membered aromatic ring, and there are few aromatic rings linked to an aliphatic ring [A]. A bicyclic aromatic ring system containing at least one nitrogen atom.

[0161] As has already been generally stated herein regarding aromatic ring systems C, each aromatic ring system C is monocyclic or bicyclic aromatic ring systems consisting of one or two five-membered rings and / or six-membered rings In some cases, at least one heteroatom (each of such heteroatoms is preferably independent) Although standing, it is appropriately selected from O, N, or S, and preferably has a small number of heteroatoms present. It appropriately contains (at least one nitrogen atom), and the total number of heteroatoms in the aromatic ring system C is In the case of a monocyclic ring system, preferably 1 or 2, and in the case of a bicyclic ring system, preferably 1, 2. It is preferable that it be 3 or 4. Also, the compound of the present invention shown in the following experimental section. As illustrated by some of the non-restrictive examples, one or two five-membered rings and Such aromatic ring system C, which consists of a 1 / 2 or 6-membered ring, preferably further comprises an aliphatic ring. A is linked to a carbon atom in the aromatic ring system C (i.e., directly via a covalent bond, or This carbon atom (via any of the alkylene linking groups further described herein) It forms part of the aromatic ring within aromatic ring system C (this ring is formed when aromatic ring system C is a monocyclic ring). (In essence, it forms an aromatic ring system C), where this aromatic ring is linked to an aliphatic ring A. In addition to this one carbon atom, at least one selected from N, S, and O (for example) It contains (preferably at least one of the heteroatoms present) one or two heteroatoms. (One of them is a nitrogen atom.)

[0162] Several non-limiting aromatic ring systems that may exist as aromatic ring system C in the compound of the present invention Examples include the following: (i) In the following tables A, B, C and D, atoms When "A" or "Q" and base R, R1, R2, R3 and R4 are referenced, such Atoms A and Q and such groups R, R1, R2, R3 and R4 are as shown in Tables A to D. As defined below, (ii) Atoms A and Q given in Tables A to D below Furthermore, the definitions of groups R, R1, R2, R3, and R4 apply only to the structures shown in the table. It is understood that this specification does not apply to any other atoms, groups, structures, or formulas described herein. sea ​​bream).

[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] Therefore, according to one non-limiting aspect of the present invention, the aromatic ring system C is defined by formulas VII-LXX. It is selected from group XIII consisting of aromatic rings / ring systems.

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

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

[0173] Therefore, in further embodiments, the present invention relates to the following. - Compounds of the present invention (as further described herein), wherein the aromatic ring system C is of formula VI From the group consisting of aromatic rings / ring systems I to LXXXIII, preferably formulas LIX to LXXXI From the group consisting of aromatic rings / ring systems of type II, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, in particular, - Compounds of formula I (as further described herein), wherein the aromatic ring system C is of formula VII From the group consisting of aromatic rings / ring systems ~LXXXIII, preferably formula LIX~LXXXII. From the group consisting of aromatic rings / ring systems I, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - Compounds of formula IV (as further described herein), wherein aromatic ring system C is of formula VI From the group consisting of aromatic rings / ring systems I to LXXXIII, preferably formulas LIX to LXXXI From the group consisting of aromatic rings / ring systems of type II, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - Compounds of formula II (as further described herein), wherein aromatic ring system C is of formula VI From the group consisting of aromatic rings / ring systems I to LXXXIII, preferably formulas LIX to LXXXI From the group consisting of aromatic rings / ring systems of type II, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - Compounds of formula V (as further described herein), wherein aromatic ring system C is of formula VII From the group consisting of aromatic rings / ring systems ~LXXXIII, preferably formula LIX~LXXXII. From the group consisting of aromatic rings / ring systems I, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - Compounds of formula III (as further described herein), wherein aromatic ring system C is of formula V From the group consisting of aromatic rings / ring systems II to LXXXIII, preferably formulas LIX to LXXX From the group consisting of aromatic rings / ring systems of type III, more preferably formulas LXXIII to LXXXII. A compound selected from the group consisting of aromatic rings / ring systems, More specifically, - Compounds of formula VI (as further described herein), wherein aromatic ring system C is of formula VI From the group consisting of aromatic rings / ring systems I to LXXXIII, preferably formulas LIX to LXXXI From the group consisting of aromatic rings / ring systems of type II, more preferably formulas LXXIII to LXXXIII A compound selected from the group consisting of aromatic rings / ring systems, Here, such compounds of the present invention (i.e., the present invention according to any of the embodiments described above) The compound is preferably further expressed as 10 micrometers relative to AT2R. Better than 1 micromol, preferably better than 1 micromol, more comfortably 0.1 micromol Affinity better than 10 nanomoles, and more preferably better than 10 nanomoles (as described in Example 2 below). (Measured according to the protocol described) (For the remainder, see this document) (Further details are provided in the specifications.)

[0174] As generally described herein, these are represented by formulas VII to LXXXIII, respectively. For each of the aromatic rings / ring systems, such rings or ring systems are aromatic in the compound of the present invention. If such aromatic rings or ring systems exist as cyclic systems C, there may be one or more (e.g., 1, 2) or three) further substituents (where suitable substituents are obvious to those skilled in the art, for example, The substituents present on the aromatic ring system C in the compound of the present invention, as exemplified in the following experimental section, and (including other suitable substituents described herein) can be appropriately substituted (or already 1 In the case of aromatic rings of formulas VII to LXXXIII having more than one substituent, they may be further appropriately substituted. The possibility of (being) being excluded. However, the expression shown as formulas VII~LXXXIII is not excluded. For each aromatic ring / ring system, in particular, such aromatic rings or ring systems are defined by formulas VII-LXX. If it is shown that one of XIII already has one or more substituents, These are aromatic ring systems C in the compounds of the present invention that do not have such (additional) substituents. It is generally preferable that it be present. Also, in specific but non-limiting embodiments of the present invention The aromatic ring system C does not have a carboxylic acid (COOH) group.

[0175] Therefore, preferably, the aromatic ring present as aromatic ring system C in the compound of the present invention is The ring system is preferably an aromatic ring / ring system having the structure described in formulas VII to LXXXIII. One, more preferably, an aromatic ring / ring having the structure described in formulas LIX to LXXXIII. One of the systems, most preferably an aroma having the structure described in formulas LXXIII to LXXXIII It consists of one of the group rings / ring systems.

[0176] Compounds of the present invention containing aromatic ring system C as described herein (particularly preferred such compounds) Some specific but non-limiting examples of the compounds of the present invention (including the compounds of the present invention) are disclosed herein. As will become apparent to those skilled in the art, and / or as illustrated in the following experimental section That is the case.

[0177] As referred to herein, the aromatic ring C is directly, but preferably, bonded via a covalent bond. or alkylene linking group (carbonyl as defined and referred to herein) (may be a group), in particular via a methylene linking group (as defined herein), an aliphatic ring This aliphatic ring is linked to and is referred to as “aliphatic ring A” as further described and mentioned herein. It is also called "Ring A" and is sometimes written as "[A]".

[0178] The aliphatic ring A is generally a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered ring, preferably It is a 5-membered, 6-membered, or 7-membered ring, most preferably a 6-membered ring, and the ring is essentially composed of carbon atoms. and one or more (for example, one or two) heteroatoms (if present, the heteroatoms are preferable) Each of these can be independently selected from O, S, and N, but most preferably, as specified herein Furthermore, it consists of nitrogen atoms as described above. In addition, aliphatic ring A has one or more double bonds. The combination (provided that the presence of these bonds does not transform the aliphatic ring A into an aromatic ring system) is appropriately While it is not ruled out that they may contain unsaturated ring A, preferably compounds containing unsaturated ring A are usually pharmaceuticals. Since it is not expected to be sufficiently stable for academic use, ring A is completely saturated. (That is, there are no double bonds in the ring.)

[0179] The aliphatic ring A is preferably a monocyclic ring, but as further described herein, Ring A contains a total of 7 to 12 atoms (including alkylene bridges), preferably a total of 7. It forms part of a "bicyclo" type structure containing 8 or 9 atoms (including alkylene bridges). A suitable alkylene bridge (as defined herein) containing one or two carbon atoms is used. It may also be a appropriately bridged monocyclic ring. For example, but not limited to, an aliphatic ring A Appropriate alkylene crosslinks (as defined herein) containing one or two carbon atoms are appropriately The cyclohexane, piperidine, or piperazine ring contained in (for example, 3,8-diazabicyclo [3.2.1] Octane and 2,5-diazabicyclo[2.2.1]heptane (as specified herein) See also formulas LXXXV and XCII, etc., positions "2" and "6" in aliphatic ring A, position Positions "2" and "5", positions "3" and "6", or positions "3" and "5" should be appropriately bridged. ) may contain. In the following experimental section, compounds A-189 and A-190 are crosslinked aliphatic compounds. This provides some specific but non-limiting examples of the compounds of the present invention containing ring A. As generally referred to in the specification, two of the ring atoms are the two "bridges" The covalent bonds appropriately "bridge" the two fused rings that share atoms, forming a system containing two fused rings. "Aliphatic 5-membered, 6-membered, 7-membered, 8-membered, 9-membered and 10-membered aliphatic ring systems (for example, formula X The aliphatic ring system of CVIII and the aliphatic ring systems present in compounds A-232 and A-233 (such as) is also a crosslinking ring structure for the purposes of this specification and the claims. It is considered that such a cross-linked ring structure or fused ring structure is also, if present, based on R x or R y Or R5~R 12 Each substituent is independently selected from those referred to herein. The obtained substituents can be appropriately substituted with one or more substituents of any choice.

[0180] The aliphatic ring A is also exemplified, for example, by a spirotype structure shown in formula C below. To that end, a spiro-type structure (preferably containing a total of 7 to 10 atoms, any such structure) It may also have a spiro structure. , group R x Or R y and / or R5~R 12 The substituents referred to herein Each of these substituents can be independently selected and can be appropriately substituted with one or more substituents of any choice.

[0181] As further described herein, the aliphatic ring A is preferably an alkylate of aromatic ring system C. The aromatic ring B is linked to the aliphatic ring A via a linking group (the aromatic ring B is not directly linked to the aliphatic ring A). (or, so that aromatic ring B is linked to aliphatic ring A via alkylene linking groups) (either of which, more preferably, is aromatic, in which the aromatic ring system C is directly linked to the aliphatic ring A) The ring system C is linked to the aliphatic ring A via an alkylene linking group (the aromatic ring B is aliphatic). (directly linked to ring A), aromatic ring system C (directly or as further described herein) It is linked (either via a chilenoid linking group) and also to aromatic ring B (here again, directly or via a chilenoid linking group). Linked (via any of the alkylene linking groups further described in the specification). As described above, if alkylene linking groups are present, they are preferably methylene linking groups. There is a certain (that is, in equations I to VI, each of them is "C (m) R A R B " and "C (n) R C R D (This is expressed as "). Also, as referred to herein, such connections If a group is present, a carbonyl group may be used instead of a methylene group (i.e., C ( m) R A R B or C (n) R C R D (where C=O).

[0182] Furthermore, as further described herein, aromatic ring system C and aromatic ring B are most preferred k is a combination of two aliphatic rings A that are opposite to each other (as defined herein). It is linked to the aliphatic ring A at the atom.

[0183] Furthermore, as further described herein, the aliphatic ring A is preferably at least one It contains nitrogen atoms, and the nitrogen atoms are in aromatic ring system C or aromatic ring B (directly or as specified herein). They are further linked (via any of the methylene linking groups described). More preferably, The aliphatic ring A contains two nitrogen atoms, one of which is directly or Linked (via any of the methylene linking groups further described herein), The other nitrogen atom is attached to aromatic ring B (either directly or via a methylene linking group as further described herein). Linked by either of the following: Here again, the aliphatic ring A is linked by one such nitrogen atom or If two such nitrogen atoms are present, aromatic ring system C and aromatic ring B are linked, respectively. The ring atoms in ring A are most preferably located opposite each other in aliphatic ring A (this (As defined in the specification).

[0184] In specific but non-limiting preferred embodiments, the aliphatic ring A described herein is a carbon source. It consists of a chromosome and 0, 1, or 2 (preferably 1 or 2, more preferably 2) nitrogen atoms. In particular, the aliphatic ring A has a total of 5, 6, or 7 (preferably 6) ring atoms (alkylene rings) If bridges exist, the material should contain (excluding any carbon atoms present in the alkylene bridges). It has become that way.

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

[0186] [ka] During the ceremony, - Each C represents a carbon atom, if present. - Each 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. - v is an integer between 1 and 4, w is an integer between 1 and 4, and the sum of (v+w) is 3, 4 , 5, 6, 7 or 8 (preferably 3, 4 or 5, and both v and w are 2) (More preferable) and the difference (vw) is either 1, 0 or -1. - Each carbon atom C is part of the R group x and base R y It has, and in the formula, each of the present groups R x Independently , hydrogen or a suitable substituent (the substituent is preferably hydrogen, methyl, ethyl, halogen) (especially selected from fluorine (F), CF3 and isopropyl), and each present base R y These are independently hydrogen or a suitable substituent (the substituent is preferably hydrogen, methyl Selected from ethyl, halogen (especially fluorine (F)), CF3, and isopropyl. ) is possible.

[0187] Furthermore, as described and illustrated herein, ring A is an alkylene bridge (as specified herein). (As defined in but not shown in scheme C) or covalent bond (also in scheme C) It may also be a ring appropriately bridged by (not shown), where the a One end of the chelene bridge or covalent bond is C (v) The carbon atoms that make up the carbon chain represented by It is connected to one of the alkylene bridges or covalent bonds, and the other end of the alkylene bridge or covalent bond is C (w) Table by It is linked to one of the carbon atoms that make up the carbon chain. As will be obvious to those skilled in the art, When ring A is crosslinked by alkylene crosslinking, 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 among One of them is substituted by alkylene bridges, and when ring A is bridged by covalent bonds, C (v) R on the carbon chain represented by x or R y one of, and C (w) Represented by R on the carbon chain x or R y One of them is replaced by the covalent bond in question.

[0188] Most preferably, ring A is not substituted with an oxygen atom (i.e., the oxygen is bonded to it) (To form a carbonyl group with the ring carbon atom.)

[0189] As mentioned above, ring A is also formed by a spirotype structure, for example, represented by the following formula C. As illustrated, spiro-type structures (preferably containing a total of 7 to 10 atoms, optional) It may have such a spiro structure. If possible, taking into account the number of available (remaining) covalent bonds on each carbon atom, Each carbon atom in the spiro-type structure also contains the group R as defined herein. x and / or base R y of It can be appropriately possessed.

[0190] Referring to schemes C and D, among the atoms Q in aliphatic ring A, In one of them, it is linked to the aromatic ring system C, and in one of the other atoms Q in the aliphatic ring A They are also linked to aromatic ring B. For this purpose, the two atoms Q are preferably aliphatic. These are located at opposite positions within ring A (as further defined herein). For example, aliphatic elements. If ring A is a 6-membered ring, the aromatic ring system C is preferably the aliphatic ring A at position "1". Linked to the ring atom, the aromatic ring B is preferably connected to the ring atom of the aliphatic ring A at position "4". The numbering of the positions / atoms in the linked aliphatic ring A is as described herein. Similarly, if the aliphatic ring A is a 7-membered ring, the aromatic ring system C is preferably located at The aromatic ring B is linked to the ring atom of the aliphatic ring A at position "1", and preferably at position "4" or It is linked to the ring atom of aliphatic ring A at position "5" (position / atom in aliphatic ring A The numbering is as described herein.

[0191] Furthermore, as described herein, the aliphatic ring A is directly (i.e.) the aromatic ring system C. (via a covalent bond between one of the atoms Q and a ring atom in the aromatic ring system C), or an aliphatic ring A An alkylene linking group (as defined herein) that links the atom Q inside to the ring atom in the aromatic ring system C (or, in particular, they may be linked via methylene linking groups (as defined herein) As further described in the book, the ring atom in the aromatic ring system C is preferably the aromatic ring A carbon atom located within an aromatic ring in the system C, and this aromatic ring is preferably at least (Also containing one heteroatom, in particular at least one nitrogen atom). Furthermore, this specification further As described, the aliphatic ring A is directly (i.e., with the other atom Q and the aromatic ring) of the aromatic ring B. (via covalent bonds between ring atoms in B) or other atoms Q in aliphatic ring A and aromatic ring B Alkylene linking groups (as defined herein) that link to the ring atom in the middle, especially methylene linking groups They may be connected via (as defined herein) (as further described herein). (The ring atom in aromatic ring B is in the ortho position relative to the acidic substituent D). Formulas I-V above In I, these are respectively "-C (m) R A R B -" and -C (n) R C R D - This is expressed as follows: where m may be 0 or 1, and n may be 0 or 1 (so (Each of these is m=0 or n=0, meaning that a direct covalent bond exists), and as a result The sum of m+n may be 2, 1, or 0. Most preferably, at least one such an alkylene linking group (as defined herein), in particular at least one such methyl A len linking group (as defined herein) exists, and m=1 and n=0, or m=0 and n =1, which means the sum of m+n is either 1 or 0 (when both m and n are Both are either 0 or 1, meaning that the sum of m+n is either 0 or 2. (However, this is not very desirable). In a particularly desirable embodiment, m=1 and n=0 ( (As in the case of the structures in equations III and VI).

[0192] According to a preferred embodiment of the ring represented by scheme C where v is 2 and w is 2, It will be obvious to those skilled in the art that aliphatic ring A is a 6-membered ring. Each carbon atom is preferably independently hydrogen, methyl, ethyl, halogen (especially fluorine ( F)) Optionally selected from CF3 and two suitable substituents. It can be replaced independently.

[0193] Such a six-membered ring can also be schematically represented by the following structure (scheme D): Here, the optional substituents are R5~R 12 As shown:

[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, and more preferably, both atoms Q are nitrogen atoms. - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is preferably Independently, hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl The pill is selected.

[0195] By some preferred but non-limiting examples, the aliphatic ring A is, for example, - A cyclohexane ring (which is appropriately substituted by choice) where the aromatic ring system C is It is linked at the "1" position of the cyclohexane ring (i.e., directly or at the alkylene linking group, In particular, via a methylene linking group (both as defined herein), Aromatic ring B is linked to the cyclohexane ring at position "4" (i.e., directly or alkyl This is either via a ylene linking group, particularly a methylene linking group, both of which are defined herein. It may be a cyclohexane ring, in particular, - A piperidine ring (which is appropriately substituted by optional choice) where the aromatic ring system C is pipe The nitrogen atom of the lysine ring is linked (i.e., directly or as defined herein) Aromatic ring B is linked to the piperidine ring at position "4" (either via a lenite linking group) (i.e., either directly or via alkylene linking groups, especially methylene linking groups) (both as defined herein) (or vice versa, where aromatic ring B is on the nitrogen atom, aromatic ring The system may be a piperidine ring (with carbon linked at position "4"), More specifically, - A piperazine ring (which is appropriately substituted by optional choice) where the aromatic ring system C is "1 It is linked to the nitrogen atom at the " position (i.e., directly or to an alkylene linking group, especially a methylene linking group) Aromatic ring B is via either a binder (both as defined herein) It is linked to the nitrogen atom at position "4" of the perazine ring (i.e., directly or through an alkylene linkage group). , in particular via a methylene linking group, both as defined herein. It may be a piperazine ring.

[0196] As described herein, as an alternative to the structure of scheme C or scheme D, an aliphatic Ring A may be a ring system of either formula XCIX or C:

[0197] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. From hydrogen, methyl, ethyl, halogens (especially fluorine (F)), CF3 and isopropyl They may be optionally and appropriately substituted with one or more suitable substituents selected from the group. .

[0198] Some non-limiting examples of aliphatic rings that may be present in the compound of the present invention as aliphatic ring A and The following are some examples:

[0199] [Table 8]

[0200] [Table 9]

[0201] Those skilled in the art will understand the disclosures herein and the compounds of the present invention illustrated in the following experimental sections. To ensure that it is easy to use, the aliphatic ring A (in the various embodiments disclosed herein) is non Substitution or substitution is acceptable. As will be obvious to those skilled in the art, when the aliphatic ring A is unsubstituted... , each R in scheme C x and R y , and each R5~R in scheme D 12 is hydrogen It is an atom.

[0202] Furthermore, as mentioned herein, if aliphatic ring A is substituted, then Each substituent is generally composed of methyl, ethyl, fluoro(F), CF3, and isopropyl. They can be independently selected from the group (preferably methyl, ethyl, and isopropyl). (Selected independently from the group consisting of ). Therefore, it is generally obvious to those skilled in the art. In sea urchin, if the aliphatic ring A is substituted, each R in scheme C x and R y , and also S Each R5~R in Keem D 12 These include hydrogen, methyl, ethyl, fluoro(F), CF3 and It can be independently selected from the group consisting of biisopropyl (preferably methyl, ethinopropyl). (i) In scheme C Regarding, base R x and R y At least one of them is methyl, ethyl, fluoro(F), CF3 Selected from the group consisting of and isopropyl (preferably methyl, ethyl and isopropyl (i) selected from the group consisting of R5 to R1 At least one of 2 is derived from methyl, ethyl, fluoro(F), CF3, and isopropyl. Selected from the group consisting of (preferably selected from the group consisting of methyl, ethyl and isopropyl) (To be selected).

[0203] If the aliphatic ring A is substituted with two or more substituents as described herein, These may preferably be the same or different. Furthermore, each of the substituents may appropriately , can exist on different carbon atoms in aliphatic ring A, but one carbon in aliphatic ring A It is also possible for an elementary atom to appropriately have two such substituents (however, A carbon atom may appropriately have two substituents. Also, to those skilled in the art, If a carbon atom in ring A has a single substituent, such a carbon atom can further contain hydrogen atoms. It is also clear that it would be good to have it.

[0204] Those skilled in the art will know that the maximum number of substituents that can be present on aliphatic ring A is the number of substituents present in aliphatic ring A. It is also clear that this depends on the number of elementary atoms and the number of substituents that each of such carbon atoms may have. Therefore, as an example rather than an limitation, it is roughly represented by scheme D. In a 6-membered aliphatic ring A, the maximum number of substituents that can exist on ring A is 8 (i.e., R5~R 12 (where each of them is a substituent described herein).

[0205] Generally but not limited to, the total number of substituents on ring A is 0, 1, 2, 3, 4, 5 or 6. Preferably 0, 1, 2, 3 or 4, more preferably 0, 1 or 2. Here again, As described herein, such substituents may be the same or different. Often, it can exist on different carbon atoms in aliphatic ring A, but one in aliphatic ring A It is also possible for the carbon atom to appropriately have two such substituents (however, Such a carbon atom can appropriately have two substituents.

[0206] In one specific but non-limiting embodiment, the total number of substituents on ring A is 0, 1, 2, 3 or 4 (preferably 0, 1 or 2), and any substituent present on the aliphatic ring A is preferred The compound is independently selected from methyl, ethyl, and isopropyl (preferably methyl). (There are). Here again, as described herein, such substituents are the same. They may be different, and can exist on different carbon atoms in aliphatic ring A, It is also possible for one carbon atom in aliphatic ring A to appropriately have two such substituents. Yes (however, such carbon atoms may appropriately have two substituents).

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

[0208] Furthermore, if the aliphatic ring A is substituted with one or more substituents described herein, The substitution group is any aliphatic ring A that can appropriately have one or more such substituents. It can appropriately exist on a carbon atom. In one specific but non-limiting embodiment, an aliphatic ring A If is substituted with one or more substituents described herein, then at least these substituents Another is the carbon or nitrogen atom in the aliphatic ring A to which the aromatic ring system C is linked in ring A. It is located on a carbon atom adjacent to (preferably a nitrogen atom). More specifically, but not limited to. According to a specific embodiment, the aliphatic ring A has 1, 2, 3, or 4 such substituents (as specified herein). (as described), in particular if it has one or two such substituents, all such substituents are In ring A, the carbon or nitrogen atom in the aliphatic ring A to which the aromatic ring system C is linked (preferably) It is appropriately located on one or both of the carbon atoms adjacent to the nitrogen atom. Here too, The substituent is preferably independently selected from methyl, ethyl, and isopropyl, and most Preferably, it is methyl.

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

[0210] Further aspects of the present invention relate to compounds of the present invention (particularly those of formula I, II, III, IV, V or V With respect to compound I, where the aliphatic ring A is unsubstituted or as described herein. It is substituted in such a way (in particular, as described in the previous paragraph), and such chemical compounds of the present invention Preferably, the substance is further such that such a compound is present in an amount of 10 micromoles relative to AT2R. Better than 1 micromol, preferably better than 1 micromol, more comfortably 0.1 micromol Better affinity, and more preferably better than 10 nanomoles (as described in Example 2 below) (Measured according to the protocol) (For the remainder, see this specification) (As further described in the book.)

[0211] Compounds of the present invention containing aliphatic ring A as described herein (particularly preferred such Some specific but non-limiting examples of compounds of the present invention (including those of the present invention) are disclosed herein. As will become apparent to those skilled in the art, and / or as illustrated in the following experimental section be.

[0212] As described herein, aromatic ring B is generally a six-membered aromatic ring containing carbon atoms. It is a ring and may optionally (and appropriately) contain one, two, or three nitrogen atoms, but Furthermore, aromatic ring B is at least still in the ortho position relative to aliphatic ring A (i.e., (Further described herein) may have an acidic substituent D. Also, one or more aromatic rings B If the above nitrogen atom is present, preferably on aromatic ring B (i.e., the substituent) Preferably, at the position on aromatic ring B as described herein. ≤ one or more substituents or such substitutions as described herein as existing. The combination of groups may still exist, and more preferably on aromatic ring B. (That is, with respect to the substituents, each is particularly or most preferred as specified herein) Regarding the position on aromatic ring B as described, each in particular and The most preferred is one or more substituents or such configurations as described herein. It is still possible to have combinations of substitutions.

[0213] Some preferred examples of aromatic rings that can form a 6-membered ring within aromatic ring B are F These are benzene, pyridine-2-yl and 1,4-pyrimidine-2-yl, and Enyl is the most preferred.

[0214] As described herein, most preferably, aromatic ring B is a 6-membered ring, but the present invention So, in its broadest sense, if aromatic ring B is a 5-membered aromatic ring (selected from O, N, or S) (The possibility of optionally containing one or two heteroatoms) is excluded. However, such a five-membered aromatic ring is preferably located on a six-membered aromatic ring B. One or more substituents or combinations of such substituents described herein remain as It can have such a thing. More preferably, such a 5-membered aromatic ring has a 6-membered aromatic ring. If present in place of a group ring, the resulting 5-membered aromatic ring B is preferably as described herein. A biological equivalent of the 6-membered aromatic ring B, more preferably represented by scheme E A biological equivalent of a six-membered aromatic ring B, more preferably represented by scheme F. A biological equivalent of the aromatic ring B, most preferably represented by scheme G, is a six-membered aromatic ring B. It is a biological equivalent of [the given name].

[0215] If a bicyclic aromatic ring system is used as aromatic ring B, the aromatic ring B is described herein. Preferred substituents (such as an isobutyl group at position 5 and fluorine at either position 3 or 4) Since compounds that do not adequately contain the element are often obtained, aromatic ring B is a monocyclic ring. It is most desirable for it to be a certain way.

[0216] As further described herein, aromatic ring B is formed when aliphatic ring A is linked to aromatic ring B. The carbon atom adjacent to the carbon atom in ring B has an acidic substituent (i.e., acidic substituent D). The acidic substituent D is any suitable acidic group or substituent (the suitable group / substituent is as stated in the present). (Based on the disclosure in the detailed document, it is obvious to a person skilled in the art after some trial and error at the discretion of the person) It may be present, preferably a carboxylic acid group (i.e., a -C(=O)-OH group), acyl A fufoamide group (for example, but not limited to, the general formula CONHSO2R or SO2) NHCOR, where R is -C1~C8 alkyl, CH2(C1~C8 cycloal (Kill), CH2 (heterocyclyl having 1 to 6 ring atoms), C1 to C8 alkoxy or (The acyl sulfonamide group is a C1-C8 amine), a tetrazole group, or tetrazole A group that is a biological equivalent of a group (as defined herein) (e.g., but not limited to 4H -Selected from the group consisting of (1,2,4-oxadiazole-5-one group), more preferably The material is tetrazole or a biological equivalent thereof, most preferably tetrazole.

[0217] As further described herein, aromatic ring B is preferably methyl, ethyl, Propyl, isopropyl, cyclopropyl, methylcyclopropyl, n-butyl, sec -Butyl, isobutyl, cyclobutyl, methylcyclobutyl, vinyl, allyl, isobuty Nyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, i Sobutoxy, difluoroethoxy, methoxyethyloxy, fluorine, chlorine, cyano, oxy Silane, cyclopropoxy, cyclobutoxy, cyclopentoxy, N-acetyl, substitution and Having at least one further substituent selected from the group consisting of and unsubstituted carbamoyl, This substituent (if present) is most preferably the carbon atom to which the acidic substituent D is linked. It exists on the carbon atom in ring B that is in the para position relative to its position in ring B (for example, aromatic ring B If it is a six-membered aromatic ring such as a phenyl ring, then "5" according to the numbering system used. (position), in this case, the substituent is as follows: schemes E and F and further as provided herein. The substituent R3 shown in the scheme and part of the formula is preferably This is a butyl group, exemplified by compounds of formulas III and VI, for example.

[0218] As further described herein, acidic substituents [D] and methyl, ethyl, propyl Isopropyl, n-butyl, sec-butyl, isobutyl, methoxy, ethoxy, n - Selected from the group consisting of propoxy, isopropoxy, and methylmethoxy, at least Another further substituent (this substituent is preferably as referred to herein) In addition to being butyl (located in the para position relative to the acidic substituent D), the aromatic ring B is optionally selected In the selection, one or more (such as one or two) appropriate substituents (as defined herein) These substituents may be appropriately substituted, and these substituents are those of schemes E-G and formulas I-V as described herein. These are shown as R1, R2, and R4 in section I.

[0219] Therefore, in a specific but non-limiting manner, aromatic ring B is generally as follows: It has an overall structure that can be represented in a simplified manner (Scheme E):

[0220] [ka] During the ceremony, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - X and Y are either nitrogen atoms or carbon atoms, and both X and Y are Either it is a carbon atom, or only one of X or Y is a nitrogen atom (the other of X and Y is carbon). (Elementary atoms), - Z is a nitrogen atom or a carbon atom, - R1, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alcohol Xyamine (-NH2) or C1-C2 substituted amines (e.g., dimethylamine or diene) Selected from the group consisting of ethylamine and cyano, - R2, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) or consisting of a C1-C2 substituted amine (e.g., dimethylamine or diethylamine) Selected from the group, R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1 ~8 alkyl groups (e.g., sec-butyl, and especially isobutyl), e.g., fluorine-substituted groups. Methyl group (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy, -O- CF3, methoxyethyl oxy(-O-(CH2)2-O-CH3) or difluoroethyl Xy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cyclo Butoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo Lukyl, -O-cycloalkyl, -NH-cycloalkyl, -N(C1~C3)-cyclo Alkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, heteroalkyl Ryl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Ryl, -N(C1~C3)-heterocyclyl, vinyl or methyl-substituted vinyl (e.g., - CH=CHCH3, -CH=C(CH3)2 or -CH=CH2), or allyl or methyl Isobutenyl substituted allyl (e.g., -CH2CH=CH2), isobutenyl, or methyl-substituted isobutenyl A selection from the group consisting of nyl (e.g., =C(CH3)2) and cyano, most preferably , isobutyl (i.e., as in the compounds of the present invention of formula III and / or formula VI) ), - R4, if present, is H or halogen (F, Cl, Br or I, preferably F or It is selected from the group consisting of Cl, however, - X, Y, and Z form an aromatic ring structure (i.e., a planar conjugated ring). Selected in such a way (i.e., from carbon atoms or nitrogen atoms, respectively), Furthermore, however, - If X is a nitrogen atom, then R1 does not exist. Furthermore, however, - If Y is a nitrogen atom, then R2 does not exist. Furthermore, however, - If Z is a nitrogen atom, then R4 does not exist.

[0221] Preferably, only one of X, Y, and Z is a nitrogen atom (the others of X, Y, and Z are carbon atoms). (where X is a primary atom), more preferably, only one of Y and Z is a nitrogen atom (where X is a carbon atom). (and Y and Z are also carbon atoms), more preferably Z is a nitrogen atom (Both X and Y are carbon atoms). Most preferably, X, Y and Z are all carbon atoms. It is an atom (i.e., ring B is a substituted phenyl ring that does not contain a nitrogen atom).

[0222] In a preferred but non-limiting embodiment, the aromatic ring B can be schematically represented as follows: Having a body structure (Scheme F):

[0223] [ka] Therefore, the acidic substituent represented by [D] and substituents R1, R2, R3 and / or R It contains or essentially consists of a phenyl ring substituted with 4, in the formula, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl groups (e.g., sec-butyl, and especially iso-butyl), e.g., fluorine Substitutive methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy groups, - O-CF3, methoxyethyloxy(-O-(CH2)2-O-CH3), or difluoro Ethoxy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) Clobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo -C1-C3-C1alkyl, -O-Cycloalkyl, -NH-Cycloalkyl, -N(C1~C3)-C1alkyl Chloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl Krill (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Cyclyl, -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 iso Selected from the group consisting of butenyl (e.g., =C(CH3)2) and cyano, the most preferred The lesser is isobutyl (i.e., the lesser is in the compounds of the present invention of formula III and / or formula VI) sea ​​urchin), - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

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

[0225] [ka] During the ceremony, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

[0226] Compounds of the present invention containing aromatic ring B as described herein (particularly preferred such compounds) Some specific but non-limiting examples of compounds of the present invention (including those of the present invention) are disclosed herein. As will become apparent to those skilled in the art, and / or as illustrated in the following experimental section be.

[0227] In a specific but non-limiting embodiment, the present invention relates to a compound 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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula I by any means thereof, and (iii) the at least A single aromatic ring (i.e., an aromatic ring containing carbon atoms to which the remainder of the compound of formula I is linked) It preferably contains at least one (e.g., one or two) heteroatoms, and the heteroatoms ( If present, preferably each is appropriately selected independently from N, S and O. Preferably, at least one of the heteroatoms (if present) is a nitrogen atom, and [C] The aromatic ring system shown is preferably an aromatic ring / ring system of formulas VII to LXXXIII. From the group consisting of, more preferably the group consisting of aromatic rings / ring systems of formulas LIX to LXXXIII More preferably, a group consisting of aromatic rings / ring systems of formulas LXXIII to LXXXIII. An aromatic ring or ring system selected from, - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0. It is either one, preferably 1 or 0 (when m=0, R A. and R B It does not exist, n If =0, R C and R D (It is understood that it does not exist), m is preferably 1. n is preferably 0, - R A , R B , R C and R D Each of these, if present, contains hydrogen, methyl and / or triphosphate. Either independently selected from fluoromethyl, or A +R B If they exist, they connect Together with the bonded carbon atoms, it forms a carbonyl (C=O) group, or R C +R D If present, they form a carbonyl (C=O) molecule together with the carbon atom to which they are bonded. ) forms a group (in other words, R A +R B They come together and are replaced by a single oxygen atom. The oxygen atom is then bonded to a carbonyl group with the carbon atom to which it is bonded, or R C + R DIf present, they are combined and substituted by a single oxygen atom, and the oxygen source The atom to which the child is bonded forms a carbonyl group), preferably with a hydrogen atom each. can be, - [A] is one of the ring systems schematically represented by the following scheme C,

[0229] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 If one atom Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms, then v is An integer between 1 and 4 (i.e., 1, 2, 3 or 4), and w is an integer between 1 and 4 (i.e., 1, 2, 3 or 4) and the sum of (v+w) is 3, 4, 5, 6, 7 or 8 (preferably (or 3, 4, or 5, and it is more preferable that both v and w are 2), difference (v -w) is either 1, 0, or -1, and each R present is x and each existing R y is good Mashiku independently consists of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. A ring system selected from the following group, and more particularly represented by the following scheme D,

[0230] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 (One atom Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms), R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them preferably independently contains water Selected from the group consisting of methyl, ethyl, fluoro(F), CF3 and isopropyl. Alternatively, it is a ring system of formula XCIX or C,

[0231] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. Selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. The substituents may be optionally and appropriately substituted with one or more suitable substituents. - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - X and Y are either nitrogen atoms or carbon atoms, and both X and Y are Either it is a carbon atom, or only one of X or Y is a nitrogen atom (the other of X and Y is carbon). (Elementary atoms), - Z is a nitrogen atom or a carbon atom, - R1, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alcohol Xyamine (-NH2) or C1-C2 substituted amines (e.g., dimethylamine or diene) Selected from the group consisting of ethylamine and cyano, - R2, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) or consisting of a C1-C2 substituted amine (e.g., dimethylamine or diethylamine) Selected from the group, - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl groups (e.g., sec-butyl, and especially iso-butyl), e.g., fluorine Substitutive methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy groups, - O-CF3, methoxyethyloxy(-O-(CH2)2-O-CH3), or difluoro Ethoxy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) Clobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo -C1-C3-C1alkyl, -O-Cycloalkyl, -NH-Cycloalkyl, -N(C1~C3)-C1alkyl Chloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl Krill (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Cyclyl, -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 iso Selected from the group consisting of butenyl (e.g., =C(CH3)2) and cyano, the most preferred It is isobutyl, - R4, if present, is H or halogen (F, Cl, Br or I, preferably F or It is selected from the group consisting of Cl, however, - X, Y, and Z form an aromatic ring structure (i.e., a planar conjugated ring). Selected in such a way (i.e., from carbon atoms or nitrogen atoms, respectively), Furthermore, however, - If X is a nitrogen atom, then R1 does not exist. Furthermore, however, - If Y is a nitrogen atom, then R2 does not exist. Furthermore, however, - If Z is a nitrogen atom, then R4 does not exist.

[0232] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. It is better than moles, and more preferably better than 10 nanomoles, the same of formula I The present invention relates to compounds such as the following. In a more specific embodiment, the present invention further relates to (i) each of which is further described herein The aromatic ring system [C], aliphatic ring [A] and acidic substituent [D] described, and (ii) the Each of X, Y, and Z present in the compound of formula I, and specific combinations of atoms X, Y, and Z (iii) substituents R1, R2, R3 and R present in the compound of formula I 4 (if any), each of the substituents R1, R2, R3 and R4 Combinations, and (iv) m and n (as described herein, each independently) (v) substituents R present in the compound of formula I (which may be 0 or 1), and (v) substituents R present in the compound of formula I A , RB , R C and R D Each of (if any), and such substituent R A , R B , R C and R D (vi) Any combination of the above, as well as any further additions present in such compounds of formula I. substituents (e.g., aromatic ring systems [C] and / or lipids, as further described herein) Aberrant ring system [A](on), and specific combinations of such substituents present in the compound of formula I. Each combination is such that the compound of formula I is present in a quantity of 10 micromoles or more relative to AT2R. Good, preferably better than 1 micromol, more preferably 0.1 micromol Better than, and even more preferably better than 10 nanomoles of affinity (see Example 2 below) (and such) (measured according to the protocol described) This concerns the compound of formula I (which is a combination of these).

[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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula II by any means thereof Another aromatic ring (i.e., an aromatic ring containing carbon atoms to which the remainder of the compound of formula II is linked) The ring preferably contains at least one (e.g., one or two) heteroatoms, and the heteroatom The children (if any) are preferably independently and appropriately selected from N, S, and O. More preferably, at least one of the heteroatoms (if present) is a nitrogen atom, [ The aromatic ring system represented as C] is preferably an aromatic ring of formula VII to LXXXIII / From the group consisting of ring systems, more preferably from aromatic rings / ring systems of formulas LIX to LXXXIII. From the group, more preferably from aromatic ring / ring system of formulas LXXIII to LXXXIII An aromatic ring or ring system selected from the group, - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0. It is either one, preferably 1 or 0 (when m=0, R A. and R B It does not exist, n If =0, R C and R D (It is understood that it does not exist), m is preferably 1. n is preferably 0, -R A , R B , R C and R D If present, hydrogen, methyl and / or trifluoro Selected independently of methyl, R A +R B If present, the carbons to which they are bonded. Together with an atom, it forms a carbonyl (C=O) group, or R C +R D The place where In combination, they form a carbonyl (C=O) group together with the carbon atoms to which they are bonded. In other words, R A +R B They come together and are replaced by a single oxygen atom, and the acid The elementary atom forms a carbonyl group with the carbon atom to which it is bonded, or R C +R D does exist In that case, they come together and are replaced by a single oxygen atom, and the oxygen atom is bonded A carbon atom and a carbonyl group are formed, preferably each being a hydrogen atom. - [A] is one of the ring systems schematically represented by the following scheme C,

[0235] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 If one atom Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms, then v is An integer between 1 and 4 (i.e., 1, 2, 3 or 4), and w is an integer between 1 and 4 (i.e., 1, 2, 3 or 4) and the sum of (v+w) is 3, 4, 5, 6, 7 or 8 (preferably (or 3, 4, or 5, and it is more preferable that both v and w are 2), difference (v -w) is either 1, 0, or -1, and each R present is x and each existing R y is good Mashiku independently consists of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. A ring system selected from the following group, and more particularly represented by the following scheme D,

[0236] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 (One of the atoms Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms), R5 R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is independently, preferably Independently from the group consisting of hydrogen, methyl, ethyl, fluoro(F), CF3, and isopropyl A suitable substituent may be selected, or a ring system of the formula XCIX or C.

[0237] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. Selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. The substituents may be optionally and appropriately substituted with one or more suitable substituents. - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, (for example, general formula CONHSO2R or SO2NHCOR, where R is a -C1-C8 alkyl, C H2 (C1-C8 cycloalkyl), CH2 (heterocycline having 1-6 ring atoms) ), acylsulfonamide group which is a C1-C8 alkoxy or C1-C8 amine), teto A group that is a biological equivalent (as defined herein) of a razole group or a tetrazole group (e.g.) For example, but not limited to, the group consisting of a 4H-1,2,4-oxadiazole-5-one group. Selected from, more preferably tetrazole or its bioequivalent, most preferably It is tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl groups (e.g., sec-butyl, and especially iso-butyl), e.g., fluorine Substitutive methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy groups, - O-CF3, methoxyethyloxy(-O-(CH2)2-O-CH3), or difluoro Ethoxy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) Clobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo -C1-C3-C1alkyl, -O-Cycloalkyl, -NH-Cycloalkyl, -N(C1~C3)-C1alkyl Chloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl Krill (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Cyclyl, -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 iso Selected from the group consisting of butenyl (e.g., =C(CH3)2) and cyano, the most preferred It is isobutyl, - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

[0238] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. It is better than moles, and more preferably better than 10 nanomoles, the same as in formula II The present invention relates to compounds such as the following. In a more specific embodiment, the present invention relates to (i) each of which is further described herein Aromatic ring systems [C], aliphatic rings [A] and acidic substituents [D] as described above, and (ii) Each of the substituents R1, R2, R3, and R4 (if present) in the compound of formula II such substituents R1, R2, R3 and R4, as well as specific combinations of such substituents R1, R2 and R3 and R4, and (i ii) m and n (as described herein, may each be independently 0 or 1) ), and (iv) substituents R present in the compound of formula II A , R B , R C and R D of Each (if any), and such substituent R A , R B , R C and R D specific combination (v) Any further substituents present in such compounds of formula II (e.g. If, as further described herein, on aromatic ring systems [C] and / or aliphatic ring systems [A] ), and certain combinations of such substituents present in the compound of formula II are Each of the compounds in formula II is better than 10 micromoles relative to AT2R. Better than 1 micromol, more preferably better than 0.1 micromol More preferably, an affinity better than 10 nanomoles (as described in Example 2 below) (and such combinations) The present invention relates to compounds of formula II (as further described herein).

[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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula III by any of the means thereof, and (iii) the less Both contain one aromatic ring (i.e., an aromatic ring containing a carbon atom to which the remainder of the compound of formula III is linked). The group ring preferably contains at least one (e.g., one or two) heteroatoms, The atoms (if present) are preferably appropriately selected independently from N, S, and O. More preferably, at least one of the heteroatoms (if present) is a nitrogen atom. The aromatic ring system represented as [C] is preferably an aromatic ring of formula VII to LXXXIII. From the group consisting of rings / ring systems, more preferably aromatic ring / ring systems of formulas LIX~LXXXIII From the above group, more preferably, aromatic ring / ring system of formula LXXIII~LXXXIII An aromatic ring or ring system selected from the following group, - m is either 1 or 0, - R A and R B Each of these, if present, contains hydrogen, methyl and / or trifluoromethyl Selected independently from R, or R A +R B If they exist, they are connected. Together with a carbon atom, it forms a carbonyl (C=O) group (in other words, R A. +R B They come together and are replaced by a single oxygen atom, and the carbon to which that oxygen atom is bonded (forming an elementary atom and a carbonyl group), preferably each being a hydrogen atom, - [A] is one of the ring systems schematically represented by the following scheme C,

[0241] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 If one atom Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms, then v is An integer between 1 and 4 (i.e., 1, 2, 3 or 4), and w is an integer between 1 and 4 (i.e., 1, 2, 3 or 4) and the sum of (v+w) is 3, 4, 5, 6, 7 or 8 (preferably (or 3, 4, or 5, and it is more preferable that both v and w are 2), difference (v -w) is either 1, 0, or -1, and each R present is x and each existing R y is good Mashiku independently consists of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. A ring system selected from the following group, and more particularly represented by the following scheme D,

[0242] [ka] In the formula, each atom Q is independently a carbon atom or a nitrogen atom (preferably at least 1 (One of the atoms Q is a nitrogen atom, and more preferably both atoms Q are nitrogen atoms), R5 R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is independently, preferably Independently from the group consisting of hydrogen, methyl, ethyl, fluoro(F), CF3, and isopropyl A suitable substituent may be selected, or a ring system of the formula XCIX or C.

[0243] [ka] In the formula, the ring system of formula XCIX or formula C, if present, is preferably independent of each other. Selected from the group consisting of hydrogen, methyl, ethyl, fluorine (F), CF3, and isopropyl. The substituents may be optionally and appropriately substituted with one or more suitable substituents. - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

[0244] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. Better than moles, and more preferably better than 10 nanomoles, the formula III The present invention relates to such compounds. In a more specific embodiment, the present invention relates to (i) each of which is specified herein Further described aromatic ring systems [C], aliphatic rings [A] and acidic substituents [D], and (ii ) Each of the substituents R1, R2, and R4 (if present) in the compound of formula III , as well as specific combinations of such substituents R1, R2 and R4, and (iii)m (which may be 0 or 1 as described herein), and (iii) the formula II substituent R present in compound I A and R B Each of (if any), and such Substituent R A and R B Specific combinations of, as well as in such compounds of formula III (iv) Any further substituents present (e.g., aromatic ring systems as further described herein) [C] and / or on the aliphatic ring system [A]), and the presence of the compound of formula III in the compound. Such specific combinations of substituents each represent the compound of formula III in relation to AT2R. And, better than 10 micromoles, preferably better than 1 micromoles, more preferably Better than 0.1 micromoles, and even more preferably better than 10 nanomoles. To have affinity (measured according to the protocol described in Example 2 below) Compounds of formula III (and such combinations) (further details herein) (Regarding what is described.)

[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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula IV by any means thereof Another aromatic ring (i.e., an aromatic ring containing carbon atoms to which the remainder of the compound of formula IV is linked) The ring preferably contains at least one (e.g., one or two) heteroatoms, and the heteroatom The children (if any) are preferably independently and appropriately selected from N, S, and O. More preferably, at least one of the heteroatoms (if present) is a nitrogen atom, [ The aromatic ring system represented as C] is preferably an aromatic ring of formula VII to LXXXIII / From the group consisting of ring systems, more preferably from aromatic rings / ring systems of formulas LIX to LXXXIII. From the group, more preferably from aromatic ring / ring system of formulas LXXIII to LXXXIII An aromatic ring or ring system selected from the group, - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0. It is either one, preferably 1 or 0 (when m=0, R A. and R B It does not exist, n If =0, R C and R D (It is understood that it does not exist), m is preferably 1. n is preferably 0, - R A , R B , R C and R D If present, hydrogen, methyl and / or trifluor Selected independently from methyl, R A +R B If present, the carbon that binds them together Together with elementary atoms, they form a carbonyl (C=O) group, or R C +RD It exists In that case, they combine with the carbon atoms to which they are bonded to form a carbonyl (C=O) group. (In other words, R A +R B They come together and are replaced by a single oxygen atom, The oxygen atom forms a carbonyl group with the carbon atom to which it is bonded, or R C +R D is, existence In that case, together they are replaced by a single oxygen atom, and that oxygen atom is bonded The carbon atoms (which form a carbonyl group) are preferably hydrogen atoms, - Each 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. - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is independent, Preferably, the group consists of hydrogen, methyl, ethyl, fluoro(F), CF3, and isopropyl. A suitable substituent may be selected independently of the above, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - X and Y are either nitrogen atoms or carbon atoms, and both X and Y are Either it is a carbon atom, or only one of X or Y is a nitrogen atom (the other of X and Y is carbon). (Elementary atoms), - Z is a nitrogen atom or a carbon atom, - R1, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C3 or C4 cycloalkyl, CF3, C1-C8 alcohol Xyamine (-NH2) or C1-C2 substituted amines (e.g., dimethylamine or diene) Selected from the group consisting of ethylamine and cyano, - R2, if present, is H, halogen (F, Cl, Br or I, preferably F or Cl), C1-C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH) 2) or consisting of a C1-C2 substituted amine (e.g., dimethylamine or diethylamine) Selected from the group, - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl groups (e.g., sec-butyl, and especially iso-butyl), e.g., fluorine Substitutive methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy groups, - O-CF3, methoxyethyloxy(-O-(CH2)2-O-CH3), or difluoro Ethoxy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) Clobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo -C1-C3-C1alkyl, -O-Cycloalkyl, -NH-Cycloalkyl, -N(C1~C3)-C1alkyl Chloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl Krill (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Cyclyl, -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 iso Selected from the group consisting of butenyl (e.g., =C(CH3)2) and cyano, the most preferred It is isobutyl, - R4, if present, is H or halogen (F, Cl, Br or I, preferably F or It is selected from the group consisting of Cl, however, - X, Y, and Z form an aromatic ring structure (i.e., a planar conjugated ring). Selected in such a way (i.e., from carbon atoms or nitrogen atoms, respectively), Furthermore, however, - If X is a nitrogen atom, then R1 does not exist. Furthermore, however, - If Y is a nitrogen atom, then R2 does not exist. Furthermore, however, - If Z is a nitrogen atom, then R4 does not exist.

[0247] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. It is better than moles, and more preferably better than 10 nanomoles, the same as in formula IV The present invention relates to compounds such as the following. In a more specific embodiment, the present invention relates to (i) each of which is further described herein The aromatic ring system [C] and acidic substituent [D] described herein, and (ii) each atom Q (in this specification As described in the document, these may be carbon atoms or nitrogen atoms, preferably in small numbers. (at least one Q is a nitrogen atom), and (iii) the compound of formula IV contains Each of X, Y, and Z, as well as specific combinations of atoms X, Y, and Z, and (iv) the Each of the substituents R1, R2, R3, and R4 present in the compound of formula IV (if any) as well as specific combinations of such substituents R1, R2, R3 and R4, and (v) the substituents R5 to R present in the compound of formula IV 12 Each of the (if any) and their respective Eel substituents R5~R 12 Specific combinations of (vi)m and n (as described herein) (so that each can be independently 0 or 1), and (vii) the expression IV substituent R present in the compound A , R B , R C and R D Each of the above (if any), and Such substituent R A , R B , R C and R D Specific combinations of, as well as formula (viii) Any further substituents present in such compounds of IV (e.g., on the aromatic ring system [C]) ), and certain combinations of such substituents present in the compound of formula IV are Each of the compounds in formula IV is better than 10 micromoles relative to AT2R. Better than 1 micromol, more preferably better than 0.1 micromol More preferably, an affinity better than 10 nanomoles (as described in Example 2 below) (and such combinations) The present invention relates to compounds of formula IV (as further described herein).

[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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula V by any means thereof, and (iii) the at least One aromatic ring (i.e., an aromatic ring containing carbon atoms to which the remainder of the compound of formula V is linked) It preferably contains at least one (e.g., one or two) heteroatoms, and the heteroatoms ( If present, preferably each is appropriately selected independently from N, S and O. Preferably, at least one of the heteroatoms (if present) is a nitrogen atom, and [C] The aromatic ring system shown is preferably an aromatic ring / ring system of formulas VII to LXXXIII. From the group consisting of, more preferably the group consisting of aromatic rings / ring systems of formulas LIX to LXXXIII More preferably, a group consisting of aromatic rings / ring systems of formulas LXXIII to LXXXIII. An aromatic ring or ring system selected from, - m is 1 or 0, n is 1 or 0, and the sum of m and n is 2, 1 or 0. It is either one, preferably 1 or 0 (when m=0, R A. and R B It does not exist, n If =0, R C and R D (It is understood that it does not exist), m is preferably 1. n is preferably 0, - R A , R B , R C and R D If present, hydrogen, methyl and / or trifluor Selected independently from methyl, R A +R B If present, the carbon that binds them together Together with elementary atoms, they form a carbonyl (C=O) group, or R C +R D It exists In that case, they combine with the carbon atoms to which they are bonded to form a carbonyl (C=O) group. (In other words, R A +R B They come together and are replaced by a single oxygen atom, The oxygen atom forms a carbonyl group with the carbon atom to which it is bonded, or R C +R D is, existence In that case, together they are replaced by a single oxygen atom, and that oxygen atom is bonded The carbon atoms (which form a carbonyl group) are preferably hydrogen atoms, - Each 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. - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is independent, Preferably, the group consists of hydrogen, methyl, ethyl, fluoro(F), CF3, and isopropyl. A suitable substituent may be selected independently of the above, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R3 is H, halogen (F, Cl, Br or I, and preferably F or Cl), C1-8 alkyl groups (e.g., sec-butyl, and especially iso-butyl), e.g., fluorine Substitutive methyl groups (e.g., trifluoromethyl and CHF2), C1-C8 alkoxy groups, - O-CF3, methoxyethyloxy(-O-(CH2)2-O-CH3), or difluoro Ethoxy(-O-CH2-CHF2), cycloalkyl (e.g., cyclopropoxy, cycloalkyl) Clobutoxy or cyclopentoxy), -CH2-cycloalkyl, -O-CH2-cyclo -C1-C3-C1alkyl, -O-Cycloalkyl, -NH-Cycloalkyl, -N(C1~C3)-C1alkyl Chloalkyl, -NH-heteroalkyl, -N(C1~C3)-heteroalkyl, hetero Cyclyl (e.g., oxirane), -CH2-heterocyclyl, -O-CH2-heterocyclyl Krill (e.g., -O-CH2-oxirane), -O-heterocyclyl, -NH-heterocyclyl Cyclyl, -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 iso Selected from the group consisting of butenyl (e.g., =C(CH3)2) and cyano, the most preferred It is isobutyl, - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

[0250] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. It is better than moles, and more preferably better than 10 nanomoles, the same of formula V The present invention relates to compounds such as the following. In a more specific embodiment, the present invention further relates to (i) each of which is further described herein The aromatic ring system [C] and acidic substituent [D] described herein, and (ii) each atom Q (as specified herein) As described above, these may be independently carbon atoms or nitrogen atoms, preferably a small number (iii) at least one Q is a nitrogen atom, and (iii) the compound of formula V contains Each of the substitution groups R1, R2, R3, and R4 (if any) and such substituents R1, R 2. Specific combinations of R3 and R4, and (v) substitutions present in the compound of formula V. Base R5~R 12 Each of (if any) and such substituents R5~R 12 specific pair (vi)m and n (as described herein, each independently of 0 (or 1), and (vi) substituent R present in the compound of formula V. A , R B , R C and R D Each of (if any), and such substituent R A , R B , R C and R D Specific combinations of, as well as any, present in such compounds of formula (viii) V Further substituents (e.g., on the aromatic ring system [C]), and present in the compound of formula V Each of these specific combinations of substituents means that the compound of formula V is in relation to AT2R. And, better than 10 micromoles, preferably better than 1 micromoles, more preferably Better than 0.1 micromoles, and even more preferably better than 10 nanomoles. To have affinity (measured according to the protocol described in Example 2 below) Compounds of formula V (and combinations thereof) are as described herein. (Regarding being done.)

[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 includes at least one aromatic ring, and (ii) the aromatic ring system includes at least one aromatic ring. Even if not, it can be done through a carbon atom present in one aromatic ring (i.e., directly via a covalent bond). , or if an alkylene linking group is present, the alkylene linking group -C (m) R A R B -of (iii) linked to the remainder of the compound of formula VI by any means thereof Another aromatic ring (i.e., an aromatic ring containing carbon atoms to which the compound remainder of formula VI is linked) The ring preferably contains at least one (e.g., one or two) heteroatoms, and the heteroatom The children (if any) are preferably independently and appropriately selected from N, S, and O. More preferably, at least one of the heteroatoms (if present) is a nitrogen atom, [ The aromatic ring system represented as C] is preferably an aromatic ring of formula VII to LXXXIII / From the group consisting of ring systems, more preferably from aromatic rings / ring systems of formulas LIX to LXXXIII. From the group, more preferably from aromatic ring / ring system of formulas LXXIII to LXXXIII An aromatic ring or ring system selected from the group, - m is either 1 or 0, - R A and R B Each of them is independently of hydrogen, methyl and / or trifluoromethyl Selected, or R A +RB If present, they are together with the carbon atoms to which they are bonded. This forms a carbonyl (C=O) group (in other words, R A. +R B They got together And, it is substituted by a single oxygen atom, and the carbon atom to which the oxygen atom is bonded and the carbon atom (forming a nyl group), preferably each being a hydrogen atom, - Each Q is independently a carbon atom or a nitrogen atom, preferably at least one Atom Q is a nitrogen atom, and more preferably, both atoms Q are nitrogen atoms. - R5, R6, R7, R8, R9, R 10 , R 11 and R 12 Each of them is independent, Preferably, the group consists of hydrogen, methyl, ethyl, fluoro(F), CF3, and isopropyl. A suitable substituent may be selected independently of the above, - The acidic substituent represented by [D] is a carboxylic acid (-COOH) group, an acyl sulfonate group. Mido group (for example, general formula CONHSO2R or SO2NHCOR, where R is - C1-C8 alkyl, CH2(C1-C8 cycloalkyl), CH2(1-6 ring atoms) Acyls (which are heterocyclyls), C1-C8 alkoxys, or C1-C8 amines) (A fluoroamide group), a tetrazole group, or a biological equivalent of a tetrazole group (as defined herein) (meaning) a group (for example, but not limited to, 4H-1,2,4-oxadiazole- Selected from the group consisting of 5-one groups, more preferably tetrazole or its biological equivalent. It is a valence, most preferably a tetrazole, - R1 is 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 amines (e.g., dimethylamine or diethylamine) and Selected from the group consisting of bicyano, - R2 is H, halogen (F, Cl, Br or I, preferably F or Cl), C1~ C8 alkyl, C1-C8 alkoxy, cycloalkyl, amine (-NH2) or C1- Selected from the group consisting of C2-substituted amines (e.g., dimethylamine or diethylamine) , - R4 is made from H or a halogen (F, Cl, Br, or I, preferably F or Cl). Selected from the group.

[0253] As further described herein, in certain embodiments, the present invention relates to affinity for AT2R The properties (measured according to the protocol described in Example 2 below) are better than 10 micromoles. It is good, preferably better than 1 micromol, and more preferably 0.1 micromol. It is better than moles, and more preferably better than 10 nanomoles, the same as formula VI The present invention relates to compounds such as the following. In a more specific embodiment, the present invention relates to (i) each of which is further described herein The aromatic ring system [C] and acidic substituent [D] described herein, and (ii) each atom Q (in this specification As described in the document, these may be carbon atoms or nitrogen atoms, preferably in small numbers. (i) at least one Q is a nitrogen atom, and (iii) present in the compound of formula VI Each of the substituents R1, R2, and R4 (if any) and such substituents R1, R2 (iv) Substituents R present in the compound of formula VI, and (iv) specific combinations of R4, and (iv) substituents R4 present in the compound of formula VI. 5~R 12 Each of (if any) and such substituents R5~R 12 Specific combinations (v)m (which may be 0 or 1 as described herein), and (vi) substituent R present in the compound of formula VI A and R B Each of the following (if any): and such substituent R A and R B Specific combinations of, as well as (vii) the same of expression VI Any further substituents present in a compound such as (e.g., on the aromatic ring system [C]), and The specific combinations of such substituents present in the compound of formula VI are, respectively, The compound of formula VI is better than 10 micromoles relative to AT2R, preferably Better than 1 micromol, more preferably better than 0.1 micromol, even better Preferably, an affinity better than 10 nanomoles (as described in Example 2 below) It is such that (and such combinations) it has (measured according to the rule) , compound.

[0254] Compounds of the present invention according to each of formulas I to VI (preferred, more preferred, particularly preferred, and (including and / or the most preferred compound), and / or refer to one of formulas I to VI to the present invention Some of the compounds of the present invention according to various embodiments and preferred embodiments of the present invention as defined in the details. Specific but non-limiting examples of will become apparent to those skilled in the art based on the disclosure herein, and or as exemplified in the following experimental section.

[0255] The compounds of the present invention are effective against pain, particularly chronic pain, and, for example, the chronic pain conditions described herein. It can be used in prevention, treatment, and / or management.

[0256] Therefore, in further embodiments, the present invention relates to the prevention, treatment and / or management of pain, particularly chronic pain. The compounds of the present invention (for example, as defined herein) in the prevention, treatment and / or management of pain Compounds of formula I, specifically compounds of formula II as defined herein, more specifically, this Compounds of formula III as defined in the specification, preferably compounds of formula IV as defined herein. More preferably, compounds of formula V as defined herein, even more preferably as defined herein Regarding the use of the compound of formula VI as defined.

[0257] In a further embodiment, the present invention relates to the prevention, treatment and / or management of pain, in particular the prevention of chronic pain. In the treatment and / or management of the compounds of the present invention (e.g., compounds of formula I as defined herein) Compounds, specifically compounds of formula II as defined herein, more specifically defined herein Compounds of formula III, preferably compounds of formula IV as defined herein, more preferably is a compound of formula V as defined herein, more preferably a compound of formula V as defined herein. This relates to the use of pharmaceutical compositions containing compound I. Such pharmaceutical compositions are generally of the same nature. As further described in the details, generally, a pharmaceutically active amount, for example, as specified herein. The dosage of the compound of the present invention described herein may be administered in an appropriate dosing regimen (for example, a single dose per day or The invention enables the administration of a quantity to a target using multiple doses / doses. Includes mixed ingredients.

[0258] In a further embodiment, the present invention relates to a pharmaceutically active amount of the compound of the present invention or a pharmaceutical compound containing the same. The substance (for example, according to the appropriate drug regimen further described herein), the subject (that is) This includes administering to subjects (who require such prevention, treatment, or management). This relates to methods for the prevention, treatment, and / or management of pain, particularly chronic pain.

[0259] Chronic pain (including neuropathic pain and inflammatory pain, and other chronic pain as described herein) For the treatment of further conditions, the compounds or compositions of the present invention are typically used over a long period of time (e.g., For example, at least one week, for example, at least one month, for example, at least three months or more, and / Or until the pain is reduced or subsided, for example, as part of a chronic treatment regimen for the management of chronic pain. It must be administered or used as part of a treatment regimen, or as part of an overall treatment regimen. This will be obvious to those skilled in the art. 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 is beneficial to the patient's overall health. The condition, nature and cause of the pain, and / or any specific pain condition involved, as well as information provided to the clinician. This treatment may be determined by the treating physician based on other relevant factors. Therapeutic regimens and medication regimens form further embodiments of the present invention.

[0260] The compounds and compositions of the present invention specifically relate to the prevention, treatment, and / or prevention of pain, particularly chronic pain. This can be used in management, and such (chronic) pain is neuropathic pain. Such neuropathic pain is neuropathic pain that originates from the peripheral parts of the nervous system (for example, three Geminal neuralgia or postherpetic neuralgia, peripheral nerve injury, painful polyneuropathy, or nerve root (In the case of a disorder) may be, or may originate from the central nervous system and / or be related to the central nervous system Involved neuropathic pain (e.g., spinal cord injury or brain injury, stroke or multiple sclerosis) This may be the case in chronic neuropathic pain that develops as a result of the disease. Corresponding / related treatment methods form further embodiments of the present invention.

[0261] In specific but non-limiting embodiments, the compounds and compositions of the present invention (for example, as specified herein) Compounds of formula I as defined, specifically compounds of formula II as defined herein, more specifically This includes a compound of formula III as defined herein, preferably a compound of formula IV as defined herein. Compounds, more preferably compounds of formula V as defined herein, and even more preferably the present specification Compounds of formula VI as defined in this document, or pharmaceutical compositions containing them, are used to treat (peripheral) nerve disorders. It can be used in prevention, treatment and / or management. Such use and corresponding / related treatment The treatment method forms a further embodiment of the present invention.

[0262] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, for the prevention of trigeminal neuralgia , can be used for treatment and / or management. Such use and corresponding / related treatment methods This forms a further aspect of the present invention.

[0263] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this The compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is used after peripheral nerve injury. It can be used for the prevention, treatment and / or management of chronic NP. Such use and corresponding / related The treatment method described herein forms a further aspect of the present invention.

[0264] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is used for painful polyneuropathy. It can be used for the prevention, treatment and / or management of disorders. Such use and corresponding / related The treatment method forms a further aspect of the present invention.

[0265] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is used for postherpetic neuralgia. It can be used for the prevention, treatment and / or management of the following. Such use and corresponding / related treatment The method forms a further aspect of the present invention.

[0266] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is used to treat painful radiculopathy. It can be used for the prevention, treatment and / or management of the following. Such use and corresponding / related treatment The method forms a further aspect of the present invention.

[0267] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is a substance that causes spinal cord injury (SCI). It can be used for the prevention, treatment and / or management of chronic central NPs related to ). And corresponding / related treatment methods form further embodiments of the present invention.

[0268] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this The compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is related to brain injury. It can be used for the prevention, treatment and / or management of chronic central pulmonary necrosis. Related treatment methods form further embodiments of the present invention.

[0269] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is used for chronic central nervous system disorders after stroke. It can be used for the prevention, treatment, and / or management of sexual pain. The treatment method forms a further aspect of the present invention.

[0270] However, without being limited to any particular mechanism or hypothesis, the compounds of the present invention are In the prevention, treatment, or management of types of neuropathic pain generally associated with the peripheral nervous system ( In other words, it is more effective (compared to types of neuropathic pain that are generally associated with the central nervous system). It is expected that there is a high probability that this will be related to and / or originate from the peripheral nervous system. The type of neuropathic pain that occurs (for example, pain caused by disease, dysfunction, or injury of the peripheral nerves) The use of the compounds of the present invention in the prevention, treatment and / or management of (caused) is generally, It should be noted in general that this will form preferred applications and embodiments of the present invention.

[0271] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this The compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is related to multiple sclerosis. It can be used for the prevention, treatment and / or management of related chronic central NPs. Corresponding / related treatment methods form further embodiments of the present invention.

[0272] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is for the prevention of inflammatory pain. , can be used for treatment and / or management. Such use and corresponding / related treatment methods This forms a further aspect of the present invention.

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

[0274] In a further embodiment, the present invention relates to chronic neuropathies arising from the peripheral nervous system in the subject. Regarding methods for the prevention, treatment and / or management of pain, the method relates to a pharmaceutically active amount The compound of the present invention or a pharmaceutical composition containing the same (for example, as further described herein) (According to the medication regimen), the target (i.e., the person requiring such prevention, treatment or management) This includes administering the drug to the target population.

[0275] In a further embodiment, the present invention relates to the central nervous system arising from the peripheral portion of the nervous system in the subject. Methods for the prevention, treatment, and / or management of chronic neuropathic pain resulting from and / or related to In relation to this, this method involves using a pharmaceutically active amount of the compound of the present invention or a pharmaceutical composition containing the same. For example, in accordance with appropriate drug regimens further described herein, the subject (i.e., so This includes administering the drug to subjects (such as those requiring prevention, treatment, or management).

[0276] In a further embodiment, the present invention relates to a pharmaceutically active amount of the compound of the present invention or a pharmaceutical compound containing the same. The substance (for example, according to an appropriate dosage regimen further described herein) is administered to the subject (i.e., This includes administering to subjects (who require such prevention, treatment, or management). This relates to methods for the prevention, treatment, and / or management of peripheral neuropathy.

[0277] In a further embodiment, the present invention relates to a pharmaceutically active amount of the compound of the present invention or a pharmaceutical compound containing the same. The substance (for example, according to the appropriate drug regimen further described herein), the subject (that is) This includes administering to subjects (who require such prevention, treatment, or management). This relates to methods for the treatment and / or management of diabetic neuropathy.

[0278] In a further embodiment, the present invention relates to a pharmaceutically active amount of the compound of the present invention or a pharmaceutical compound containing the same. The substance (for example, according to the appropriate drug regimen further described herein), the subject (that is) Pain, including administering to subjects requiring such prevention, treatment, or management. In particular, with respect to methods for the prevention, treatment and / or management of chronic pain, said (chronic) pain is: Pain conditions, namely trigeminal or postherpetic neuralgia, peripheral nerve injury, painful polyneuropathy As a result of nerve damage, painful radiculopathy, spinal cord or brain injury, stroke, or multiple sclerosis Chronic neuropathic pain that develops, chronic NP after peripheral nerve injury, and spinal cord injury (SCI) related Chronic central neuropathies (NPs), chronic central neuropathies associated with brain injury, chronic central pain after stroke, multiple indurations Chronic central NP associated with a disease, and / or chronic pain resulting from tissue injury (not limited to) However, it is one of the conditions that include chronic pain after surgery and phantom limb pain after amputation.

[0279] Here again, for the treatment of any of the chronic pain conditions described herein, the present invention The compound or composition shown is suitable for long periods of time (for example, at least one week, for example, at least one month). For example, for at least three months and / or until the pain is reduced or subsided, for example, chronic pain As part of a chronic treatment regimen for pain management, or as part of an overall treatment regimen It will be obvious to those skilled in the art that it must be administered or used in such a chronic condition. The present invention as a treatment regimen or pain management regimen, and as part of such a regimen. The use of the compound or composition depends on the patient's overall condition, the nature and cause of the pain, and / or involvement. Based on the specific pain condition, as well as other relevant factors that are apparent to the clinician, the physician will determine who will treat the pain. This may be determined by the physician. Such treatment regimens and medication regimens are further developments of the present invention. To form a manner.

[0280] Here again, in the context of the various pain conditions referred to herein, these pain symptoms The prevention, treatment, and / or management of pain is based on the pain and / or the intensity and severity of the pain. To reduce, alleviate, and / or reduce the duration of pain, and to reduce sensitivity to pain. To reduce, alleviate and / or reduce hypersensitivity, to reduce, alleviate and / or reduce hyperalgesia or reduce, and / or reduce, allodynia. It is clear that this also includes delaying the onset of pain.

[0281] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this Compounds of formula VI as defined in the specification, or pharmaceutical compositions containing them, cause hyperalgesia, specific This includes hyperalgesia associated with chronic pain, more specifically neuropathic pain and / or inflammatory pain. Hyperalgesia related to, for example, pain related to one of the specific pain conditions referred to herein. It is used to reduce, alleviate, and / or mitigate hypersensitivity. Such use and corresponding Related treatment methods form further embodiments of the present invention.

[0282] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is a cause of allodynia, Physically, it is allodynia associated with chronic pain, more specifically neuropathic pain and / or inflammation. Allodynia associated with symptomatic pain, for example, one of the specific pain conditions referred to herein Used to reduce, mitigate, and / or alleviate related allodynia. The use and corresponding / related therapeutic methods form a further aspect of the present invention.

[0283] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is for inflammatory pain, for example. If hypersensitivity to pain resulting from tissue damage and inflammation is reduced, alleviated, and / or reduced, It is used for such purposes. Such uses and corresponding / related therapeutic methods are further developments of the present invention. It forms a certain form.

[0284] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this Compounds of formula VI as defined in the specification, or pharmaceutical compositions containing them, are used to treat trauma and / or related injuries. To reduce and alleviate pain caused by and / or associated with inflammatory pain, specifically inflammatory pain. Used to alleviate and / or reduce. Such use and corresponding / related treatments The law forms a further aspect of the present invention.

[0285] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, reduces postoperative pain. Used to alleviate and / or reduce. Such use and corresponding / related treatments The method forms a further aspect of the present invention.

[0286] Here again, for the prevention, treatment and / or management of any of the aforementioned pain conditions, the present invention The compound or composition is used in accordance with an appropriate treatment regimen and / or for the management of the pain condition involved. Those skilled in the art should know that it must be administered or used as part of an overall therapeutic regimen. It is clear (for example, until the pain subsides or is reduced, and / or the underlying disease) Or it may be applicable until the condition is treated or alleviated, or in the case of a chronic disease. (This can be chronic). Such treatment regimens or pain management regimens, and such The use of the compounds or compositions of the present invention as part of a regimen affects the patient's overall condition and pain. The nature and cause of the pain, and / or the specific pain conditions involved, as well as other information that is evident to the clinician. Based on the relevant factors, it may be determined by the treating physician. Such treatment regimens and The drug regimen forms a further embodiment of the present invention.

[0287] Furthermore, prevention, treatment and / or treatment of any type of pain and / or pain condition described herein. This is part of the use of the compound or composition of the present invention in management, the compound or composition of the present invention The use of the substance for the prevention, treatment and / or management of pain (such as chronic pain) is known to be known It can be appropriately combined with the administration or use of one or more other compounds or active substances, particularly It is for the prevention, treatment and / or management of specific types of pain or pain conditions involved. Appropriately combined with the administration or use of one or more other compounds or active substances that are known in themselves. It will also be obvious to those skilled in the art that this is possible. Such compounds and active substances are described herein. It is obvious to those skilled in the art based on the disclosure, and as part of such a treatment regimen The use of the compounds of this invention in combination with other compounds and active substances such as the overall patient The condition, nature and cause of the pain, and / or any specific pain condition involved, as well as information available to the clinician. This treatment may be determined by the treating physician based on other relevant factors. Therapeutic regimens and medication regimens form further embodiments of the present invention.

[0288] Furthermore, as described herein, the compounds of the present invention (formula I as defined herein) Compounds of formula II as defined herein, more specifically those specified herein Compounds of formula III as defined, preferably compounds of formula IV as defined herein, more preferably More preferably, a compound of formula V as defined herein, more preferably as defined herein A compound of formula VI (such as) is present in the pharmaceutical composition (as described herein), and / or Used for therapeutic purposes (as further described herein) and / or therapeutic methods (as further described herein) When used as part of (as described in), such compounds of the present invention are preferably Better than 10 micromoles, more comfortably better than 1 micromoles, even better Preferably, an affinity for AT2R better than 0.1 micromol (see Example 2 below). (Measured according to the protocol described in [the document]), and especially better than 10 nanomoles It may have affinity for AT2R.

[0289] As referred to herein, the compounds of the present invention are angiotensin II receptor Type 2, AT2R-mediated signaling and / or AT2R and / or AT2R-mediated The pathways and / or biological processes involving signal transduction, and the targets that require them. In the prevention and treatment of diseases and disorders that can be prevented or treated by regulation in It is also expected that it may be usable. Furthermore, the compounds and compositions are angiotensin II receptors. Compounds that can compete for the binding of one or more natural ligands to type 2, and that are suitable for targets that require it. It can be used for the prevention and treatment of diseases and disorders that can be prevented or treated by administration. It is expected that this will happen.

[0290] Such diseases include those related to AT2R and / or AT2R-mediated signaling. Diseases referred to in the art as such, as well as known modulators (in particular, AT2R The use of ligand binding to and competing modulators) and / or AT2R and / or The use of known inhibitors and / or antagonists of AT2R-mediated signaling is appropriate. This includes, but is not limited to, other diseases and disorders described in the technical field. For example, For example, diseases and disorders listed in International Publication No. 2019 / 179515 (details below). (The items listed in detail are referenced.)

[0291] Therefore, in another specific but non-limiting embodiment, the compounds and compositions of the present invention (e.g.) For example, compounds of formula I as defined herein, specifically compounds of formula II as defined herein. Compounds, more specifically compounds of formula III as defined herein, preferably as defined herein Compounds of formula IV as defined herein, more preferably compounds of formula V as defined herein, and even more Preferably a compound of formula VI as defined herein, or a pharmaceutical composition containing the same. Geotensin II receptor type 2, AT2R-mediated signaling and / or AT2R and / Or the AT2R-mediated signaling pathway and / or biological process, By adjusting to the target group in need, in particular, appropriate treatment or medication can be administered to that group. Regimen (the patient's condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and This is determined by the treating physician and is based on other factors that may be appropriately considered by the treating physician. The present invention provides one or more pharmaceutically active amounts (e.g., doses) according to the method which may be determined by the present invention. By administering the compound, the prevention and / or treatment of diseases and disorders that can be prevented or treated Used for medical treatment. Such use and corresponding / related treatment methods, as well as such treatment Therapeutic regimens and medication regimens form further embodiments of the present invention.

[0292] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this A compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is one or more natural compounds. Gandr's binding to the angiotensin II receptor is competitive with other compounds that require it. By administering it to elephants, in particular, appropriate treatment or drug regimens (patient condition) may be administered to the subject. The condition, the nature of the disease involved, the severity of the disease and / or its symptoms, and the treating physician This is determined and can be decided by the treating physician based on other factors that may be appropriately considered. ) Administering one or more pharmaceutically active amounts (e.g., doses) of the compounds of the present invention according to the instructions. It is used to prevent and / or treat diseases and disorders that can be prevented or treated by it. Such uses and corresponding / related treatment methods, as well as such treatment regimens and drug regimens Dimen forms a further embodiment of the present invention.

[0293] In another specific but non-limiting embodiment, the compounds and compositions of the present invention (for example, the present specification) Compounds of formula I as defined in this document, specifically compounds of formula II as defined herein, more specifically Specifically, compounds of formula III as defined herein, preferably of formula I as defined herein. Compounds of formula V, more preferably compounds of formula V as defined herein, and even more preferably this The compound of formula VI as defined in the specification, or a pharmaceutical composition containing the same, is for the following diseases and disorders. Harm (for example, as described in International Publication No. 2019 / 179515 as AT2R-mediated disorder) It is used for the prevention and / or treatment of one of the (mentioned) conditions. - Cerebrovascular disorders (including cerebral vasospasm and cerebral ischemia), cognitive impairment (amnesia, senile dementia) (including AIDS-related dementia and Down syndrome), central nervous system disorders or conditions (alcohol-related dementia) Addiction to drugs, anxiety, depression or mood disorders, epilepsy, hyperactivity, pain, Parkinson's disease. Illness, mental illness, sleep disorders, autonomic nervous system irregularities, and tardive dyskinesia, schizophrenia Respiratory diseases (bronchial diseases), including demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis. (Including convulsions, asthma, and chronic obstructive airway disease), neuronal tumors, inflammatory diseases (inflammatory bowel disease) Digestive (GI) diseases or conditions (including ulcerative colitis and osteoarthritis), gastrointestinal (GI) diseases or conditions (ulcerative colitis, Crohn's disease) (including incontinence), vasodilation caused by impaired blood flow, allergic diseases (eczema, (Including allergies such as rhinitis and contact dermatitis), vasospasm (angina, migraine, and Raynaud's). (including diseases), fibrous and collagen diseases (including scleroderma and eosinophilic schistosomiasis, reflex sympathetic Neurological dystrophy (including shoulder-hand syndrome), stress-related somatic disorders, peripheral neuropathy, Neuralgia, autoimmune diseases (including systemic erythema), lupus, rheumatoid arthritis, psoriasis, and graft-related illnesses. The primary illness, as well as rheumatic diseases including connective tissue inflammation. - Neuropathic diseases (primary and secondary neuropathy, including peripheral neuropathy, for example) These include related symptoms (hyperesthesia, hyperalgesia, allodynia, spontaneous burning sensation, sensory paralysis, Weakness, including burning pain, stabbing pain and loss of reflexes, preferably neuropathic pain, in which case secondary Neuropathies include: diabetic neuropathy, herpes zoster-associated neuropathy, and uremia. Related neurological disorders, amyloidosis-related neurological disorders, neurological disorders, hereditary motor and sensory neurological disorders, inheritance Transmissible sensory neuropathy, hereditary sensory and autonomic neuropathy, hereditary neuropathy with ulcer injury, nitrate Caused by lofrantoin neuropathy, sausage-like swelling neuropathy, and nutritional deficiencies. Neuropathies, neurological disorders and complex regional pain syndrome, repetitive movements (typing or assembly line work) Neurological disorders caused by (such as work), antiretroviral drugs (e.g., Zalcita) Vinn and didanosine), antibiotics (e.g., nitrazole and isoniazid), gold Caused by compounds, chemotherapy drugs (e.g., vincristine), alcohol, and lead. Neuropathies, peripheral neuropathy caused by arsenic, mercury and organophosphorus insecticides, Peripheral neuropathy associated with the staining process (e.g., Guillain-Barré syndrome), - Neuronal hypersensitivity, including hyperalgesic conditions such as fibromyalgia and irritable bowel syndrome. A state characterized by, - Including neuronal hypersensitivity, breast pain, interstitial cystitis, vulvodynia, and cancer-induced neuropathy. Disorders related to abnormal nerve regeneration, - Inflammatory pain that may result from a condition characterized by inflammation (chemical burns, abrasions or Burns and other burns, autoimmune diseases such as rheumatoid arthritis, inflammatory diseases such as Crohn's disease and colitis (Including intestinal diseases, osteoarthritis, carditis, dermatitis, myositis, neuritis, and collagen vascular diseases), - The above-mentioned nerve disorders (such as peripheral neuropathy), as well as carpal tunnel syndrome and ulnar nerve neuropathy. It may be associated with Guillain-Barré syndrome, facioscapular muscular dystrophy, and herniated discs. Nerve conduction velocity disorders, - Cell proliferation disorders such as cancer (leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cancer) (including basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, lung cancer), and non- Sputum hyperplasia (sputum, keloids, psoriasis, sputum disorders, and scar tissue reduction and cosmetic tissue repair) (including skin conditions such as,) - A condition associated with an imbalance between bone resorption and bone formation, including osteoporosis.

[0294] This method is based on the appropriate treatment or medication regimen (patient's condition, nature of the disease involved, disease and The severity of the symptoms and / or the condition, as determined and appropriately considered by the treating physician. (This may be determined by the physician treating based on other factors) one or more pharmaceutical This involves administering an active amount (e.g., a dose) of the compound of the present invention to the subject.

[0295] In a further embodiment, the present invention relates to a pharmaceutically active amount of the compound of the present invention or a pharmaceutical compound containing the same. The substance (for example, according to the appropriate drug regimen further described herein), the subject (that is) This includes administering to subjects (who require such prevention, treatment, or management). This relates to methods for the prevention, treatment, and / or management of diabetes, particularly type II diabetes.

[0296] The compounds of the present invention are obtained by methods known in themselves, for example, by using well-known techniques of organic chemistry. Structurally related compounds can be prepared by methods that are known in themselves. A specific but non-restrictive method will be explained in the following experimental section.

[0297] Desired compounds of the present invention, and / or starting materials, precursors, and used in their preparation. / or the intermediate is functionally sensitive to the reaction conditions used in the preparation of the compound of the present invention. Bases (i.e., if they are not properly protected, undesirable reactions under those conditions) If the reaction includes receiving a response, it can be protected during the reaction using an appropriate protecting group, and then Furthermore, after the completion of the reaction and / or in the subsequent or final steps in the preparation of the compound of the present invention, It will also be clear that the protecting group can be properly removed. Appropriate protecting group, and Methods and conditions for inserting and removing them are obvious to those skilled in the art and are standard practices in organic chemistry. A standard handbook, for example, Greene and Wuts, "Protective e groups in organic synthesis”,3 rd Editi It is commonly described in on, Wiley and Sons, 1999. One or more The compounds of the present invention, in which the functional groups are protected with appropriate functional groups, are used for the production of the compounds of the present invention and / Alternatively, it can be found to be used as an intermediate in synthesis, which in itself represents a further aspect of the present invention. It will also be obvious to those skilled in the art that this forms a certain shape.

[0298] For pharmaceutical purposes, the compounds of the present invention are available as free acids or free bases, and / or These are pharmaceutically acceptable acid addition salts and / or base addition salts (e.g., non-toxic organic or inorganic). In the form of a hydrate, solvate and / or complex (obtained using an acid or base), It can be used in the form of a prodrug or predrug such as an ester. Such salts, hydrates, solvates, etc., and their preparations are obvious to those skilled in the art. For example, U.S. Patent No. 6,372,778(A), U.S. Patent No. 6,369,086(A), The same is described in Nos. 6,369,087(A) and Nos. 6,372,733(A). Salts, hydrates, solvates, etc., are referenced.

[0299] Generally, for pharmaceutical use, the compounds of the present invention are used in combination with at least one of the compounds of the present invention. , at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant A pharmaceutical formulation comprising a nucleotide and one or more further pharmaceutically active compounds of any choice. It can be formulated as follows. As a non-limiting example, such formulations can be administered orally or parenterally. Administration (e.g., by intravenous, intramuscular, or subcutaneous injection or intravenous infusion), local administration, inhalation Administration methods include transdermal patch administration, implant administration, and suppository administration. It may be in a suitable form. Such a suitable dosage form may be in the manner of administration and its preparation. Depending on the method of use and the carrier, diluent, and excipient, it may be a solid, semi-solid, or liquid. This is clear to the traders, and here again, for example, U.S. Patent No. 6,372,778(A), and the same No. Nos. 6,369,086(A), 6,369,087(A), and 6,372,7 No. 33(A), and Remington's Pharmaceutical Sciences Standard handbooks, such as the latest edition of ences, are referenced.

[0300] Some preferred but non-limiting examples of such formulations include administration as a bolus. and / or tablets, pills, powders, lozenges, sachets, cachets, etc. for continuous administration. Lixyl preparations, suspensions, emulsions, liquids, syrups, aerosols, ointments, creams, ro Suppositories, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders ( Examples include those that are typically redissolved before use, and these are themselves suitable for such formulations. Carriers, excipients, and diluents, such as lactose, dextrose, sucrose, and sorbitol. Lu, mannitol, starch, acacia gum, calcium phosphate, alginate, traga Cant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, poly Ethylene glycol, cellulose, (sterilized) water, methylcellulose, methyl and propyl Hydroxybenzoate, talc, magnesium stearate, edible oil, vegetable oil and mineral oil Alternatively, they can be formulated with appropriate mixtures thereof. The formulation may optionally contain other drugs. A scientifically active substance (which may or may not produce a synergistic effect with the compound of the present invention) , as well as lubricants, wetting agents, emulsifiers and suspending agents, dispersants, disintegrants, fillers, and preservatives. It is commonly used in pharmaceutical formulations such as agents, sweeteners, flavoring agents, flow regulators, and release agents. The composition may also contain other substances, such as natural gels or synthetic polymers. Using liposomes or hydrophilic polymer matrices based on the above, the active contained therein The compound may be formulated to provide rapid, sustained, or delayed release.

[0301] The above formulation can be prepared by methods known in itself, and this is the activity that is usually used. Mix the substance with one or more pharmaceutically acceptable carriers, under sterile conditions as necessary. This includes U.S. Patent No. 6,372,778(A), U.S. Patent No. 6,369,086( A), No. 6,369,087(A) and No. 6,372,733(A), and above Further prior art, and Remington's Pharmaceutical S Standard handbooks, such as the latest edition of CENCES, are referenced.

[0302] The pharmaceutical formulations of the present invention are preferably in unit dosage forms, for example, boxes, blisters, vials. A bottle, sachet, ampoule, or any other suitable single-dose or multi-dose holder. The container or vessel (which may be appropriately labeled) may optionally include product information and / or usage information. It can be properly packaged with one or more leaflets, including instructions. Generally, such The unit dose is 1 to 1000 mg, usually 5 to 500 mg of at least one compound of the present invention. For example, approximately 10, 25, 50, 100, 200, 300, or 400 mg per unit dose. It contains.

[0303] The compounds depend on the specific formulation in which they are primarily used and the condition to be treated or prevented, It is administered via various routes, including oral, rectal, percutaneous, subcutaneous, intravenous, intramuscular, or intranasal routes. Oral and intravenous administration are generally preferred. At least one compound of the present invention is generally It is administered in an "effective dose," which is the desired therapeutic dose in the individual being administered at the appropriate time. Any amount of the compound of formula I or VI above, sufficient to achieve a therapeutic or preventive effect. This means that the effective amount is usually determined by the condition being prevented or treated and the route of administration. Typically, the dosage is 0.01 to 1000 mg per kilogram of patient body weight per day, more frequently. The dosage is 0.1 to 500 mg, for example 1 to 250 mg, for example approximately 5, 10, 20, 50, 100 The dose is 150, 200, or 250 mg, which is a single daily dose, administered once or twice a day. It can be administered in divided doses or essentially continuously, for example, by intravenous infusion. The appropriate dosage, route of administration, and further treatment regimen should be determined based on the patient's age, sex, and general health condition, as well as Depending on factors such as the nature and severity of the disease / symptoms to be treated, the treating clinician will This can be determined. Here too, U.S. Patent No. 6,372,778(A) and No. 6,369 Nos. 086(A), 6,369,087(A), and 6,372,733(A) No., and the above further prior art, as well as Remington's Pharmaceutical Standard handbooks, such as the latest edition of Cal Sciences, are referenced.

[0304] Therefore, in further embodiments, the present invention relates to at least one compound of the present invention and at least Compositions containing one suitable carrier (i.e., a carrier suitable for pharmaceutical use), especially drugs This invention relates to compositions for scientific use. The present invention also relates to the preparation of such compositions. Regarding the use of compounds from the Meiji era.

[0305] Furthermore, it is anticipated that the above compounds and compositions may have value in the field of veterinary medicine. For the purposes of this specification, this includes not only the prevention and / or treatment of diseases in animals. Instead, for economically important animals such as cows, pigs, sheep, chickens, and fish, animal production Length and / or weight and / or the amount of meat or other products obtained from the animal and / or This also includes improving quality. Therefore, in further embodiments, the present invention includes at least One compound of the present invention and at least one suitable carrier (i.e., suitable for veterinary use) The present invention relates to compositions for veterinary use containing such carriers. This invention relates to the use of the compound in the preparation of the product. [Brief explanation of the drawing]

[0306] [Figure 1] This graph shows the results obtained in the CCI model of Example 3. [Figure 2] This graph shows the results obtained in the CCI model of Example 3.

[0307] The present invention relates to the following experimental section and the CCI model used in Example 3) These results are explained by Figures 1 and 2, which are graphs showing the results obtained. The exhibits and drawings do not limit the scope of the present invention in any way. Laboratory Department: Example 1: Synthesis Procedure Synthesis of intermediates Intermediate 1

[0308] [ka]

[0309] Step (i): 4-bromo-2-(piperazin-1-yl)benzonitrile Piperazine (107.5g, 1250.0 mmol) and acetonitrile (500mL) Stirring of 4-bromo-2-fluorobenzonitrile (50 g, 250.0 mmol) in ) After adding to the solution, the reaction was continued at 80°C for 12 hours. Completion of the reaction was confirmed by TLC. After that, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was RINKAN (3 × 50 Extracted with 0 mL. The combined organic layers were washed with saturated brine and dried with anhydrous sodium sulfate. It was dried and evaporated under reduced pressure. The crude rubbery solid (57.0 g, crude) was proceeded to the next step without purification. Used.

[0310] Step (ii): 4-(2-methylpropane-1-en-1-yl)-2-(piperazine- 1-Il)benzonitrile 4-bromo-2-(piperazine-1-yl)be in 1,4-dioxane (500 mL) In a stirred solution of nzzonitrile (57.0 g, 214.2 mmol), 4,4,5,5-tetonitrile was added. Lamethyl-2-(2-methylpropa-1-en-1-yl)-1,3,2-dioxabolo Ran (46.76g, 257.0 mmol), followed by K2CO3 (73.89g, 535 0.4 mmol) was added, and argon was blown into the resulting mixture for 20 minutes. Then, P Add d(dppf)Cl2 (15.7g, 21.4mmol), and then the reaction mixture 1 The mixture was heated to 0°C for 10 hours. After confirming the completion of the reaction by TLC, the reaction mixture was vacuumed. The volatile substances are removed by evaporation, the residue is redissolved in ethyl acetate, and then water and saturated brine are added. It was washed with . Then it was dried with anhydrous sodium sulfate and evaporated under reduced pressure, 4-(2 -methylpropa-1-en-1-yl)-2-(piperazine-1-yl)benzonitrile (47.0g) was obtained and 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 4-(2-methylpropane-1-en-1-yl) in CH2Cl2 (300 mL) at 0°C Stirring )-2-(piperazin-1-yl)benzonitrile (47g, 194.8 mmol) Et3N (81.0 mL, 584.3 mmol) was added to the mixed solution. The solution was left at 0°C for 1 Stir for 0 minutes, then add Boc-anhydrous (63.8g, 292.5 mmol), The reactants were stirred for a further 3 hours at room temperature. After confirming the completion of the reaction by TLC, the reaction proceeded. The mixture was diluted with cold water and extracted with CH2Cl2 (3 × 300 mL). The combined organic layer was then extracted. The sample was washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. Crude product was subjected to column chromatography using silica gel (20-30% EtOA in hexane). Purified by c), tert-butyl 4-(2-cyano-5-(2-methylpropane 1-E-1-yl)phenyl)piperazine-1-carboxylate is obtained as a white solid. (53.2g, 80%).

[0312] Step (iv): tert-butyl 4-(2-cyano-5-isobutylphenyl)piper Zin-1-carboxylate In MeOH (200 mL), tert-butyl 4-(2-cyano-5-(2-methyl butyl Ropa-1-en-1-yl)phenyl)piperazine-1-carboxylate (52g, 1 A 9.4 mmol) stirred solution was subjected to a Parr hydrogenation using a Parr hydrogenator at a concentration of 5 kg / cm³. 2 H2 Hydrogenation was performed under reduced pressure and at ambient temperature for 5 hours on 10% Pd / C (5.2g). LC-MS analysis was performed. Therefore, after confirming the completion of the reaction, the reaction mixture is passed through a Celite® bed and filtered. It was then evaporated in a vacuum. The crude residue (47.5g) was used in the next process without further purification. I used it.

[0313] Step (v): 4-Isobutyl-2-(piperazin-1-yl)benzonitrile hydrochloride tert-butyl 4-(2-cyano-5-isobutane) in 1,4-dioxane (50 mL) Tylphenyl)piperazine-1-carboxylate (47.5g, 138.5mmol) To the stirred solution, add HCl (g) from dioxane (150 mL) at 0°C, and then dissolve The liquid was slowly warmed to room temperature, and stirring was continued at room temperature for 3 hours. Completion of the reaction was confirmed by TLC. Afterward, the reaction mixture was reduced to dryness under reduced pressure. The crude residue was further triturated with hexane. Obtain -Isobutyl-2-(piperazine-1-yl)benzonitrile hydrochloride (35.0g) Ta.

[0314] Intermediate 2

[0315] [ka]

[0316] Step (i): 2,6-difluoro-4-(2-methylpropane-1-en-1-yl) Nzonitrile 4-bromo-2,6-difluorobenzonitrile in 1,4-dioxane (100 mL) In a stirred solution of (5.0g, 22.93 mmol), add 4,4,5,5-tetramethyl-2 -(2-methylpropa-1-en-1-yl)-1,3,2-dioxaborolane(5.0 (1g, 27.52 mmol), followed by K2CO3 (7.92g, 57.34 mmol) The mixture was then added, and argon was blown into the resulting mixture for 20 minutes. Subsequently, Pd(dppf)C Add l2 (0.935g, 1.156 mmol), then react the mixture at 80°C for 6 hours. The mixture was heated. After confirming the completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure. The volatile substances were removed. The residue was dissolved in ethyl acetate, washed with water and saturated brine, and then subjected to anhydrous sulfurization. The crude residue was obtained by drying with sodium acid and evaporating under reduced pressure. Crude compounds are eluted in silica gel using column chromatography with 15-20% phosphate in hexane. Purified by tography, 2,6-difluoro-4-(2-methylpropane-1-ene) -1-yl)benzonitrile was obtained as a colorless, rubbery substance (4.0 g, 90%).

[0317] Step (ii): 2,6-difluoro-4-isobutylbenzonitrile 2,6-difluoro-4-(2-methylpropane-1-1-yl)be in MeOH A stirred solution of nzzonitrile (4g, 20.72 mmol) is prepared using a Parr hydrogenation apparatus. 5 kg / cm 2 Under H2 pressure, at ambient temperature for 3 hours, on 10% Pd / C (0.4g) Hydrogenation was performed. After confirming the completion of the reaction by LC-MS, the reaction mixture was treated with Celite( (Registered Trademark) Filtered through a bed and evaporated in a vacuum. The crude residue was hydrated in hexane for 20-25 minutes. Purified by silica chromatography using % alkyl compounds, 2,6-difluorocarbon -4-Isobutylbenzonitrile was obtained as a colorless, rubbery substance (3.3 g, 82%).

[0318] Step (iii): 2-Fluoro-4-isobutyl-6-(piperazine-1-yl)bene Zonitrile 2,6-difluoro-4-isobutylbenzonitrile in acetonitrile (25 mL) (2g, 10.25 mmol) in a stirred solution, piperazine (2.20g, 25.64mm (ol) was added, and the reaction mixture was maintained at 80°C for 12 hours. The completion of the reaction was confirmed by TLC. After confirming this, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was ¼( Extraction was performed using 2 x 100 mL solutions. The combined organic layers were washed with saturated brine and anhydrous sodium sulfate solution. It was dried with um and evaporated under reduced pressure. It was obtained as a grayish-white solid (2.40 g, 95%). The resulting crude residue was used as is in the following processes.

[0319] Intermediate 3

[0320] [ka]

[0321] Step (i): Methyl 4-bromo-2-fluorobenzoate 4-bromo-2-fluorobenzoic acid (5.0g, 22.83%) in MeOH (50mL) Add H2SO4 (25 mL) to the stirred solution of mmol) at 0°C, and then stir the reaction mixture for 8 minutes. The mixture was cooled to 0°C and stirred continuously for 5 hours. After confirming the completion of the reaction by TLC, the reaction mixture was evaporated to dryness. After solidifying, water is added, and the resulting solution is treated with saturated NaHCO3, then ethyl acetate (3 × 10⁻⁶) Extraction was performed with 0 mL of brine. The combined organic layers were washed with water and saturated brine, and then with anhydrous sodium sulfate. It was dried. Evaporated under reduced pressure to obtain a crude residue (4.93g, crude), which was further purified. It was used in the next step without any further action.

[0322] Step (ii): Methyl 4-bromo-2-(piperazin-1-yl)benzoate Methyl 4-bromo-2-fluorobenzoate (4. To a stirred solution of 8g, 20.6 mmol, add piperazine (8.86g, 103.0 mmol) The solution was then stirred at 80°C for 12 hours. The completion of the reaction was confirmed by TLC. Therefore, after confirmation, the reaction mixture was evaporated to dryness, water was added, and the resulting solution was ¼ Extraction was performed using (3 × 100 mL). The combined organic layers were washed with saturated brine and anhydrous sodium sulfate. Dry with alium and evaporate under reduced pressure to obtain methyl 4-bromo-2-(piperazine-1-I). (L) Benzoate (5.33 g, crude) was obtained and used as is in the next step.

[0323] Step (iii): Methyl 2-(4-(benzo[d]thiazole-2-ylmethyl)pipette Radin-1-yl)-4-bromobenzoate Methyl 4-bromo-2-(piperazin-1-yl) in 1,4-dioxane (50 mL) ) In a stirred solution of benzoate (5.0 g, 16.72 mmol), add Et3N (6.95 ml) Add L (50.15 mmol) at 0°C, followed by 2-(chloromethyl)benn after 10 minutes. Zo[d]thiazole (3.65 g, 20.06 mmol) was added. The resulting reaction mixture The mixture was stirred at 100°C for 10 hours. After confirming the completion of the reaction by TLC, cold water was added. It was added to the mixture and then extracted with CH2Cl2 (3 × 100 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum to remove the crude residue. The residue was obtained and subjected to column chromatography using silica gel (35-45% E in hexane). Further purification with tOAc) yields the expected compound, methyl 2-(4-(benzo[d ] Thiazol-2-ylmethyl)piperazine-1-yl)-4-bromobenzoate (5 0.17g, 69% was obtained.

[0324] Intermediate 4 (alternative pathway for Intermediate 2)

[0325] [ka]

[0326] Step (i): 4-Bromo-2-fluoro-6-(piperazin-1-yl)benzonitrile Ru Piperazine (0.986 g, 11.4 mmol) in acetonitrile (20 mL) Stirring of 4-bromo-2,6-difluorobenzonitrile (0.5 g, 2.29 mmol) After adding to the solution, the reaction was continued at 80°C for 14 hours. After confirming the completion of the reaction by TLC, The reaction mixture was evaporated to dryness. Next, the crude residue was treated with 2-4% MeOH in CH2Cl2. The 4-bromo- 2-Fluoro-6-(piperazin-1-yl)benzonitrile in a rubbery liquid (0.51g) It was obtained as 78%).

[0327] Step (ii): 2-Fluoro-4-(2-methylpropa-1-en-1-yl)-6- (piperazine-1-yl)benzonitrile 4-bromo-2-fluoro-6-(piperazine-) in 1,4-dioxane (20 mL) In a stirred solution of 1-yl)benzonitrile (0.5 g, 1.76 mmol), add 4, 4, 5, 5-Tetramethyl-2-(2-methylpropa-1-en-1-yl)-1,3,2-diode Xaborolane (0.385g, 2.1mmol), followed by K2CO3 (0.608g, 4 0.4 mmol) was added, and argon was blown into the resulting mixture for 20 minutes. Then, P Add d(dppf)Cl2 (0.065g, 0.088 mmol), and then the reaction product The mixture was heated to 80°C for 12 hours. After confirming the completion of the reaction by TLC, the reaction mixture was thoroughly heated. The volatile substances are removed by evaporation in the air, the residue is redissolved in ethyl acetate, and then water and saturated bran are added. It was washed with water. Then it was dried with anhydrous sodium sulfate and evaporated under reduced pressure, and 2-F Luoro-4-(2-methylpropa-1-en-1-yl)-6-(piperazine-1-yl) Benzonitrile was obtained and used in the next step without further purification.

[0328] Step (iii): tert-butyl 4-(2-cyano-3-fluoro-5-(2-methyl Lupropa-1-en-1-yl)phenyl)piperazine-1-carboxylate 2-fluoro-4-(2-methylpropane-1-ene-1) in CH2Cl2 (25 mL) Et3N(0. 62 mL (4.4 mmol) was added. The solution was stirred at 0°C for 10 minutes, and then Boc- Anhydrous (0.575 g, 2.64 mmol) was added, and the reaction was continued at room temperature for another 14 hours. After confirming the completion of the reaction by TLC, cold water was added to the reaction mixture, and this was converted to CH2 Extraction was performed with Cl2 (3 × 300 mL). The combined organic layers were washed with saturated brine and anhydrous sulfur The product was dried with sodium acid and evaporated under reduced pressure. The resulting crude product was then dried in silica gel. Purified by chromatography (20-30% phenyl in hexane), t-butyl 4-(2-cyano-3-fluoro-5-(2-methylpropane-1-1- (0.4)(phenyl)piperazine-1-carboxylate was obtained as a colorless rubbery substance. 1g, 2 processes, 65%.

[0329] Step (iv): tert-butyl 4-(2-cyano-3-fluoro-5-isobutyl phosphate Enyl piperazine-1-carboxylate In MeOH (20 mL), tert-butyl 4-(2-cyano-3-fluoro-5-( 2-Methylpropane-1-en-1-yl)phenyl)piperazine-1-carboxylate A stirred solution of (0.4g, 1.11 mmol) was subjected to a Parr hydrogenation apparatus, and 5 kg / cm 2 Hydrogenation was performed under H2 pressure at ambient temperature for 2 hours on 10% Pd / C (0.1g). After confirming the completion of the reaction by LC-MS, the reaction mixture is placed on a Celite® floor. The compound was filtered through and concentrated in a vacuum to obtain the desired compound as a colorless rubbery substance (0.36 g, 90%).

[0330] Step (v): 2-Fluoro-4-isobutyl-6-(piperazin-1-yl)benzo Trill hydrochloride tert-butyl4-(2-cyano-3-fluoro-5-isobutylphenyl)pipera Zin-1-carboxylate (0.35 g, 0.97 mmol) in 1,4-dioxane Dissolve in 4M HCl (20 mL) at 0°C, then slowly warm the solution to room temperature. The mixture was stirred at warm temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was allowed to dry under reduced pressure. The crude residue was further tritulated with diethyl ether to obtain 2-fluoro-4-isopropyl alcohol. Tyl-6-(piperazin-1-yl)benzonitrile hydrochloride is a grayish-white solid (0.25g) It was obtained as 89%).

[0331] Intermediate 5

[0332] [ka]

[0333] Step (i): 2-Chloro-6-methyl-4-(2-methylpropane-1-en-1-yl) ) Benzonitrile 2,4-dichloro-6-methylbenzonitrile in 1,4-dioxane (10 mL) In a stirred solution of 0.25 g, 1.34 mmol, add 4,4,5,5-tetramethyl-2-( 2-Methylpropane-1-en-1-yl)-1,3,2-dioxaborolane (0.27g (1.47 mmol), followed by the addition of K2CO3 (0.46 g, 3.35 mmol), Argon was blown into the resulting mixture for 20 minutes. Then, Pd(dppf)Cl2(0 Add 0.049g (0.067 mmol) and then heat the reaction mixture at 100°C for 12 hours. The reaction was completed by TLC, and the reaction mixture was evaporated in a vacuum. The substance was removed, the residue was redissolved in ethyl acetate, and washed with water and saturated brine. Subsequently, After drying with anhydrous sodium sulfate and evaporating under reduced pressure, column chromatography was performed using silica gel. Obtained by Graph (10-15% siRNA in hexane), 2-chloro-6-methyl- 4-(2-methylpropane-1-en-1-yl)benzonitrile is a grayish-white solid (0.2 It was obtained as 1g, 77%).

[0334] Step (ii): tert-butyl 4-(2-cyano-3-methyl-5-(2-methyl butyl Ropa-1-en-1-yl)phenyl)piperazine-1-carboxylate 1,4-Dioxane (10 mL) contains 2-chloro-6-methyl-4-(2-methylpro Stirred solution of per-1-en-1-yl)benzonitrile (0.21 g, 1.02 mmol) tert-butylpiperazine-1-carboxylate (0.228g, 1.23mm) (ol), followed by K3PO4 (0.541g, 2.55 mmol) and BINAP (0. (0.25 g, 0.041 mmol) was added. Argon was blown over the resulting mixture for 20 minutes. It was packed. Next, P(tBu)3.BF4 (0.012g, 0.041mmol), followed by Add Pd(dba)2 (0.030g, 0.051 mmol), then add the reaction mixture to 10 The mixture was heated to 0°C for 14 hours. After confirming the completion of the reaction by TLC, the reaction mixture was placed under vacuum. The volatile substances are removed by evaporation, the residue is redissolved in ethyl acetate, and then water and saturated brine are added. Washed. Dried on anhydrous sodium sulfate, concentrated in vacuum, and then on silica gel. The desired compound is obtained by column chromatography (25-30% siRNA in hexane). The substance was obtained as a pale yellow, rubbery material (0.15 g, 41%).

[0335] Step (iii): tert-butyl 4-(2-cyano-5-isobutyl-3-methyl methyl phosphate Enyl piperazine-1-carboxylate In MeOH (20 mL), tert-butyl 4-(2-cyano-3-methyl-5-(2 -methylpropane-1-en-1-yl)phenyl)piperazine-1-carboxylate( A stirred solution of 0.15 g (0.42 mmol) was subjected to a Parr hydrogenation apparatus, and 5 kg of water was used. / cm 2 Hydrogenated under H2 pressure at ambient temperature for 2 hours on 10% Pd / C (40 mg). After confirming the completion of the reaction by LC-MS, the reaction mixture is placed on a Celite® floor. The compound was filtered through a filter and concentrated in a vacuum to obtain the expected hydrogenated compound as a colorless, rubbery substance. (0.12g, 80%).

[0336] Step (iv): 4-Isobutyl-2-methyl-6-(piperazin-1-yl)benzo Trill hydrochloride tert-butyl4-(2-cyano-5-isobutyl-3-methylphenyl)piperazi n-1-carboxylate (0.12g, 0.336 mmol) in 1,4-dioxane Dissolve in 4M HCl (10 mL) at 0°C, then slowly warm the solution to room temperature. The mixture was stirred at warm temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was allowed to dry under reduced pressure. The crude residue was further triturated with diethyl ether to obtain 4-isobutyl-2-methyl Lu-6-(piperazin-1-yl)benzonitrile hydrochloride is a grayish-white solid (0.08g, It was obtained as 81%). Intermediate 6

[0337] [ka]

[0338] Step (i): 2-Chloro-4-cyclopropyl-6-methylbenzonitrile 2,4-dichloro-6-methylbenzonitrile in 1,4-dioxane (10 mL) To a stirred solution of 0.3g, 1.61 mmol, add cyclopropylboronic acid (0.152g, (1.77 mmol), followed by the addition of K2CO3 (0.555 g, 4.025 mmol). Then, argon was blown into the resulting mixture for 20 minutes. Next, Pd(dppf)Cl2( Add 0.058 g (0.0805 mmol), then react the mixture at 100°C for 12 hours. The mixture was heated. After confirming the completion of the reaction by TLC, the reaction mixture was evaporated in a vacuum. The volatile substances were removed, the residue was redissolved in ethyl acetate, and washed with water and saturated brine. After drying on anhydrous sodium sulfate and evaporating under reduced pressure, the column was dried on silica gel. Chromatography (10-13% phenylethylamine in hexane) was performed to obtain 2-chloro-4-sulfate. Clopropyl-6-methylbenzonitrile was obtained as a rubbery liquid (0.21 g, 68%). Ta.

[0339] Step (ii): tert-butyl 4-(2-cyano-5-cyclopropyl-3-methyl Phenyl)piperazine-1-carboxylate 2-chloro-4-cyclopropyl-6-methyl methyl ester in 1,4-dioxane (10 mL) To a stirred solution of nzzonitrile (0.2 g, 1.047 mmol), add tert-butylpiper Din-1-carboxylate (0.232g, 1.25 mmol), followed by K3PO4 (0.555g, 2.617 mmol) and BINAP (0.026g, 0.0418m A mole of P(tB) was added. Argon was blown into the resulting mixture for 20 minutes. Next, P(tB) u)3.BF4 (0.012g, 0.0418mmol) followed by Pd(dba)2 (0. Add 0.30g (0.0523 mmol), then heat the reaction mixture at 100°C for 14 hours. After confirming the completion of the reaction by TLC, the reaction mixture was evaporated in a vacuum to remove volatile substances. The substance was removed, the residue was redissolved in ethyl acetate, and washed with water and saturated brine. Anhydrous sulfuric acid The solution was dried on sodium, concentrated in a vacuum, and then subjected to column chromatography on silica gel. The desired compound is subjected to a solution of phenyl (25-30% phosphate in hexane) to produce a pale yellow, rubbery substance. (0.18g, 51%) was obtained.

[0340] Step (iii): 4-Cyclopropyl-2-methyl-6-(piperazine-1-yl) Nzonitrile hydrochloride tert-butyl 4-(2-cyano-5-cyclopropyl-3-methylphenyl)pipette Radin-1-carboxylate (0.18g, 0.527mmol) is mixed with 1,4-dioxa Dissolve in 4M HCl (10 mL) at 0°C, then slowly warm the solution to room temperature. The mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was dried under reduced pressure. It solidified. The crude residue was further triturated with diethyl ether to obtain 4-cyclopropyl- 2-methyl-6-(piperazin-1-yl)benzonitrile hydrochloride is a grayish-white solid (0. It was obtained as 12g, 82%).

[0341] Intermediate 7

[0342] [ka]

[0343] Step (i): 2,6-Dichloro-4-cyclopropylbenzonitrile 4-bromo-2,6-dichlorobenzonitrile in 1,4-dioxane (25 mL) To a st...

Claims

1. A compound of the following formula, 【Transformation 5】 During the ceremony, [C] is a monocyclic or polycyclic aromatic ring system of C5 to C10, wherein (i) the aromatic ring system comprises at least one aromatic ring, (ii) the aromatic ring system is linked to the remainder of the compound via carbon atoms present in the at least one aromatic ring, and (iii) the at least one aromatic ring has at least one heteroatom selected from N, S, and O. m is 1 or 0, and n is 0. R Ａ , R Ｂ , R Ｃ and R Ｄ If present, R is independently selected from hydrogen, methyl and / or trifluoromethyl. Ａ +R Ｂ If present, they combine with the carbon atoms to which they are bonded to form a carbonyl (C=O) group. [D] is tetrazole, Y is a carbon atom, R １ is selected from the group consisting of H, F, Cl, Br, I, C １ to C ８ alkyl, C ３ or C ４ cycloalkyl, CF ３ , C １ to C ８ alkoxy, amine (—NH ２ ), or C １ to C ２ alkyl-substituted amine, dimethylamine, diethylamine, and cyano R ２ H, F, Cl, Br, I, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, cycloalkyl, amine (-NH ２ ), selected from the group consisting of dimethylamine and diethylamine, R ３ H, F, Cl, Br, I, C １ ~ ８ Alkyl, fluorine-substituted methyl group, C １ ~C ８ Alkoxy, -O-CF3, -O-(CH ２ ) ２ -O-CH3, -O-CH ２ -CHF2, C3-C6 cycloalkyl, -CH ２ -C3 to C6 cycloalkyl, -O-CH ２ -C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -NH-C3-C6 cycloalkyl, -N(C １ ~C ３ Alkyl)-C3-C6 cycloalkyl, -NH-3-10 member heteroalkyl, -N(C １ ~C ３ Alkyl)-3-10 member heteroalkyl, 3-10 member heterocyclyl, -CH ２ -3 to 10-membered heterocyclyl, -O-CH ２ -3 to 10-membered heterocyclyl, -O-3 to 10-membered heterocyclyl, -NH-3-membered heterocyclyl, -N(C) １ ~C ３ Selected from the group consisting of alkyl)-3 to 10-membered heterocyclyl, vinyl or methyl-substituted vinyl, allyl or methyl-substituted allyl, isobutenyl or methyl-substituted isobutenyl, and cyano, where the 3 to 10-membered heterocyclic group has 1 to 2 heteroatoms independently selected from N, O, and S. R ４ If present, it is selected from the group consisting of H, F, Cl, Br, and I. Each of R5, R6, R7, R8, R9, R10, R11, and R12 is a compound independently selected from the group consisting of hydrogen, methyl, ethyl, halogen, CF3, and isopropyl, wherein the compound is not 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]pyridazine.

2. The compound according to claim 1, wherein [C] is a monocyclic aromatic ring system of C5 to C10.

3. A compound of the following formula, 【Transformation 6】 During the ceremony, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ and R １２ Each of these is independently hydrogen, methyl, ethyl, fluoro(F), CF ３ A compound according to claim 1, independently selected from the group consisting of and isopropyl.

4. R A is hydrogen, R B is hydrogen, R1 is selected from the group consisting of H, F, C1-C4 alkyl, C3 cycloalkyl, and NH(C1-C2 alkyl), R2 is selected from the group consisting of H, F, Cl, Br, I, C1-C4 alkyl, C1-C8 alkoxy, and C3 cycloalkyl. R 4 is H or F, R 5 is hydrogen, methyl, ethyl, or isopropyl. R 6 is hydrogen or methyl R7 is hydrogen, methyl or ethyl, R9 is hydrogen or methyl R11 is hydrogen or methyl Each of R8, R10, and R12 is hydrogen, and The compound according to claim 1, wherein D is a tetrazole.

5. The following: 2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[1-[2-(2H-tetrazole-5-yl)phenyl]-4-piperidyl]methyl]-1,3-benzothiazole; 1-methyl-2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-methyl-2-[[4-[5-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-methyl-2-[[4-[5-[(E)-propen-1-yl]-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-Methyl-2-[[4-[5-propyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 1-Methyl-2-[[4-[5-(2-methylpropen-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 2-[[4-[5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[4-[5-ethoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-(2-methylpropen-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-ethyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-isopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]-1,3-benzothiazole; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopropoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopropylmethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(2,2-difluoroethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(2-methoxyethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopentaoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(oxetan-3-ylmethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(1-piperidyl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-(4-methylpiperazine-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-7H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-7-methylpyrido[1,2-a]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]oxazolo[4,5-b]pyridine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-8-methylpyrido[1,2-a]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methylpyrido[1,2-a]pyrimidine-4-one; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylpyrazolo[1,5-a]pyrimidine-7-one; 7-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-thiazolo[3,2-a]pyrimidine-5-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrido[1,2-a]pyrimidine-4-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylquinoline-2-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-quinazolin-4-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylquinoxaline-2-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]imidazo[1,2-a]pyridine; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-indazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-isoxazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-1,2,4-oxadiazole; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methyl-thiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrimidine; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methylisoxazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrazine; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methyl-1H-pyrimidine-4-one; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]thiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]oxazole; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methylpyrimidine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methyl-1H-pyrimidine-4-one; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]3,5-dimethylisoxazole; 5-Cyclopropyl-3-[[4-[5-Isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]isoxazole; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methylpyrimidine; 1-[(2,5-dimethylpyrazole-3-yl)methyl]-4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methylimidazole-4-yl)methyl]piperazine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridine-2-carbonitrile; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,2,4-oxadiazole; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methylpyridazine; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methylpyridazine; 1-[(2,3-dimethylimidazole-4-yl)methyl]-4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methoxypyridazine; 2-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-ethoxy-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-4-fluoro-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-fluoro-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-ethyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[3,5-dicyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-isobutyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-ethyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[3-cyclopropyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 3-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-ethoxy-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[2-fluoro-3-isobutyl-6-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-isobutyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-isobutyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-ethyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-cyclopropyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[2-ethyl-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[3-ethyl-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 1-[(4-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(5-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(3-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-methoxy-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-fluoro-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-fluoro-2-pyridyl)methyl]piperazine; 1-[(3,5-dimethyl-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methoxy-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-methyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[[4-(trifluoromethyl)-2-pyridyl]methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methyl-2-pyridyl)methyl]piperazine; 1-[(5-chloro-3-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(3-chloro-5-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(4,5-dimethoxy-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-3-methyl-2-pyridyl)methyl]piperazine; 6-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridine-3-carbonitrile; 1-[(4-chloro-5-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(3,5-difluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 3-[1-[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]ethyl]pyridazine; [4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]pyridazine-3-yl-methanone; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[1-(2-pyridyl)ethyl]piperazine; [4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]-(2-pyridyl)methanone; 2-[[4-[2-fluoro-3-isobutyl-6-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[1-[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]ethyl]-5-methyl-thiazole; 3-[[(2S)-4-[5-(1,2-diduterio-2-methylpropyl)-3-fluoro-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]pyridazine; and 2,2,3,3,5,6,6-heptaduterio-1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-(pyridazin-3-ylmethyl)-5-(triduteriomethyl)piperazine, A compound selected from the group consisting of the following.

6. The following compound: 2-[[4-[5-cyclopropyl-3-fluoro-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]imidazo[1,2-a]pyridine; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[[4-[3,5-dicyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 3-[[2-ethyl-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 2-[[4-[3-ethyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 3-[[4-[3-cyclopropyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-ethyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 5-Isobutyl-N-methyl-3-[4-(pyridazin-3-ylmethyl)piperazin-1-yl]-2-(2H-tetrazole-5-yl)aniline; 2-[[4-[3-cyclopropyl-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 3-[[3-ethyl-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-isobutyl-3-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,5-dimethyl-piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,2-dimethyl-piperazine-1-yl]methyl]pyridazine; 3-[1-[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]ethyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,6-dimethyl-piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,3-dimethyl-piperazine-1-yl]methyl]pyridazine; 1-[(4-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(3-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-2-pyridyl)methyl]piperazine; 1-[(3,5-dimethyl-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; [4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]pyridazine-3-yl-methanone; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[1-[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]ethyl]-5-methyl-thiazole; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[[(2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]-5-methyl-thiazole; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methyl-2-pyridyl)methyl]piperazine; 1-[(5-chloro-3-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 2-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,6-dimethyl-piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[1-[(2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]ethyl]-5-methyl-thiazole; 3-[[(2S)-4-[2-fluoro-3-isobutyl-6-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]pyridazine; 3-[[(2R,6R)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,6-dimethyl-piperazine-1-yl]methyl]pyridazine; 3-[[(2S,6R)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,6-dimethyl-piperazine-1-yl]methyl]pyridazine; 3-[[(2S,6S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2,6-dimethyl-piperazine-1-yl]methyl]pyridazine; (2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-1-[(4-methoxy-2-pyridyl)methyl]-2-methylpiperazine; (2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-1-[(3-methyl-2-pyridyl)methyl]piperazine; (2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-1-[(4-methyl-2-pyridyl)methyl]piperazine; [4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]-(2-pyridyl)methanone; (2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-1-(2-pyridylmethyl)piperazine; and (2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-1-[1-(2-pyridyl)ethyl]piperazine; A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

7. The following compound: 2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[1-[2-(2H-tetrazole-5-yl)phenyl]-4-piperidyl]methyl]-1,3-benzothiazole; 1-methyl-2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-methyl-2-[[4-[5-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-methyl-2-[[4-[2-(2H-tetrazole-5-yl)-5-(trifluoromethyl)phenyl]piperazine-1-yl]methyl]benzimidazole; 1-methyl-2-[[4-[5-[(E)-propen-1-yl]-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole, 1-Methyl-2-[[4-[5-propyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 1-Methyl-2-[[4-[5-(2-methylpropen-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]benzimidazole; 2-[[4-[5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[4-[5-ethoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-benzimidazole; 2-[[1-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]-4-piperidyl]methyl]-1-methyl-benzimidazole; 2-[[4-[2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[2-(2H-tetrazole-5-yl)-5-(trifluoromethyl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-(2-methylpropen-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[5-ethyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-isopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]-1,3-benzothiazole; 2-[[4-[5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopropoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopropylmethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(2,2-difluoroethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(2-methoxyethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(cyclopentaoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(oxetan-3-ylmethoxy)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-(1-piperidyl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-(4-methylpiperazine-1-yl)-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-7H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-7-methylpyrido[1,2-a]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]oxazolo[4,5-b]pyridine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-8-methylpyrido[1,2-a]pyrimidine-4-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methylpyrido[1,2-a]pyrimidine-4-one; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylpyrazolo[1,5-a]pyrimidine-7-one; 7-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-thiazolo[3,2-a]pyrimidine-5-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrido[1,2-a]pyrimidine-4-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylquinoline-2-one; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methylquinoazoline-4-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methylquinoxaline-2-one; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1-methyl-indazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-isoxazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-1,2,4-oxadiazole; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methyl-thiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrimidine; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-isoxazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-cyclopropyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyrazine; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methyl-1H-pyrimidine-4-one; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]thiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]oxazole; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methylpyrimidine; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methyl-1H-pyrimidine-4-one; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]3,5-dimethylisoxazole; 5-Cyclopropyl-3-[[4-[5-Isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]isoxazole; 5-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-2-methylpyrimidine; 1-[(2,5-dimethylpyrazole-3-yl)methyl]-4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methylimidazole-4-yl)methyl]piperazine; 6-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridine-2-carbonitrile; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,2,4-oxadiazole; 1-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(1-methylimidazole-4-yl)methyl]piperazine; 1-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(1-methylpyrazole-3-yl)methyl]piperazine; 4-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methylpyridazine; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methylpyridazine; 1-[(2,3-dimethylimidazole-4-yl)methyl]-4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 3-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-6-methoxypyridazine; 2-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[3-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[4-ethoxy-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-4-fluoro-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-fluoro-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-cyclopropyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 2-[[4-[5-cyclopropyl-3-ethyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 4-[4-(1,3-benzothiazole-2-ylmethyl)piperazine-1-yl]-2-cyclopropyl-N-ethyl-5-(2H-tetrazole-5-yl)aniline; 2-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]1,3-benzothiazole; 2-[[4-[5-isobutyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-1,3-benzothiazole; 4-[4-(1,3-benzothiazole-2-ylmethyl)piperazine-1-yl]-2-isobutyl-5-(2H-tetrazole-5-yl)aniline; 4-[4-(1,3-benzothiazole-2-ylmethyl)piperazine-1-yl]-2-isobutyl-N-methyl-5-(2H-tetrazole-5-yl)aniline; 4-[4-(1,3-benzothiazole-2-ylmethyl)piperazine-1-yl]-N-ethyl-2-isobutyl-5-(2H-tetrazole-5-yl)aniline; 2-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 2-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-3H-quinazolin-4-one; 3-[[4-[3-fluoro-5-methoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[2-fluoro-3-isopropoxy-6-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-ethyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-cyclopropyl-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-ethoxy-5-isopropoxy-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[4-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[2-fluoro-3-isobutyl-6-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 3-[[4-[5-isobutyl-4-methyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridazine; 2-Isobutyl-N-methyl-4-[4-(pyridazin-3-ylmethyl)piperazin-1-yl]-5-(2H-tetrazole-5-yl)aniline; N-ethyl-2-isobutyl-4-[4-(pyridazin-3-ylmethyl)piperazin-1-yl]-5-(2H-tetrazole-5-yl)aniline; 3-[[(2S)-4-[5-isobutyl-2-(2H-tetrazole-5-yl)-3-pyridyl]-2-methyl-piperazine-1-yl]methyl]pyridazine; 3-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-isopropyl-piperazine-1-yl]methyl]pyridazine; 1-[(5-chloro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-methoxy-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-fluoro-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-fluoro-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(3-methoxy-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(5-methyl-2-pyridyl)methyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[[4-(trifluoromethyl)-2-pyridyl]methyl]piperazine; 1-[(3-chloro-5-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(4,5-dimethoxy-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[(4-methoxy-3-methyl-2-pyridyl)methyl]piperazine; 6-[[4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]pyridine-3-carbonitrile; 1-[(4-chloro-5-fluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[(3,5-difluoro-2-pyridyl)methyl]-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]piperazine; 1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-[1-(2-pyridyl)ethyl]piperazine; [(2S)-4-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]-(2-pyridyl)methanone; 2-[[4-[2-fluoro-3-isobutyl-6-(2H-tetrazole-5-yl)phenyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 2-[[4-[5-isobutyl-2-(2H-tetrazole-5-yl)-3-pyridyl]piperazine-1-yl]methyl]-5-methyl-thiazole; 3-[[(2S)-4-[5-(1,2-duterio-2-methylpropyl)-3-fluoro-2-(2H-tetrazole-5-yl)phenyl]-2-methyl-piperazine-1-yl]methyl]pyridazine; and 2,2,3,3,5,6,6-heptaduterio-1-[3-fluoro-5-isobutyl-2-(2H-tetrazole-5-yl)phenyl]-4-(pyridazin-3-ylmethyl)-5-(triduteriomethyl)piperazine; A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition which may contain a pharmaceutically acceptable carrier comprising the compound described in Claim 1.

9. The pharmaceutical composition according to claim 8, for use in the prevention, treatment and / or management of pain, including chronic pain.

10. The pharmaceutical composition according to claim 9, wherein the pain is diabetic peripheral neuropathy pain.

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