Pyridine derivatives useful as HCN2 regulators

Abstract

Formula (I) [Formula 1] TIFF2024509143000097.tif39170 (wherein the substituents are defined herein) and pharma- ceutical acceptable salts thereof. The compound is a hyperpolarization-activated cyclic nucleotide-regulated ion channel 2 (HCN2) inhibitor. Pharmaceutical compositions containing the compound and uses of the compound for the treatment or prevention of conditions mediated by HCN2, including neuropathic pain, are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to indazole compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds for the treatment of conditions mediated by hyperpolarizing activated cyclic nucleotide-regulated ion channels 2 (HCN2), such as the treatment of pain, particularly inflammatory and / or neuropathic pain. [Background technology]

[0002] Pain perception is the ability to detect potentially harmful stimuli to the body, either internal or external, such as extreme temperature or tissue damage, and arises from the activation of nociceptors. Nociceptors transmit information to the brain, where the perception of acute pain occurs. Pain perception is a vital sense that warns individuals of existing or imminent injury that results in acute pain signals. However, in patients with chronic pain, these warning signals can persist even without a real threat, imposing significant limitations on lifestyle and work patterns. Pain results in approximately 40 million doctor visits per year, approximately 4 billion lost workdays, and a substantial decline in quality of life for many patients.

[0003] Inflammatory pain (IP) results from increased excitability of peripheral nociceptive nerve fibers, which is generated by the action of inflammatory mediators released from damaged, inflamed, or stressed tissue on nociceptive (pain-sensing) nerve endings. IP can be chronic or acute. Acute IP is associated with an immediate inflammatory response following tissue damage or injury, and includes injuries such as postoperative pain, toothache, and sprains or muscle tears. Generally, acute IP resolves as the injury heals. However, IP can also be chronic. Chronic IP is characteristic of many conditions, such as infections, injuries, osteoarthritis, and rheumatoid arthritis.

[0004] IP is typically treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or, in more severe cases, opioids, both of which are effective but have significant side effects. Undesirable side effects associated with NSAIDs include gastric and renal complications, along with an increased incidence of myocardial infarction. Side effects associated with opioids include constipation and central nervous system side effects, such as cognitive impairment, sedation, and addiction. Furthermore, even at normal doses, sedatives promote respiratory depression and are a cause of many premature deaths.

[0005] Neuropathic pain (NP) is a form of chronic pain caused by damage and / or dysfunction of sensory nerves in the peripheral or sympathetic nervous system, such as peripheral fibers (Aβ, Aδ, and C fibers) and central neurons, and lesions or diseases of the somatosensory system. Damage to the somatosensory system leads to disruption of the transmission of sensory signals to the brain, resulting in pain. Symptoms of neuropathic pain include paresthesia (e.g., hyperesthesia, hyperalgesia, allodynia (pain to non-noxious stimuli), and hyperalgesia) to painful and other stimuli, and / or persistent pain, typically perceived as deep pain and throbbing pain. NP is often long-lasting and typically persists after the apparent resolution of the primary cause.

[0006] An estimated 50 million people worldwide suffer from chronic non-malignant pain, defined as pain lasting more than three months and not associated with cancer. Neuropathic pain affects approximately 8% of people in Western countries at some point in their lives.

[0007] Painful diabetic neuropathy (PDN), which is pain resulting from nerve damage caused by type 2 diabetes, has grown rapidly with the increasing incidence of obesity and represents a significant patient burden with very few effective treatment options at this stage. Postherpetic neuralgia (PHN), which is long-term pain following the onset of herpes zoster (shingle), is also a serious problem, especially among the elderly. Pain caused by either cancer or the chemotherapy agents used to treat it (chemotherapy-induced peripheral neuropathy, CIPN) imposes an additional patient burden, and a patient's ability to tolerate chemotherapy-induced neuropathic pain is often a limiting factor in treatment. Postoperative neuropathic pain can occur after surgery, causing chronic pain in patients, which can persist long after the surgical wound has healed. In addition to these major patient groups, there are many rarer but severe neuropathic pain conditions, including trigeminal neuralgia, complex regional pain syndrome (CRPS), and pudendal neuralgia. Furthermore, many clinicians believe that elements of neuropathic pain exist in many common conditions, including nerve injury or compression, such as lower back pain, post-traumatic nerve injury (e.g., cervical sprain from a car accident), fibromyalgia, and carpal tunnel syndrome, based on the fact that medications used to treat neuropathic pain have some effectiveness in these conditions.

[0008] Existing therapies for NP, such as gabapentinoids, serotonin, norepinephrine selective reuptake inhibitors (SNRIs), and tricyclic antidepressants, have low efficacy, with as many as 70% of patients reporting limited relief or no relief at all. The number needed to treat (NNT) to achieve 50% relief in a single patient is typically in the range of 7–10 (Finnerup, NB et al., 2015, Lancet Neurol. 14, 162-173). There are also many side effects associated with existing therapies for NP. For example, gabapentin, the current first-line therapy for NP, causes sedation, while amitriptyline (a tricyclic antidepressant), along with numerous drug interactions, has psychoactive effects such as sedation, nightmares, sexual dysfunction, and confusion.

[0009] New treatments for pain, particularly IP and NP, are still needed.

[0010] Hyperpolarization-activated, cyclic nucleotide-regulating (HCN) ion channels include four isoforms, HCN1, 2, 3, and 4, which are activated by hyperpolarization within the membrane potential range of -60 to -90 mV. h (I q or I f These channels have an inward current (also known as ion channels) (Kaupp & Seifert (2001) “Molecular diversity of pacemaker ion channels.” Annu. Rev. Physiol 63:235-257; Biel et al., (2002) “Cardiac HCN channels: structure, function, and modulation.” Trends Cardiovasc. Med. 12(5):206-212).

[0011] HCN isoforms play an important pacemaker role in both cardiac and nervous tissue.

[0012] HCN4 is a major regulator of cardiac rhythm. Inducible detection of cardiac HCN4 induced a progressive decrease in heart rate in mice that became fatal after several days (Baruscotti et al., “Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene HCN4”; Proc.Natl.Acad.Sci.USA 108,2011,1705-1710). HCN2 is expressed in atrial and ventricular cardiac tissue, but appears to be largely excluded from the pacemaker region and sinoatrial node in both animals and humans (Herrmann S, Layh B & Ludwig A. "Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart". J. Mol. Cell. Cardiol. 51, 997-1006, 2011; Herrmann S, Hofmann F, Stieber J & Ludwig A. "HCN channels in the heart: lessons from mouse mutants". Br. J. Pharmacol. 166 "501-509" 2012; Chandler "NJ, et al. "Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker." Circulation 119(12): 1562-1575, 2009).The role of HCN2 may be less critical than that of HCN4, as cardiac function is relatively normal in both HCN2 systemic knockout mice and human HCN2 deletion mutants, suggesting that HCN2 selective blockers do not cause bradycardia (Ludwig et al. "Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2" EMBO J 22, 2003, 216-224; and DiFrancesco et al., "Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy"; J Neurosci. 31, 2011, 17327-17337).

[0013] HCN1 and HCN2 are the major isoforms expressed in both brain and somatosensory neurons (Ludwig et al 2003, op. cit.).

[0014] NPs have traditionally been attributed to sensitization and / or remodeling of the central nervous system. However, more recent studies have shown that pain can persist for longer periods due to recurrent firing of peripheral nociceptors even after the initial injury has seemingly resolved, as demonstrated by the use of peripheral restriction blockers of HCN ion channels and by recording activity in single nociceptors (pain-sensing nerve fibers). These findings suggest that peripheral restriction blockers of HCN ion channels may offer a new class of analgesics. (Young et al.,“Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarization-activated cyclic nucleotide-gated ion channels”;Pain.155;2014,1708-19;Noh,S.,et al.(2014).“The heart-rate-reducing agent,ivabradine,reduces mechanical allodynia in a rodent model of neuropathic pain.”Eur.J.Pain 18(8):1139-1147;Serra,J.,et al.(2012),“Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats.”Pain 153(1):42-55;Tsantoulas,C.,et al.(2016).“HCN2 ion channels:basic science opens up possibilities for therapeutic intervention in neuropathic pain. (This is outlined in Biochem. J. 473(18):2717-2736.)

[0015] The negative range of HCN ion channel activation means they are hardly activated at the resting membrane potential of nerve fibers, which rarely exceeds -60 mV. However, many inflammatory mediators, particularly the potent pro-inflammatory substances PGE2 and bradykinin, bind to Gs-coupled GPCRs, which therefore activate adenylyl cyclase, thereby causing an increase in cAMP (cyclic adenosine monophosphate), which therefore directly binds to the C-terminal domain of HCN ion channels. The voltage range of activation for HCN2 and HCN4 isoforms, rather than HCN1 and HCN3, is shifted positively by the increased intracellular cAMP. Thus, inward currents passing through activated HCN2 ion channels in nociceptive nerve fibers cause recurrent firing, leading to pain perception in vivo (Emery et al., “HCN2 ion channels play a central role in inflammatory and neuropathic pain”; Science 333, 2011, 1462-1466).

[0016] Several studies have shown increased HCN2 channel expression and / or I in nociceptors after nerve injury or inflammation. h Although an electric current was observed, other studies have either failed to find any change in expression or even found a decrease (Tsantoulas, C., et al. (2016), as outlined above). Increased inward I h The current is expected to shift the membrane potential to a more depolarized value, thereby lowering the activation threshold. Upregulation of HCN2 is expected to affect the neuronal I hConsistent with increased current and hyperexcitability, this was demonstrated in the cell bodies and terminals of nociceptive neurons in preclinical models of inflammatory pain. The same is not true for neuropathic pain models that do not show changes in HCN ion channel expression or have been reported to show decreased HCN ion channel expression (Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM & Dubin AE., 2003, Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J. Neurosci. 23, 1169-1178; Tsantoulas et al., 2017, op. cit.). However, as outlined above (Tsantoulas et al., 2016, outlined above), enhanced I- h There is another path to the electric current.

[0017] HCN2 is expressed in nociceptive (pain-sensing) neurons, and voltage-dependent regulation of HCN2 by inflammatory mediators such as PGE2 has been shown to be a major factor in IP. Blocking and / or targeted gene deletion of HCN2 has also been shown to result in analgesia in mouse models of inflammatory pain (including pain induced by injection of PGE2, carrageenan, and formalin) (Emery et al. 2011, op. cit.).

[0018] In a mouse model of chronic constriction injury (CCI) of neuronal disorders (NPs) with a genetic deletion of HCN2 from nociceptors, the mice did not show signs of NP after nerve lesions (Emery et al., 2011, op. cit.). Subsequent studies have shown that ivabradine, a non-selective blocker of HCN ion channels, is an effective analgesic in various mouse models of neuropathic pain, including models of nerve injury, cancer chemotherapy, and diabetic neuropathy (Young et al., 2014, op. cit.; Tsantoulas et al., 2017, op. cit.). Further evidence regarding the central role of HCN2 ion channels in animal pain models is described in Emery et al., “HCN2 ion channels: an emerging role as the pacemakers of pain,” Trends Pharmacol. Sci. 33(8):2012, 456-463; and Tsantoulas et al., “Hyperpolarization-activated cyclic nucleotide-gated 2(HCN2) ion channels drive pain in mouse models of diabetic neuropathy,” Sci Transl. Med 9, 2017, eaam6072. This study suggests that HCN2 selective blockers may offer effective treatment for NP and IP.

[0019] The analgesia observed in these mouse models was achieved by blocking or genetically deleting HCN2 ion channels in peripheral nociceptive neurons alone, because the HCN2 blockers used were restricted to the periphery, and the targeted gene deletion was restricted to peripheral nociceptive neurons. In the mouse models, global gene deletion of all HCN2, in contrast, caused epilepsy and did not cause weight gain or premature death (Ludwig et al. Int.J.Mol.Sci.2015 Jan;16(1):1429-1447). Therefore, peripherally restricted HCN2 blockers are expected to provide effective analgesics for NP and IP while also avoiding central nervous system-mediated side effects that may be associated with blocking HCN2 channels in the brain. Avoiding or minimizing central nervous system side effects would also address major issues with other analgesics such as opioids and gabapentinoids. Selective HCN2 blockers can also avoid some or all of the undesirable gastric, renal, and cardiac side effects associated with NSAIDs or constipation caused by sedatives.

[0020] Experiments (Tsantoulas C et al. 2017, cited above) showed that both ivabradine and HCN2 gene deletions targeted at nociceptors induced complete analgesia in a mouse model of diabetic neuropathy that very well mimicked the human condition. These experiments demonstrated that neuropathic pain originates primarily from the periphery, as the interventions were peripheral in both cases, with ivabradine being peripherally restricted and the HCN2 gene deletion targeting peripheral nociceptors. The idea that peripheral HCN2 blockade would result in effective analgesia contrasts with the common view that NP is a central nervous system phenomenon that will require central nervous system osmotic therapy, particularly to treat NP.

[0021] Several non-selective HCN ion channel blockers are known, including ZD7288, zatebrazine, silobradine, KW-3407, YM758, and ivabradine. These compounds were primarily developed as bradycardias (Romanelli et al. Current Topics in Medicinal Chemistry, 16:1764-1791 and Postea et al. Nature Reviews Drug Discovery 10, 2011, 903-914).

[0022] Ivabradine, a non-selective and peripherally restrictive HCN blocker, was approved by the FDA for the treatment of symptoms associated with stable angina and heart failure. Ivabradine targets HCN4 and HCN1 channels, which are crucial for heart rate regulation in these conditions, and its mode of action is to induce bradycardia by blocking HCN4 and HCN1, thereby reducing the cardiac oxygen requirement. Therefore, although the aforementioned studies have shown that ivabradine provides an analgesic effect on NP, this compound is not clinically suitable as an analgesic due to its effects on cardiac pacemaking associated with HCN4 and / or HCN1 inhibition. Thus, preferred analgesics targeting the HCN2 ion channel, for example, for pain treatment, should not interact with HCN4 and / or HCN1 to a considerable extent in order to avoid or minimize cardiac side effects such as bradycardia.

[0023] International Publication No. 02 / 100408 discloses a method for treating neuropathic pain using compounds that reduce the electrical current mediated by HCN pacemaker channels in sensory cells. This document focuses on the modulation of HCN1 and HCN3 and discloses ZD7288, ZM-227189, zatebrazine, DK-AH268, arininidine, and ivabradine as possible analgesics.

[0024] WO 97 / 40027 discloses certain benzisoxazole and benzimidazole compounds described as being useful in the treatment of various psychotic disorders.

[0025] WO 99 / 18941 claims I h modulators for use in the treatment of psychiatric disorders.

[0026] WO 2011 / 003895 discloses certain benzisoxazole compounds substituted by a carboxamido group at the 5-, 6- or 7-position on the benzisoxazole ring. These compounds may be useful in the treatment of neuropathic pain or inflammatory pain, and are described as being I h channel blockers. This reference describes that the compounds disclosed in the prior applications WO 97 / 40027 and WO 99 / 18941 have higher central nervous system penetration compared to the carboxamido-substituted compounds claimed in WO 2011 / 003895, leading to undesirable side effects.

[0027] WO 2011 / 000915 discloses certain zatebradine derivatives described as selectively inhibiting one or more HCN isoforms.

[0028] WO 2011 / 019747 discloses certain propofol derivatives described as being useful as HCN channel modulators for the treatment of chronic pain.

[0029] There remains a need for HCN channel inhibitors, particularly compounds that selectively inhibit the HCN2 channel.

[0030] Tinnitus is the conscious perception of sound heard in the absence of an external physical sound source. Tinnitus typically manifests itself as a ringing, buzzing, whistling, or hissing sound in the ear. It is estimated that 25.3% of adult Americans experience tinnitus, and 7.9% experience it frequently (Shargorodsky et al., Prevalence and characteristics of tinnitus among US adults. Am.J.Med. 2010 Aug;123(8):711-8). Tinnitus can have a serious impact on quality of life, for example, by affecting sleep and the ability to concentrate and perform intellectual tasks. Tinnitus can also lead to anxiety, depression, and, in extreme cases, suicide.

[0031] Tinnitus can be caused by many factors, including exposure to loud noises, age-related hearing loss, ear or head injury, ear infections, tumors affecting the auditory nerve, and certain ear diseases (e.g., Meniere's disease). Tinnitus is also a known side effect of certain drugs, such as salicylates (e.g., mesalamine or aspirin, especially when taken in high doses), quinine antimalarial agents, aminoglycoside antibiotics, certain chemotherapy drugs, particularly platinum cytotoxic agents (e.g., cisplatin, carboplatin, and oxaliplatin), and loop diuretics (e.g., furosemide, ethacrine, and torsemide). Tinnitus is also associated with auditory dysfunction such as hyperacusis, sound distortion, sound aversion syndrome, phonophobia, and central auditory processing disorder.

[0032] There are currently no FDA-approved drug therapies for the treatment of tinnitus, and therefore there is an unmet medical need for an effective treatment of this condition.

[0033] The inventors have for the first time demonstrated that HCN2 inhibitors are effective in treating tinnitus in an animal model of this condition. Tinnitus is generally considered to be a central nervous system phenomenon originating in the brain and resulting in associated noise in the ear (Henry et al. Underlying Mechanisms of Tinnitus: Review and Clinical Implications; J.Am.Acad.Audiol. 2014 January; 25(1):5-126). Therefore, it was anticipated that central nervous system penetration therapy would be necessary to treat tinnitus. Contrary to this expectation, the examples herein demonstrate that peripherally restrictive HCN blockers, ivabradine, and the peripherally restrictive HCN2 inhibitors of the present invention provide effective treatment for tinnitus in an in vivo model of this condition. These results suggest that peripherally restrictive HCN2 inhibitors may provide effective treatment for tinnitus and related conditions such as Meniere's disease, along with the additional benefit of a reduced risk of central nervous system-related side effects due to HCN2 inhibition in the brain. [Overview of the project] [Means for solving the problem]

[0034] According to the present invention, formula (I): [ka] (In the formula, X 1 is N or CR 1 and; R 1 H, Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR B1 , C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~6 Selected from alkyl-, R 1 Any alkyl, alkenyl, alkynyl, or cycloalkyl group in the C 1~4 Alkyl, C1~4 Haloalkyl and -OR B2 It is optionally substituted with 1 to 4 substituents independently selected from; R 2 Each time it appears independently, Halo, C 1~6 Alkyl and C 1~6 Selected from haloalkyl groups; X 2 is N or CR 32 and; X 3 is N or CR 33 and; R 32 and R 33 These are independently H, Halo, -CN, and C. 1~6 Alkyl, C 1~6 Haloalkyl, -NR A3 R A3 and -OR B3 Selected from; R 3 Each instance of these appears independently as Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -NR A3 R A3 and -OR B3 Selected from; R 4 , R 5 and R 6 These are H and C, respectively, independently. 1~4 Selected from alkyl groups, or R 5 and R 6 C 3~6 Forms a cycloalkyl group; R 7 H, Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, -C(O)NR A4 R A4 , -N(R A4 )C(O)R B4 and -C(O)R B4 Selected from; and R 8, independently at each occurrence, is selected from H, halo, -CN, nitro, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -OR 10 , -NR 10 R 11 , -S(O) x R 10 , -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10A , -C(O)NR 10 R 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)NR 10 R 11 , -N(R 11 )C(O)OR 10 , -N(R 11 )SO2R 10 , -SO2NR 10 R 11 , C 3~6 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group is optionally substituted with 1 to 4 R 12 groups, and said phenyl or heteroaryl group is optionally substituted with 1 to 4 R 13 groups; R 81 and R 82 are each independently selected from H, halo, -CN, C 1~4 alkyl, C 1~4 haloalkyl, -OH and -OR B8 ; R 9 is selected from H, halo, -CN and C 1~6 alkyl; R 10 , independently at each occurrence, is selected from H, C 1~6 alkyl, C 1~6 haloalkyl and C 3~6 cycloalkyl; wherein said alkyl or cycloalkyl group is optionally substituted with 1 to 4 R14 It is optionally substituted in the base; R 10A C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 Selected from cycloalkyl groups; the alkyl or cycloalkyl group has 1 to 4 R groups. 14 It is optionally substituted in the base; R 11 These appear independently, each time H and C appear. 1~6 Selected from alkyl groups; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-7 membered heterocycline, and the heterocycline is a halo, =O,C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B7 Optionally substituted with one or two substituents selected from; R 12 and R 14 Each of these appears independently: Halo, =O, -CN, Nitro, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, -OR B5 , -NR A5 R A5 , -S(O) x R B5 , -C(O)R B5 , -NR A5 C(O)R B5 -C(O)NR A5 R A5 , -NR A5 SO2R B5 and -SO2NR A5 R A5 Selected from; R 13 Each of these appears independently as Halo, -CN, Nitro, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, -OR B6 , -NR A6 R A6 , -S(O) x RB6 , -C(O)R A6 , -NR A6 C(O)R B6 -C(O)NR A6 R A6 , -NR A6 SO2R B6 -SO2NR A6 R A6 Selected from; R B1 These appear independently, each time H and C appear. 1~6 Selected from alkyl groups; R B3 Each of these appears independently, with H and C. 1~6 Alkyl and C 1~6 Selected from haloalkyl groups; R B2 , R B4 , R B5 , R B6 , R B7 Each of these appears independently, with H and C. 1~4 Alkyl and C 1~4 Selected from haloalkyl groups; R B8 Each instance of it appears independently, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups; R A3 , R A4 , R A5 and R A6 These appear independently, each time H and C appear. 1~4 Selected from alkyl groups; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, or 2; and x is an integer that is independently selected from 0, 1, 2, and 3 each time it appears; however, (i)X 1 If is N, then X2 is CR 32 And X3 is CR 33 and; (ii)X 1 CR 1 And R 1If it is -CN, then X2 is CR 32 And X3 is CR 33 and; (iii)X 1 CR 1 And R 1 If R is -CF3, 8 It is not -SO2Me; (iv)X 2 and X 3 (It is not possible for both to be N) Compounds or pharmaceutically acceptable salts thereof are provided.

[0035] A pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient is also provided.

[0036] The compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the present invention are also provided for use as pharmaceuticals. In one embodiment, the compounds of the present invention are provided for use in the treatment of diseases or conditions mediated by HCN2.

[0037] A method for treating a disease or condition mediated by HCN2 in a subject is also provided, comprising administering an effective amount of the compound or pharmaceutical composition of the present invention to the subject.

[0038] In some embodiments, the compounds of the present invention are for use in the treatment of pain, including neuropathic pain and / or inflammatory pain. In some embodiments, the compounds of the present invention are for use in the treatment of neuropathic pain, particularly chronic neuropathic pain. In some embodiments, the compounds of the present invention are for use in the treatment of peripheral neuropathic pain, particularly chronic peripheral neuropathic pain. In some embodiments, the compounds of the present invention are for use in the treatment of inflammatory pain, particularly chronic inflammatory pain.

[0039] Further embodiments provide HCN2 inhibitors for use in the treatment of tinnitus or related disorders. In some embodiments of this embodiment, the HCN2 inhibitor is a peripherally restricting HCN2 inhibitor, such as ivabradine. In some embodiments, the HCN2 inhibitor of this embodiment is a compound of the present invention. Preferably, the HCN2 inhibitor is a peripherally restricting compound of the present invention. Thus, compounds of the present invention are also provided for use in the treatment or prevention of tinnitus or related disorders (e.g., Meniere's disease or hyperacusis). [Brief explanation of the drawing]

[0040] [Figure 1A] The HCN1 and HCN2 voltage step protocols used in Example 50A are shown below. [Figure 1B] The HCN4 voltage step protocol used in Example 50A is shown below. [Figure 2] The HCN current amplitude for Example 50B is shown. [Figure 3] The voltage protocol used for measuring the hERG signal in Example 51A is shown. [Figure 4] The voltage protocol used for measuring the hNav1.5 signal in Example 52A is shown. [Figure 5] Example 54 demonstrates the effect of pharmacological blockade of HCN2 ion channels using gap induction inhibition in the Acoustic Startle (GPIAS) test on tinnitus. [Figure 6] This example demonstrates the effect of HCN ion channel blockade on behavioral symptoms of tinnitus in the short-term (salicylate) model according to Example 54. [Figure 7] This example demonstrates the effect of HCN ion channel blockade on behavioral signs of tinnitus in the noise exposure model according to Example 54. [Figure 8] The effect of HCN2 gene deletion on the auditory brainstem response (ABR) threshold to pulsed sounds in Example 56 is shown. In Figure 8, the white circle data points are from auditory-targeted HCN2-deficient mice. The shaded data points are from wild-type (WT) mice. [Figure 9]This figure shows the mechanoanalgesic effect of the compound in Example 2 in a mouse neuropathic pain model tested using von Fleigh filaments. The compound in Example 2 showed complete analgesia at an intraperitoneal (ip) dose of 0.2 mg / kg. The effect is shown compared to the vehicle ("Veh") and ivabradine ("IVA") administered at 5 mg / kg ip. Significance over vehicle infusion is shown in the figure (*, p<0.05). The mechanical pain threshold on the y axis is shown normalized to baseline before partial sciatic nerve injury (PSNL) performed 5 days prior to testing the compound in this model. [Figure 10] This shows the effect of ivabradine intraperitoneal (ip) dose on heart rate (left axis, black circles) and inflammatory pain (right axis, white circles) in a formalin model of inflammatory pain in Black6 mice. [Figure 11] The effects of the compounds of Example 2 administered intraperitoneally (ip) at doses of 0.05, 0.1, and 0.2 mg / kg (Figure (A)) and 0.5, 1, and 2 mg / kg (Figure (B))) on heart rate in Black6 mice are shown. [Figure 12] This shows the mechanoanalgesic effect of the compound in Example 4 in a mouse neuropathic pain model tested using von Fley filaments. The compound was tested at 2 mg / kg intraperitoneal (ip) (Figure (A)) and 10 mg / kg intraperitoneal (ip) (Figure (B)) compared with ivabradine ("IVA") and vehicle control ("Veh") administered intraperitoneally (ip) at 5 mg / kg. The mechanical pain threshold on the y-axis is shown normalized to baseline before partial sciatic nerve injury (PSNL) performed 5 days prior to testing the compound in this model. The transverse dotted line shows the mechanical pain threshold in the contralateral (unoperated) limb. [Figure 13]The effect of the compound from Example 4, administered intraperitoneally (ip) at a dose of 2 mg / kg, on bradycardia as a percentage of baseline heart rate in Black6 mice is shown. The compound was compared with ivabradine ("IVA") and a vehicle control ("Veh") administered intraperitoneally (ip) at a dose of 5 mg / kg. [Modes for carrying out the invention]

[0041] definition Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below.

[0042] As used herein, "HCN2" refers to "hyperpolarization-activated cyclic nucleotide-dependent potassium and sodium channel 2". The reference sequence of the full-length human HCN2 mRNA transcript is available from the GenBank database under accession number NM_001194, version NM_001194.3.

[0043] The terms "compound of the present invention," "HCN2 inhibitor of the present invention," and "HCN2 blocker of the present invention" refer to a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, including any of the examples listed herein.

[0044] The terms “to treat” or “treatment” refer to any indication of success in treating or improving a disease, condition, or pathology, including any objective or subjective parameter, such as reduction; remission; decrease of symptoms or making the condition or pathology more tolerable to the patient; slowing the rate of degeneration or debilitation; making the final stage of degeneration less debilitating; or improving the patient’s physical or mental health. For example, certain methods described herein treat pain, particularly inflammatory pain and / or neuropathic pain, by reducing the symptoms of pain. The terms “to treat” and their conjugations refer to the prevention of a condition, pathology, or disease (for example, preventing the onset of one or more symptoms of inflammatory pain or neuropathic pain).

[0045] In the context of substances or the activity or function of substances related to a disease or condition, the terms “related” or “associated with” mean that the disease or condition is caused (whole or in part) by the substance or the activity or function of the substance, or that the symptoms of the disease or condition are caused (whole or in part) by it. For example, symptoms of a disease or condition related to HCN2 channel activity may be symptoms caused (whole or in part) by an increase in the level of HCN2 channel activity or an increase in channel expression. When used herein, anything described as related to a disease may be a causative substance or a target for the treatment of the disease. For example, a disease related to an increase in the level of HCN2 channel activity may be treated with an agent effective in reducing the level of HCN2 channel activity (e.g., a compound described herein).

[0046] In this specification, terms such as “inhibit,” “block,” “block,” or “block” in relation to HCN2 inhibitors mean negatively affecting (e.g., reducing) the level of activity or function of the HCN2 channel (e.g., the components of the HCN2 channel compared to the level of activity or function of the channel in the absence of the inhibitor). In some embodiments, inhibition refers to a reduction in disease or symptoms of disease (e.g., pain associated with an increased level of HCN2 activity). In some embodiments, inhibition refers to a reduction in the level of channel current. For example, compounds of the present invention may bind to an HCN2 channel to produce an allosteric effect that blocks or prevents current flow through the channel or inhibits the action of the channel. Thus, inhibition may include blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing or downregulating channel activity or the amount of channel protein.

[0047] Throughout this specification and the claims, the terms “includes” and “contains” and their variations mean “includes, but not limited to,” and they are not intended to exclude (are not excluded) other parts, additives, components, integers, or processes. Throughout this specification and the claims, the singular includes the plural unless the context should interpret it otherwise. In particular, where the indefinite article is used, this specification should be understood to assume both the plural and singular forms unless the context should interpret it otherwise.

[0048] The term "halo" or "halogen" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine, chlorine, or bromine.

[0049] C m~n The term refers to a group having m to n carbon atoms.

[0050] "C 1~6The term "alkyl" refers to linear or branched hydrocarbon chains containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. 1~4 "Alkyl" similarly refers to such groups containing four or fewer carbon atoms. Alkylene groups are divalent alkyl groups and can similarly be linear or branched and may have two bonding sites to the rest of the molecule. Furthermore, alkylene groups may correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are listed below. Substituents for alkyl groups may be halogens, e.g., fluorine, chlorine, bromine and iodine, OH, C1-C4 alkoxys. Other substituents for alkyl groups may be used instead.

[0051] "C 1~6 "Haloalkyl", for example, "C 1~4 The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, such as fluorine, chlorine, bromine, and iodine, which is independently selected each time it appears. The halogen atom can be located at any position in the hydrocarbon chain. For example, C 1~6 Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloromethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl and 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoroethyl and 2-fluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl. Haloalkyl can be a fluoroalkyl, i.e., a hydrocarbon chain substituted with at least one fluorine atom.

[0052] "C 2~6The term "alkenyl" refers to a branched or linear hydrocarbon chain having 2, 3, 4, 5, or 6 carbon atoms and containing at least one double bond. The double bond may exist as an E or Z isomer. The double bond may be at any possible position in the hydrocarbon chain. For example, "C 2~6 "Alkenyl" can be etenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl.

[0053] "C 2~6 The term "alkynyl" includes a branched or linear hydrocarbon chain having 2, 3, 4, 5, or 6 carbon atoms and containing at least one triple bond. The triple bond can be at any possible position in the hydrocarbon chain. For example, "C 2~6 "Alkinyl" can be ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

[0054] "C 3~6 The term "cycloalkyl" includes saturated hydrocarbon ring systems containing 3, 4, 5, or 6 carbon atoms. For example, "C3-C6 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane, or bicyclo[1.1.1]pentane.

[0055] The terms "heterocyclyl," "heterocyclic," or "heterocyclic" refer to saturated or partially saturated 3- to 7-membered non-aromatic monocyclic or bicyclic groups that contain one, two, or three heteroatoms independently selected from O, S, and N in the ring system (in other words, one, two, or three atoms forming the ring system are selected from O, S, and N). Partial saturation means that the ring may contain one or two double bonds. This is especially true for monocyclic rings having 5 to 7 members. The double bond will typically be between two carbon atoms, but can be between a carbon atom and a nitrogen atom. Bicyclic systems can be spirocondensed, i.e., the rings are linked to each other via a single carbon atom; they can be closely condensed, i.e., the rings are linked to each other via two adjacent carbon or nitrogen atoms; or they can share a bridgehead, i.e., the rings are linked to each other via two non-adjacent carbon or nitrogen atoms. Examples of heterocyclic groups include oxylanyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and cyclic ethers such as substituted cyclic ethers. Heterocycles containing at least one nitrogen in the ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, and 2,5-diazabicyclo[2.2.1]heptanyl. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiolane, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Examples include tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide, as well as sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl.A preferred value for heterocyclyl groups having one or two oxo (=O) atoms, such as 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl. Specific heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranil, tetrahydropyranil, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As those skilled in the art will understand, any heterocycle can be linked to another group via any suitable atom, such as a carbon or nitrogen atom. For example, the terms “piperidinyl” or “morpholinyl” include piperidin-1-yl or morpholin-4-yl rings (i.e., piperidino or morpholino rings) linked via ring nitrogen, and the terms also include carbon-linked rings (e.g., piperidin-4-yl or morpholin-3-yl).

[0056] The term "bridged ring system" includes ring systems in which two rings share three or more atoms; see, for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992.

[0057] The term "spironicyclic ring system" includes ring systems in which two ring systems share one common spirocarbon atom, i.e., heterocycles are linked to further carbocyclic or heterocycles via a single common spirocarbon atom.

[0058] "Heterocyryl-C" m~n "Alkyl" is C m~n A heterocyclyl group covalently bonded to an alkylene group, both of which are defined herein; heterocyclyl-C m~nAlkyl groups are linked to the rest of the molecule via carbon atoms in the alkylene group. m~n "Alkyl", "Heteroaryl-C" m~n "Alkyl" is defined in the same way.

[0059] -C replaced with -NRR m~n "Alkyl" and "C substituted with -OR" m~n Similarly, "alkyl" is C m~n This refers to an -NRR or -OR group covalently bonded to an alkylene group, where the group is linked to the rest of the molecule via a carbon atom in the alkylene group.

[0060] "R 10 and R 11 The reference to "They form a 4-7 member heterocycline together with the nitrogen to which they are bound" is R 10 and R 11 This refers to the bonding of two nitrogen atoms to the same nitrogen atom, forming a nitrogen-linked heterocycline. For example, the group-NR 10 R 11 These can form, for example, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, or morpholine-4-yl groups.

[0061] When the term "aromatic" is applied to substituents as a whole, it includes monocyclic or polycyclic ring systems having 4n+2 electrons in the conjugated π system within the ring or ring system, where all atoms contributing to the conjugated π system are in the same plane.

[0062] The term "aryl" includes aromatic hydrocarbon ring systems. These ring systems have 4n+2 electrons in a conjugated π system within the ring, and all atoms contributing to the conjugated π system are in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0063] The term "heteroaryl" includes aromatic monocyclic or bicyclic rings incorporating one or more heteroatoms (e.g., 1 to 4, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. The ring or ring system has 4n+2 electrons in the conjugated π system, and all atoms contributing to the conjugated π system are in the same plane.

[0064] A heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring. The ring may contain about four or fewer heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain three or fewer heteroatoms, more commonly two or fewer, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or it may be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0065] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0066] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, and triazinyl.

[0067] The term "optionally substituted" includes any of the substituted groups, structures, or molecules, as well as those that are not substituted.

[0068] When any substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0069] If a portion is substituted, it can be substituted at any point in the portion that is chemically possible and satisfies the valence requirements. A portion can be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; optionally, there may be 1 or 2 substituents on the base. If there are two or more substituents, the substituents may be the same or different.

[0070] Substituents exist only where they are chemically possible, and those skilled in the art can determine, without undue effort (either experimentally or theoretically), whether their substitution is chemically possible or not.

[0071] Ortho, meta, and para substitutions are well understood terms in the art. To avoid misunderstanding, "ortho" substitution means: [ka] As indicated by the bond terminating at , this is a substitution pattern in which adjacent carbons have substituents, whether it is a single group or part of another molecule, such as the fluoro group in the example below. [ka]

[0072] A "meta" substitution is a substitution pattern where two substituents are located on carbon atoms separated by one carbon atom from each other; that is, there is a single carbon atom between the substituted carbons. In other words, the substituent is located on the second atom away from the atom with the other substituent. For example, the following groups are meta-substituted. [ka]

[0073] A "para" substitution is a substitution pattern where two substituents are located on carbon atoms separated by two carbon atoms from each other; that is, there are two carbon atoms between the substituted carbon atoms. In other words, the substituent is located on a third atom, away from the atom with the other substituent. For example, the following groups are para-substituted. [ka]

[0074] [ka] or * A bond ending with "" indicates that the bond is attached to another atom not shown in the structure. A bond ending within a cyclic structure and not with an atom in the cyclic structure indicates that the bond could be attached to any of the atoms in the cyclic structure, provided the valence allows it.

[0075] Features, integers, properties, compounds, chemical parts, or groups described in conjunction with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, provided they are not incompatible. All features and / or steps of any method or process disclosed herein (including any appended claims, abstract, and drawings) can be combined in any combination, except in any combination in which at least some of such features and / or steps are incompatible. The present invention is not limited to the details of any of the embodiments described above. The present invention extends to any novel one or any novel combination of any features and / or steps of any method or process disclosed herein (including any appended claims, abstract, and drawings), or to any novel one or any novel combination of steps of any method or process disclosed herein.

[0076] The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application and published herein, and the contents of all such papers and documents are incorporated herein by reference.

[0077] The various functional groups and substituents constituting the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More commonly, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525, for example 500 or less.

[0078] Any preferred or desirable feature of any compound in the present invention may also be a preferred feature of any other embodiment.

[0079] This invention envisions pharmaceutically acceptable salts of the compounds of the present invention. These may include acid additions and base salts of the compounds.

[0080] A suitable acid addition salt is formed from an acid that forms a non-toxic salt. Examples include acetate, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesilate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0081] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Half-salts of acids and bases, such as half-sulfates and half-calcium salts, may also be formed. For an overview of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0082] A pharmaceutically acceptable salt of the compound of the present invention can be prepared, for example, by one or more of the following methods: (i) by reacting the compound of the present invention with a desired acid or base; (ii) by removing an acid or base instability protecting group from a suitable precursor of the compound of the present invention, or by opening the ring of a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) By converting one salt of the compound of the present invention to another salt by reaction with a suitable acid or base or by using a suitable ion exchange column.

[0083] These methods are typically carried out in solution. The resulting salt can be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to nearly non-ionized.

[0084] Compounds having the same molecular formula but differing in the bonding properties or arrangement of their atoms or their spatial arrangement are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, it may be bonded to four different groups, resulting in a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their chiral center, described by Cahn and Prelog's R and S order rules or by the way the molecule rotates its plane of polarization, and are expressed as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." If the compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is possible. A combination of (R) and (S) stereoisomers may result in a diastereomer mixture or a single diastereomer. The compounds of the present invention may exist as a single stereoisomer or as a mixture of stereoisomers, e.g., a racemic mixture and a mixture of other enantiomers and a mixture of diastereomers. If the mixture is a mixture of enantiomers, the enantiomer excess may be any of those disclosed above. If the compound is a single stereoisomer, the compound may further contain other diastereoisomers or enantiomers as impurities. Therefore, a single stereoisomer does not necessarily have a 100% enantiomer excess (ee) or diastereomer excess (de), but may have at least about 85% ee or de.

[0085] The compounds of the present invention may have one or more chiral centers; therefore, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise specified, the descriptions or nomenclature of specific compounds in this specification and claims are intended to include both individual enantiomers and mixtures thereof, racemates, or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or separation of racemic forms (see the description in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomer centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that have HCN2 inhibitory activity.

[0086] Z / E (e.g., cis / trans) isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0087] If necessary, conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using chiral high-performance liquid chromatography (HPLC) or chiral supercritical fluid chromatography (SFC). Thus, the chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form by chromatography, typically HPLC, in an asymmetric resin having a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50 volume% isopropanol, typically 2-20% and in specific examples 0-5 volume% alkylamine, e.g., 0.1% diethylamine. Alternatively, when chiral SFC is used in a supercritical fluid, CO2 is generally used as the mobile phase. The properties of the supercritical fluid can be modified by including one or more cosolvents, e.g., methanol, ethanol or isopropanol, acetonitrile or ethyl acetate or other alcohols. The enriched mixture is obtained by concentration of the eluate.

[0088] Alternatively, the racemate (or racemate precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of the present invention contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomer mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. Enantiomers of a compound can also be prepared using a chiral auxiliary group during the synthesis of the compound, in which a suitable chiral intermediate is reacted with the intermediate of the compound, and then one or more diastereoselective conversions are performed. The resulting diastereomers are then separated using conventional methods such as those described above, and then the chiral auxiliary group is removed to obtain the desired enantiomer.

[0089] When any racemic mixture crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemic mixture) mentioned above, in which a single homogeneous form of crystal containing both enantiomers is produced in equimolar amounts. The second type is a racemic mixture or aggregate, in which two forms of crystals, each containing a single enantiomer, are produced in equimolar amounts.

[0090] While both crystalline forms present in a racemic mixture may have identical physical properties, they can also have different physical properties compared to a true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art—see, for example, “Stereochemistry of Organic Compounds” by ELEliel and SHWilen (Wiley, 1994).

[0091] The compounds and salts described herein may be isotope-labeled (or "radioactively labeled"). Thus, one or more atoms may be substituted with atoms having atomic masses or mass numbers different from those typically found in nature. Examples of radionuclides that may be incorporated include: 2 H (also written as "D" in the case of deuterium), 3 H (also written as "T" in the case of tritium), 11 C, 13 C, 14 C, 15 O, 17 O, 18 O, 13 N, 15 N, 18 F, 36 Cl, 123 I, 25 I, 32 P, 35 Examples include S. The radionuclides used will depend on the specific application of the radiolabeled derivative. For example, in an in vitro competitive assay, 3 H or 14 C is often useful. In radioimaging applications, 11 C or 18F is often useful. In one embodiment, the radionuclide is 3 It is H. In one embodiment, the radioactive nuclide is 14 It is C. In one embodiment, the radionuclide is 11 It is C. Furthermore, in one embodiment, the radionuclide is 18 It is F.

[0092] Isotope-labeled compounds can generally be prepared by methods similar to those described, using appropriate isotope-labeled reagents instead of conventional techniques known to those skilled in the art or previously used unlabeled reagents.

[0093] Selective substitution of hydrogen atoms with deuterium in a compound can modulate the metabolism, PK / PD properties, and / or toxicity of the compound. For example, deuteration can increase the half-life or decrease the clearance of the compound in vivo. Deuteration can also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It should be understood that the present invention encompasses deuterated derivatives of the compound of formula (I). As used herein, the term deuterated derivative refers to the compound of the present invention in which at least one hydrogen atom is substituted with deuterium at a particular position. For example, C 1~4 -One or more hydrogen atoms in the alkyl group are substituted with deuterium, resulting in deuterated C 1~4 -Alkyl groups, such as CD3, may be formed.

[0094] The specific compounds of the present invention may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms or pharmaceutically acceptable salts thereof that have HCN2 inhibitory activity.

[0095] Certain compounds of the present invention may exhibit polymorphism, and it should be understood that the present invention also encompasses all such forms having HCN2 inhibitory activity.

[0096] The compounds of the present invention may exist in several different tautomers, and references to the compounds of the present invention include all such forms. To avoid misunderstanding, if a compound may exist in one of several tautomers and only one is specifically described or indicated, all others are nevertheless encompassed by the compounds of the present invention. Examples of tautomers include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / aci-nitro, as well as the keto, enol, and enolate forms. [ka]

[0097] The in vivo effect of the compound of the present invention may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compound of the present invention.

[0098] It should be further understood that preferred pharmaceutically acceptable prodrugs of the compound of formula (I) also form an embodiment of the present invention. Thus, the compounds of the present invention encompass prodrug forms of the compounds, and the compounds of the present invention may be administered in prodrug form, i.e., compounds that are broken down in the human or animal body to release the compounds of the present invention. Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs may be formed if the compounds of the present invention contain preferred groups or substituents to which character-modifying groups can be bonded. Examples of prodrugs include bio-cleavable ester derivatives that can be formed at carboxyl or hydroxyl groups in the compounds of the present invention and bio-cleavable amide derivatives that can be formed at carboxyl or amino groups in the compounds of the present invention.

[0099] Accordingly, the present invention includes the compounds of the present invention as defined herein, when made available by organic synthesis and when made available in the human or animal body by cleavage of its prodrug. Accordingly, the present invention includes the compounds of formula (I) produced by organic synthesis means and such compounds produced in the human or animal body by metabolism of precursor compounds, i.e., the compounds of formula (I) may be synthetically produced compounds or metabolically produced compounds.

[0100] A suitable pharmaceutically acceptable prodrug of the compound of the present invention is one that, based on reasonable medical judgment, is suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity.

[0101] Various forms of prodrugs are described in the following literature, for example: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0102] compound In one embodiment, the compound of formula (I) is of formula (II): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the compound of formula (I) is of formula (III): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment, the compound of formula (I) is of formula (IV): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0105] In one embodiment, the compound of formula (I) is of formula (V): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0106] In one embodiment, the compound of formula (I) is of formula (VI): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0107] In one embodiment, the compound of formula (I) is of formula (VII): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the compound of formula (I) is of formula (VIII): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the compound of formula (I) is of formula (IX): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0110] The specific compounds of the present invention include, for example, compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or pharmaceutically acceptable salts thereof, in which formulas, unless otherwise specified, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 32 , R 33 , R 81 , R 82 , R 9 , R 10 Each of X1, X2, X3, n, and m has one of the meanings defined above or in one or more of the following paragraphs (1) to (135).

[0111] 1. X1 is CR 1 And R 1 H, Halo, -CN, C 1~4 Alkyl, C1~4 Haloalkyl, -OR B1 , C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~3 Selected from alkyl-, R 1 The alkyl, alkenyl, alkynyl, or cycloalkyl group in the above is a halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B2 It is optionally substituted with 1 to 4 substituents that are independently selected from the original molecule.

[0112] 2.X1 is CR 1 And R 1 is, Haro, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR B1 , C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~3 Selected from alkyl-, R 1 The alkyl, alkenyl, alkynyl, or cycloalkyl group in the above is a halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B2 It is optionally substituted with 1 to 4 substituents that are independently selected from the original molecule.

[0113] 3.X1 is CR 1 And R 1 is, Haro, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~5 Cycloalkyl, C 3~5 Cycloalkyl-C 1~3 Selected from alkyl-, the alkyl or cycloalkyl group is a halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B2 It is optionally substituted with 1 to 4 substituents that are independently selected from the original molecule.

[0114] 4.X1 is CR 1 And R 1 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B1 Selected from, R 1 The alkyl group in the above is -OR B2 It is optionally replaced.

[0115] 5.X1 is CR 1 And R 1 is, Haro, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B1 Selected from, R 1 The alkyl group in the above is -OR B2 It is optionally replaced.

[0116] 6.X1 is CR 1 And R 1 The following are selected from H, F, Cl, Br, -CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methoxymethyl, 1-methoxyethyl, and 2-methoxyethyl.

[0117] 7.X1 is CR 1 And R 1 H, Halo, -CN, C 1~3 Alkyl, C 1~3 Haloalkyl and -OR B1 Selected from.

[0118] 8.X1 is CR 1 And R 1 H, Halo, -CN, C 1~3 Alkyl and C 1~3 Selected from haloalkyls (e.g., R 1 H, Halo, -CN, C 1~3 (Selected from alkyl and -CF3).

[0119] 9.X1 is CR 1 And R 1 The element is selected from H, halo, -CN, methyl, ethyl, isopropyl, and methoxy.

[0120] 10.X1 is CR 1 And R 1 The element is selected from H, halo, -CN, methyl, and ethyl.

[0121] 11. X1 is CH.

[0122] 12.X1 is CR 1 And R 1 It is -CN.

[0123] 13.X1 is CR 1 And R 1 This is a halo (for example, F, Cl, or Br).

[0124] 14.X1 is CR 1 And R 1 C 1~3 It is an alkyl group (for example, methyl).

[0125] 15.X1 is CR 1 And R 1 It is -CF3.

[0126] 16.X 1 is N or CR 1 And R 1 This is defined in any of paragraphs (1) through (15).

[0127] 17. X1 is N.

[0128] 18.R 2 Each time it appears independently, Halo, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0129] 19.R 2 This is Halo and C 1~3Selected from alkyl groups.

[0130] 20.R 2 This is selected from F, Cl, Br, and methyl.

[0131] 21.R 2 C 1~3 It is an alkyl group (for example, methyl).

[0132] 22.R 2 It is selected from F, Cl, and Br.

[0133] 23.R 2 This is selected from F and Cl.

[0134] 24.m is 0.

[0135] 25.m is 0, and X1 is as defined in any of (1) to (15).

[0136] 26.m is 0, and X1 is CH.

[0137] 27.m is 1.

[0138] 28.m is 1, R 2 This is defined in any of (18) to (23).

[0139] 29.R 3 Each time it appears independently, Halo, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0140] 30.R 3 Each of these appears independently, with Halo and C 1~3 Selected from alkyl groups.

[0141] 31.R 3 Each of these is independently selected from F, Cl, Br, methyl, ethyl, and isopropyl, each time it appears.

[0142] 32.R 3 Each of these elements is independently selected from F, Cl, Br, and methyl, each time it appears.

[0143] 33.n is either 0 or 1.

[0144] 34.n is 0 or 1, R 3 This is defined in any of (29) to (32).

[0145] 35.n is 1.

[0146] 36.n is 1, R 3 This is defined in any of (29) to (32).

[0147] 37.n is 0.

[0148] 38.X2 is CR 32 And R 32 Hello, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0149] 39.X2 is CR 32 And R 32 This is Halo and C 1~3 Selected from alkyl groups.

[0150] 40.X2 is CR 32 And R 32 This is selected from F, Cl, and methyl.

[0151] 41.X3 is CR 33 And R 33 Hello, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0152] 42.X3 is CR 33 And R 33 This is Halo and C 1~3Selected from alkyl groups.

[0153] 43.X3 is CR 33 And R 33 This is selected from F, Cl, and methyl.

[0154] 44. X2 is N, and X3 is CR 33 And R 33 This is Halo and C 1~3 Selected from alkyl groups.

[0155] 45.X2 is CR 32 And X3 is CR 33 That is the case.

[0156] 46.X2 is CR 32 And X3 is CR 33 And R 32 and R 33 This is defined in any of (38) to (43).

[0157] 47. Both X2 and X3 are CH.

[0158] 48.R 4 , R 5 and R 6 These are H and C, respectively, independently. 1~3 Selected from alkyl groups, or R 5 and R 6 These, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0159] 49.R 4 is either H or methyl.

[0160] 50.R 4 H is H.

[0161] 51.R 5 and R 6 These are H and C, respectively, independently. 1~3 Selected from alkyl groups.

[0162] 52.R 5 H is R 6 H and C 1~3 Selected from alkyl groups.

[0163] 53.R 5 H is R 6 C 1~3 It is an alkyl group (for example, methyl).

[0164] 54.R 5 and R 6 H is H.

[0165] 55.R 4 and R 5 H is R 6 C 1~3 It is alkyl (for example, methyl or ethyl).

[0166] 56.R 4 , R 5 and R 6 H is H.

[0167] 57.R 4 , R 5 and R 6 One of them is C 1~3 It is an alkyl group (for example, methyl), and the other two groups are H.

[0168] 58.R 9 These are H, Halo, -CN and C 1~4 Selected from alkyl groups.

[0169] 59.R 9 H, -CN and C 1~4 Selected from alkyl groups.

[0170] 60.R 9 H and C 1~4 Selected from alkyl groups.

[0171] 61.R 9 H is H.

[0172] 62.R 9 C 1~4 It is alkyl.

[0173] 63.R 9 These are methyl, ethyl, propyl, or isopropyl.

[0174] 64.R 9 It is -CN.

[0175] 65.R 7 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~5 Cycloalkyl, -N(R A4 )C(O)R B4 and -C(O)R B4 Selected from.

[0176] 66.R 7 is, Haro, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~5 Cycloalkyl, -N(R A4 )C(O)R B4 and -C(O)R B4 Selected from.

[0177] 67.R 7 -CN, -N(R A4 )C(O)R B4 and -C(O)R B4 Selected from.

[0178] 68.R 7 H, halo and C 1~4 Selected from alkyl groups.

[0179] 69.R 7 C 1~4 These are haloalkyl groups (e.g., -CF3, -CH2F, -CHF2, or -CH2CF3).

[0180] 70.R 7 This is Halo and C 1~3Selected from alkyl groups.

[0181] 71.R 7 This is selected from F and methyl.

[0182] 72.R 7 This is a halo (for example, F).

[0183] 73.R 7 C 1~3 It is alkyl (for example, methyl or ethyl).

[0184] 74.R 7 H is H.

[0185] 75.R 8 These appear independently, each time representing H, Halo, -CN, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenil, C 2~4 Alkinyl, -OR 10 , -NR 10 R 11 , -S(O) x R 10 (where x is 0, 1, or 2, preferably 1 or 2), -C(O)R 10 -C(O)NR 10 R 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)NR 10 R 11 , -N(R 11 )C(O)OR 10 , -N(R 11 )SO2R 10 -SO2NR 10 R 11 , C 3~6 Selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl; The alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl group has 1 to 4 R 12 The group is optionally substituted with a group, and the phenyl or heteroaryl group has 1 to 4 R13 It is optionally substituted in the base.

[0186] 76.R 8 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 10 , -NR 10 R 11 -S(O)2R 10 -C(O)NR 10 R 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)NR 10 R 11 , -N(R 11 )C(O)OR 10 , -N(R 11 )SO2R 10 , C 3~6 Selected from cycloalkyls, 4-6 membered heterocyclines, and 5- or 6 membered heteroaryls containing one or two ring nitrogen atoms; The alkyl, cycloalkyl, or heterocyclyl group comprises 1 to 4 R 12 The group is optionally substituted with a group, and the heteroaryl group has 1 to 4 R 13 It is optionally substituted in the base.

[0187] 77.R 8 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 10 -S(O)2R 10 -C(O)NR 10 R 11 , C 3~5 Selected from cycloalkyls, 4-6 membered heterocyclines and heteroaryls containing one ring nitrogen atom and one further ring heteroatom optionally selected from O, S, and N, wherein the heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; The alkyl, cycloalkyl, or heterocyclyl group comprises 1 to 4 R 12The group is optionally substituted with a group, and the heteroaryl group has 1 to 4 R 13 It is optionally substituted in the base.

[0188] 78.R 8 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 10 -S(O)2R 10 -C(O)NR 10 R 11 , C 3~5 Selected from cycloalkyls, 4-6 membered heterocyclils, and heteroaryls, wherein the heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl, and the 4-6 membered heterocyclil is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; The alkyl, cycloalkyl, or heterocyclyl group comprises 1 to 4 R 12 The group is optionally substituted with a group, and the heteroaryl group has 1 to 4 R 13 It is optionally substituted in the base.

[0189] 79.R 8 H, Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10 , -NR 10 R 11 , -S(O) x R 10 (where x is 0, 1, or 2, preferably 1 or 2), -C(O)NR 10 R 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)NR 10 R 11 , -N(R 11 )C(O)OR 10 -SO2NR 10 R 11 and -N(R 11 )SO2R 10 Selected from; The aforementioned alkyl group is HAL, -CN, -OR B5 , -NR A5 R A5 -S(O)2R B5 , -C(O)R B5 , -NR A5 C(O)R B5 -C(O)NR A5 R A5 , -NR A5 SO2R B5 and -SO2NR A5 R A5 It is optionally substituted with one or two substituents selected from the following.

[0190] 80.R 8 The heteroaryl is selected from 4-6 membered heterocyclyls and heteroaryls, wherein the heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl and isoxazolyl; the heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; The aforementioned 4-6 member heterocyclyl group is a halo, C 1~4 Optionally substituted with 1 to 4 groups independently selected from alkyl, -OH, and =O; The aforementioned heteroaryl group is a halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR B6 and -NR A6 R A6 It is arbitrarily substituted with 1 to 4 groups selected independently of it.

[0191] 81.R 8 The heteroaryl is selected from a 4 or 5-membered heteroaryl, and the heteroaryl is a halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR B6 and -NR A6 R A6 It is arbitrarily substituted with 1 to 4 groups selected independently of it.

[0192] 82.R 8 -CN, -OR 10, -NR 10 R 11 -S(O)2R 10 -C(O)NR 10 R 11 -SO2NR 10 R 11 , -C 1~4 Alkyl-CN, -C 1~4 Alkyl-OR B5 , -C 1~4 Alkyl-NR A5 R A5 , -C 1~4 Alkyl-S(O)2R B5 , -C 1~4 Alkyl-C(O)NR A5 R A5 and -C 1~4 Alkyl-SO2NR A5 R A5 Selected from.

[0193] 83.R 8 -CN, -OR 101 , -NR 101 R 111 -S(O)2R 112 -C(O)NR 101 R 111 -SO2NR 101 R 111 , -C 1~4 Alkyl-CN, -C 1~4 Alkyl-OR B5 , -C 1~4 Alkyl-NR A5 R A5 , -C 1~4 Alkyl-S(O)2R B5 , -C 1~4 Alkyl-C(O)NR A5 R A5 and -C 1~4 Alkyl-SO2NR A5 R A5 Selected from; R 101 H, C 1~3 Alkyl and C 1~6 Selected from cycloalkyl; R 111 H and C are independent of each other. 1~3 Selected from alkyl; R 112 C 1~4It is alkyl.

[0194] 84.R 8 Each instance of these appears independently as Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkyl-OR B5 , -C 1~3 Alkyl-C 3~6 Cycloalkyl, -C 1~4 Alkyl-NR A5 C(O)R B5 , -C 1~4 Alkyl-C(O)NR A5 R A5 , -C 1~4 Alkyl-NR A5 SO2R B5 , -C 1~4 Alkyl-SO2NR A5 R A5 -OH, -OC 1~4 Alkyl, -OC 2~4 Alkyl-OR B5 -OC 2~4 Alkyl-NR A5 R A5 -NH2, -N(R 11 )C 1~4 Alkyl, -N(R 11 )C 2~4 Alkyl-OR B5 , -N(R 11 )C 2~4 Alkyl-NR A5 R A5 -S(O)2C 1~4 Alkyl, -C(O)NH2, -C(O)N(R) 11 )C 1~4 Alkyl, -C(O)N(R 11 )C 1~4 Alkyl-C 3-6 Cycloalkyl, -C(O)N(R 11 )C 2~4 Alkyl-OR B5 ,-C(O)N(R 11 )C 2~4 Alkyl-NR A5 R A5Azetidine-1-yl-C(O)-, pyrrolidine-1-yl-C(O)-, piperidine-1-yl-C(O)-, piperazine-1-yl-C(O)-, morpholine-1-yl-C(O)-, -N(R 11 )C(O)-C 1~4 Alkyl, -N(R 11 )C(O)NH2, -N(R 11 )C(O)NH(C 1~4 Alkyl), -N(R 11 )C(O)N(C 1~4 Alkyl)2,-N(R 11 )C(O)O(C 1~4 Alkyl), -N(R 11 )SO2(C 1~4 Alkyl), C 3~6 Selected from cycloalkyls, 4-6 membered heterocyclyls, and heteroaryls, wherein the heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl, and the heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; Said C 3~6 Cycloalkyl or 4-6 membered heterocyclyl groups are halos, C 1~4 Optionally substituted with 1 to 4 groups independently selected from alkyl, -OH, and =O; The aforementioned heteroaryl group is a halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR B6 and -NR A6 R A6 It is arbitrarily substituted with 1 to 4 groups selected independently of it.

[0195] 85.R 8 -C(O)NH2, -C(O)N(H)C 1~3 Alkyl and -C(O)N(C 1~3 Selected from alkyl)2.

[0196] 86.R 8 is -S(O)2R 10 For example, -S(O)2C 1~4 Alkyl or -S(O)2C3~6 Selected from cycloalkyl groups.

[0197] 87.R 8 is -S(O)2C 1~4 Alkyl, preferably selected from -S(O)2Me.

[0198] 88.R 8 H, Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkyl-OR B5 -OH, -OC 1~4 Alkyl, -OC 2~4 Alkyl-OR B5 , -C(O)C 1~4 Alkyl, -S(O)2C 1~4 Alkyl, -C(O)NH2, -C(O)N(H)C 1~4 Alkyl and -C(O)N(C 1~4 Selected from alkyl)2.

[0199] 89.R 8 H, halogen (e.g., F, Cl, Br), -CN, C 1~4 Selected from alkyl, -CH2CH2-OH, -CH2CH2-OMe, -OCH2CH2-OH, -OCH2CH2-OMe, -S(O)2Me, -C(O)NH2, -C(O)N(H)Me, and -C(O)N(Me)2.

[0200] 90.R 8 Each of these elements is independently selected from halo (e.g., F or Br), -CN, methyl, ethyl, methoxy, -S(O)2Me, and -CF3, each time it appears.

[0201] 91.R 8 Each of these elements is independently selected from halo (e.g., F or Br), -CN, methyl, ethyl, and -S(O)2Me, each time it appears.

[0202] 92.R 8 Each of these is independently selected from -CN, methyl, ethyl, and -S(O)2Me, each time it appears.

[0203] 93.R 8 C 1~4 It is alkyl.

[0204] 94.R 8 It is -CN.

[0205] 95.R 8 This is a halo (for example, F, Cl, or Br).

[0206] 96.R 8 H is H.

[0207] 97.R 81 and R 82 These are H, Halo, and C, independently. 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 Selected from haloalkyl groups.

[0208] 98.R 81 and R 82 These are H, Halo, and C, independently. 1~4 Alkyl, -CF3, and -OC 1~4 Selected from alkyl groups.

[0209] 99.R 81 and R 82 These are H, Halo, and C, independently. 1~3 Selected from alkyl, -CF3, and -OCH3.

[0210] 100.R 81 H is R 82 Hello, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 Selected from haloalkyl groups.

[0211] 101.R 81 H is R 82 Hello, C 1~4Alkyl, -CF3, and -OC 1~4 Selected from alkyl groups.

[0212] 102.R 81 H is R 82 The compound is selected from halo (e.g., F), methyl, -CF3, and -OMe.

[0213] 103.R 81 H is R 82 It is a halo.

[0214] 104.R 81 H is R 82 C 1~4 It is alkyl.

[0215] 105.R 82 H is R 81 Hello, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 Selected from haloalkyl groups.

[0216] 106.R 82 H is R 81 Hello, C 1~4 Alkyl, -CF3, and -OC 1~4 Selected from alkyl groups.

[0217] 107.R 82 H is R 81 The compound is selected from halo (e.g., F), methyl, -CF3, and -OMe.

[0218] 108.R 82 H is R 81 It is a halo.

[0219] 109.R 82 H is R 81 C 1~4 It is alkyl.

[0220] 110.R81 It is a halo.

[0221] 111.R 81 H is H.

[0222] 112.R 82 It is a halo.

[0223] 113.R 82 H is H.

[0224] 114.R 82 and R 81 H is H.

[0225] 115.R 81 Hello, C 1~4 Alkyl, -CF3, and -OC 1~4 Selected from alkyl; R 82 H is; R 7 This is H, Halo, -CF3, or C 1~3 It is alkyl; R 8 This is defined in any of (75) to (96).

[0226] 116.R 81 Hello, C 1~4 Alkyl, -CF3, and -OC 1~4 Selected from alkyl; R 82 H is; R 7 H or C 1~3 It is alkyl; R 8 This is defined in any of (75) to (96).

[0227] 117.R 81 is a halo; R 82 H is; R 7 H or C 1~3 It is alkyl; R 8 This is defined in any of (75) to (96).

[0228] 118.R 82 Hello, C 1~4 Alkyl, -CF3, and -OC1~4 Selected from alkyl; R 81 H is; R 7 This is H, Halo, -CF3, or C 1~3 It is alkyl; R 8 This is defined in any of (75) to (96).

[0229] 119.R 82 Hello, C 1~4 Alkyl, -CF3, and -OC 1~4 Selected from alkyl; R 81 H is; R 7 H or C 1~3 It is alkyl; R 8 This is defined in any of (75) to (96).

[0230] 120.R 10 These appear independently, each time H and C appear. 1~4 Selected from alkyl groups, wherein the alkyl group is halo, -CN, or -OR B5 and -NR A5 R A5 It is optionally replaced by; R 11 These appear independently, each time H and C appear. 1~4 Selected from alkyl groups; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-6 membered heterocycline selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, and the heterocycline is halo, =O,C 1~4 Alkyl, C 1~4 Haloalkyl and -OR B7 It is optionally substituted with one or two substituents selected from the following.

[0231] 121.R 10 and R 11 These appear independently, each time H and C appear. 1~4 Selected from alkyl groups.

[0232] 122.X1 CR 1 And R 1 C 1~6 If it is a haloalkyl (e.g., -CF3), then R 8 is -SO2R 10 isn't it.

[0233] 123.X 1 CR 1 And; R 1 C 1~6 It is a haloalkyl (e.g., -CF3); R 8 H, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -OC 2~4 alkyl-OH, -OC 2~4 Alkyl-OMe, -NH2, -N(H)C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 1~4 Alkyl-OR B5 , -C 1~4 Alkyl-NR A5 R A5 , C 3~6 Selected from cycloalkyls, 4- to 6-membered heterocyclines, and 5 or 6-membered heteroaryls; Said C 3~6 Cycloalkyl or 4-6 membered heterocyclyl groups are C 1~4 Optionally substituted with 1 to 4 groups independently selected from alkyl, -OH, and =O; The aforementioned heteroaryl group is C 1~4 Alkyl, -OR B6 and -NR A6 R A6 It is arbitrarily substituted with 1 to 4 groups selected independently of it.

[0234] 124.X 1 CR 1 And; R 1 C 1~4 It is a haloalkyl group (e.g., -CF3), and R 8 H, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -OC 2~4Alkyl-OR B5 and -C 1~4 Alkyl-OR B5 Selected from.

[0235] 125.R 7 , R 8 , R 81 and R 82 H is H.

[0236] 126.R 7 , R 8 , R 81 and R 82 is H; X1 is CR 1 And R 1 It is a halo.

[0237] 127.R 7 , R 8 , R 81 and R 82 At least one of them is not H.

[0238] 128.X2 is CR 32 And X3 is R 33 And R 7 , R 8 , R 81 and R 82 At least one of them is Halo, C 1~4 Alkyl and C 1~4 Selected from haloalkyl groups.

[0239] 129.R 81 is a halo (for example, F), and R 7 C 1~3 It is alkyl.

[0240] 130.R 7 C 1~3 Selected from alkyl and halo; R 8 H, C 1~3 Selected from alkyl and -CN.

[0241] 131.R 7 C 1~3 Selected from alkyl and halo; R8 H, C 1~3 Selected from alkyl and -CN; X2 is N.

[0242] 132.X1 is CR 1 And R 1 n is selected from H and a halo (e.g., F, Cl, or Br); n is 0; R 4 , R 5 and R 6 is H; X3 is CH; R 7 is selected from H, F, or Me; R 8 H, -CN, C 1~3 Alkyl, 2-hydroxyethyl, 2-methoxyethyl, and -S(O)2C 1~3 Selected from alkyl; R 82 is selected from H and F; R 81 H is H.

[0243] 133. One or more hydrogen atoms in a compound are deuterium.

[0244] 134. group [ka] teeth, [ka] (In the formula, * (This indicates the bond point to the rest of the molecule.) Selected from.

[0245] 135. group [ka] is, formula [ka] It belongs to them.

[0246] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein, X1 is CR1 and; R 1 is selected from H, halo, -CN, C 1~4 alkyl and C 1~4 haloalkyl; m is 0 or 1; R 2 is selected from halo, C 1~4 alkyl and C 1~4 haloalkyl; R 9 is selected from H and C 1~4 alkyl; X2 is CH or N; X3 is CR 33 and R 33 is selected from H, halo and C 1~4 alkyl; n is 0; R 4 and R 5 is H; R 6 is selected from H and methyl; R 81 and R 82 are each independently selected from H, halo, C 1~4 alkyl, C 1~4 haloalkyl and -OC 1~4 alkyl (e.g., selected from H, halo or C 1~3 alkyl); R 7 is as defined in any one of paragraphs (65) to (74) above; R 8 is as defined in any one of paragraphs (75) to (96) above) is provided.

[0247] In this embodiment, R 1 may be selected from H and halo.

[0248] In this embodiment, R 1 may be H.

[0249] In this embodiment, R1 This may be a halo (for example, F, Cl, or Br).

[0250] In this embodiment, m may be 0.

[0251] In this embodiment, X2 is N and X3 is CR 33 And R 33 H, halo and C 1~3 Selected from alkyl groups; n may be 0.

[0252] In this embodiment, R 7 H, halo and C 1~3 Alkyl compounds may be selected.

[0253] In this embodiment, R 8 H, Halo, -CN, C 1~4 Alkyl, -C 1~4 alkyl-OH, -C 1~4 Alkyl-OMe, -OC 2~4 alkyl-OH, -OC 2~4 Alkyl-OMe, -C(O)NH2, -C(O)N(H)C 1~3 Alkyl, -C(O)N(C 1~3 Alkyl)2 and -S(O)2C 1~4 Alkyl compounds may be selected.

[0254] In this embodiment, R 81 is a halo; R 82 H is; R 7 H or C 1~3 It is alkyl; R 8 This may be selected from any one of the above paragraphs (75) to (96) (for example, R 8 H, Halo, -CN, C 1~4 Alkyl, -C 1~4 alkyl-OH, -C 1~4 Alkyl-OMe, -OC 2~4 alkyl-OH, -OC 2~4 Alkyl-OMe, -C(O)NH2, -C(O)N(H)C 1~3alkyl, -C(O)N(C 1~3 alkyl)2 and -S(O)2C 1~4 selected from alkyl).

[0255] In this embodiment, X1 is CR 1 ; R 1 is selected from H, F, Cl and Br; n is 0; X2 is CH or N; and X3 may be CH.

[0256] In this embodiment, X1 is CR 1 ; R 1 is selected from H, F, Cl and Br; n is 0; X2 is CH or N; X3 is CH; R 7 is halo and C 1~3 selected from alkyl; R 81 and R 82 is H; R 8 may be selected from any one of paragraphs (75) to (96) above (for example, R 8 is selected from H, -CN, C 1~4 selected from alkyl and 2-hydroxyethyl).

[0257] In this embodiment, X1 is CR 1 ; R 1 is selected from H, F, Cl and Br; n is 0; X2 is CH or N; X3 is CH; R 7 is selected from H, halo and C 1~3 selected from alkyl; R 81 and R 82 is H; R 8 is -C 1~4 alkyl-OH, -C 1~4 alkyl-OMe, -O-C 2~4 alkyl-OH, -O-C 2~4 alkyl-OMe, -C(O)NH2, -C(O)N(H)C 1~3 alkyl, -C(O)N(C 1~3 alkyl)2 and -S(O)2C 1~4 may be selected from alkyl (for example, R 8is, Haro, -CN, C 1~4 (Selected from alkyl, 2-hydroxyethyl, and -S(O)2Me).

[0258] In this embodiment, X1 is CR 1 And; R 1 is selected from H, F, Cl and Br; n is 0; X2 is CH or N; X3 is CH; R 7 H, halo and C 1~3 Selected from alkyl; R 81 This is Halo and C 1~3 Selected from alkyl; R 82 H is; R 7 H and C 1~3 Selected from alkyl; R 8 This may be selected from any one of the above paragraphs (75) to (96) (for example, R 8 H, Halo, -CN, C 1~4 Alkyl, -C 1~4 alkyl-OH, -C 1~4 Alkyl-OMe, -OC 2~4 alkyl-OH, -OC 2~4 Alkyl-OMe, -C(O)NH2, -C(O)N(H)C 1~3 Alkyl, -C(O)N(C 1~3 Alkyl)2 and -S(O)2C 1~4 (Selected from alkyl groups).

[0259] In this embodiment, R 81 Hello, C 1~3 Alkyl, C 1~3 Haloalkyl and -OC 1~3 Selected from alkyl; R 82 H is; R 8 -CN and -S(O)2R 10 (For example, -S(O)2C 1~4 Selected from alkyl; R 7 It may have any of the values ​​in any one of the paragraphs (65) to (74) above.

[0260] In this embodiment, R 82Hello, C 1~3 Alkyl, C 1~3 Haloalkyl and -OC 1~3 Selected from alkyl; R 81 H is; R 8 -CN and -S(O)2R 10 (For example, -S(O)2C 1~4 Selected from alkyl; R 7 It may have any of the values ​​in any one of the paragraphs (65) to (74) above.

[0261] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein, R 1 H, halo and C 1~3 Selected from alkyl groups; m and n are 0; R 9 H and C 1~4 Selected from alkyl groups (preferably R 9 H is; X2 is selected from N and CH; X3 is CR 33 And R 33 H, halo and C 1~3 Selected from alkyl groups; R 4 and R 5 H is; R 6 is selected from H and methyl; Base: [ka] teeth, [ka] (In the formula, * (This indicates the bond point to the rest of the molecule.) (Selected from) It will be provided.

[0262] In this embodiment, R 1 is selected from H, F, Cl, and Br (for example, R1 (This may be H.)

[0263] In this embodiment, X2 may be N.

[0264] Compounds of formulas (II) and (III) In one embodiment, the compound of formula (I) is the compound of formula (II) as defined above or a pharmaceutically acceptable salt thereof. In the compound of formula (II) or formula (III), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 81 , R 82 , R 9 X2, X3, m, and n are as defined for compounds of formula (I), or, unless otherwise specified, have any of the values ​​defined herein, including one or more of (1) to (135) (to the extent that these paragraphs are applicable to compounds of formula (II) or (III)). The following embodiments relate to compounds of formula (II) or (III).

[0265] In one embodiment of a compound of formula (II) or (III), R 7 R may have any of the values ​​in any one of the paragraphs (65) to (74) above. 7 H, halo and C 1~3 Alkyl compounds may be selected.

[0266] In one embodiment of a compound of formula (II) or (III), R 8 R may have any of the values ​​in any one of the paragraphs (75) to (96) above. 8 These are H, -CN, and -S(O)2R 10 It may be selected from the following.

[0267] In one embodiment of a compound of formula (II) or formula (III), including the embodiments described above, R 81 and R 82 One is H, and the other is Halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OC 1~4 Selected from alkyl groups.

[0268] In one embodiment of a compound of formula (II) or formula (III), R 81 and R 82 One is H, and the other is Halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OC 1~4 Selected from alkyl; R 7 H, halo and C 1~3 Selected from alkyl; R 8 -CN and -S(O)2R 10 (For example, -S(O)2C 1~4 Selected from alkyl groups.

[0269] In one embodiment of a compound of formula (II) or formula (III), R 81 and R 82 Both are H.

[0270] In one embodiment of a compound of formula (II) or formula (III), including the embodiments described above, R 1 H, Halo, C 1~3 Alkyl and C 1~3 Selected from haloalkyl groups.

[0271] In a certain embodiment of the compound of formula (II) or formula (III), m is 0, and R 1 H, C 1~3 Selected from alkyl and -CN.

[0272] In one embodiment including the above embodiments, R 1 This is Halo and C 1~3 Selected from alkyl groups.

[0273] In one embodiment of a compound of formula (II) or formula (III), including the embodiments described above, R 1 is a halo (for example, R 1 (is F).

[0274] In one embodiment of a compound of formula (II) or formula (III), including the embodiments described above, R 1 H is H.

[0275] In one embodiment of a compound of formula (II) or formula (III), including the embodiments described above, R 7 H, halo and C 1~3 Selected from alkyl groups.

[0276] In one embodiment including the above embodiments, R 9 H is H.

[0277] In one embodiment of the compound of formula (III), including the above embodiment, R 33 It is not H.

[0278] In one embodiment of the compound of formula (III), including the above embodiment, R 33 This is Halo and C 1~3 Selected from alkyl. In one embodiment of the compound of formula (III), R 33 This is selected from F, Cl, Br, and methyl.

[0279] In one embodiment of a compound of formula (II) or (III), [ka] The basis of is [ka] It may be selected from; optionally, in this embodiment, m and n are 0; R 1This may be selected from H and halo (e.g., F or Br). Preferably, in this embodiment, R 4 , R 5 and R 9 H is R 6 is H or methyl. Preferably, in this embodiment, R in formula (III) 33 H or C 1~3 It is alkyl (for example, R 33 (is either H or methyl).

[0280] Compound of formula (IV) In one embodiment, the compound of formula (I) is the compound of formula (IV) as defined above or a pharmaceutically acceptable salt thereof. In the compound of formula (IV), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 81 , R 82 , R 32 , R 33 m and n are as defined for compounds of formula (I), or, unless otherwise specified, have any of the values ​​defined herein, including one or more of (1) to (135) (to the extent that those paragraphs are applicable to compounds of formula (IV)). The following embodiments relate to compounds of formula (IV).

[0281] In one embodiment of the compound of formula (IV), R 32 and R 33 H is , and n is 0.

[0282] In one embodiment of the compound of formula (IV), R 7 R may have any of the values ​​in any one of the paragraphs (65) to (74) above. 7 H, halo and C 1~3 Alkyl compounds may be selected.

[0283] In one embodiment of the compound of formula (IV), R 8 R may have any of the values ​​in any one of the paragraphs (75) to (96) above. 8 These are H, -CN, and -S(O)2R 10 It may be selected from R. 8 C 1~3 It may be alkyl.

[0284] In one embodiment of the compound of formula (IV), including the above embodiments, R 81 H, halo and C 1~3 Selected from alkyl; R 82 H is H.

[0285] In one embodiment of the compound of formula (IV), R 81 and R 82 H is H.

[0286] In one embodiment of the compound of formula (IV), R 81 Hello, C 1~4 Selected from alkyl and -CF3; R 82 H is H.

[0287] In one embodiment of the compound of formula (IV), R 82 Hello, C 1~4 Selected from alkyl and -CF3; R 82 H is H.

[0288] In one embodiment of the compound of formula (IV), including the above embodiments, R 8 H, -CN, C 1~4 Alkyl, -S(O)2R 10 (For example, -S(O)2C 1~4 Selected from alkyl; R 7 H, halo and C 1~3 Selected from alkyl groups. Preferably, in this embodiment, R 7 and R 8 It is impossible for both to be H.

[0289] In one embodiment of the compound of formula (IV), including the above embodiments, R 9 H is H.

[0290] Compounds of formulas (V) and (VI) In one embodiment, the compound of formula (I) is the compound of formula (V) or formula (VI) as defined above, or a pharmaceutically acceptable salt thereof. In the compound of formula (V) or (VI), R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 81 , R 82 X1, X2, X3, m, and n are as defined for compounds of formula (I), or, unless otherwise specified, have any of the values ​​defined herein, including one or more of (1) to (135) (to the extent that those paragraphs are applicable to compounds of formula (V) or formula (VI)). The following embodiments relate to compounds of formula (V) or formula (VI).

[0291] In one embodiment of a compound of formula (V) or formula (VI), R 81 and R 82 One is H, and the other is Halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OC 1~4 Selected from alkyl groups.

[0292] In one embodiment of a compound of formula (V) or formula (VI), R 81 and R 82 One of them is H, and the other is C 1~4 It is alkyl.

[0293] In one embodiment of a compound of formula (V) or formula (VI), R 81 and R 82 One of them is H, and the other is a halo.

[0294] In one embodiment of a compound of formula (V) or formula (VI), R 81 and R 82 Both are H.

[0295] In one embodiment of a compound of formula (V) or formula (VI), R 8 is selected from any one of the above paragraphs (75) to (96). In one embodiment including the above embodiments, in a compound of formula (V) or (VI), R 8 H, -CN, C 1~4 Alkyl, -C(O)NH2, -C(O)N(H)C 1~4 Alkyl, -C(O)N(C 1~4 Alkyl)2,-S(O)2C 1~4 Alkyl, -C 1~4 Alkyl-OH and -C 1~4 Selected from alkyl-OMe. 8 These are H, -CN, and -S(O)2R 10 It may be selected from the following.

[0296] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, m is 0; X1 is CR 1 And; R 1 These are H, Halo, -CN and C 1~3 Alkyl compounds may be selected.

[0297] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, m is 0; n is 0; and X1 is CR. 1 And; R 1 H, halo and C 1~3 Alkyl compounds may be selected.

[0298] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, m is 0; n is 0; X2 is N; X3 is CR 33 This may be the case.

[0299] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, m is 0 and X 1 It may be CH.

[0300] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, R 81 and R 82 H is; R 8 H, -CN, C 1~4 Alkyl, -C 1~4 alkyl-OH, -C 1~4 Alkyl and -S(O)2C 1~4 Alkyl compounds may be selected.

[0301] In one embodiment of a compound of formula (V) or formula (VI), which includes any of the embodiments described above, R 9 It may be H.

[0302] Compounds of formulas (VII) and (VIII) In one embodiment, the compound of formula (I) is the compound of formula (VII) or formula (VIII) as defined above, or a pharmaceutically acceptable salt thereof. In the compound of formula (VII) or formula (VIII), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 81 , R 82 X1, X2, X3, m and n are as defined for compounds of formula (I), or unless otherwise specified, have any of the values ​​defined herein, including one or more of (1) to (135) (to the extent that those paragraphs are applicable to compounds of formula (VII) or formula (VIII)). The following embodiments relate to compounds of formula (VII) or formula (VIII).

[0303] In a certain embodiment of the compound of formula (VII) or formula (VIII), m is 0; X1 is CR1 And; R 1 These are H, Halo, -CN and C 1~3 Alkyl compounds may be selected.

[0304] In a certain embodiment of the compound of formula (VII) or formula (VIII), m is 0; X1 is CR 1 And; R 1 This may be a halo.

[0305] In a certain embodiment of the compound of formula (VII) or formula (VIII), m is 0; X1 is CR 1 And; R 1 C 1~3 It may be alkyl.

[0306] In some embodiments of the compound of formula (VII) or formula (VIII), m may be 0; X1 may be CH.

[0307] In some embodiments of a compound of formula (VII) or formula (VIII), which include any of the embodiments described above, n may be 0.

[0308] In one embodiment of a compound of formula (VII) or formula (VIII), which includes any of the embodiments described above, n is 0; X2 is N; X3 is CR 33 This may be the case.

[0309] In a certain embodiment of the compound of formula (VII) or formula (VIII), X2 and X3 are CH; n is 0.

[0310] In one embodiment including the above embodiments, R 81 H, halo and C 1~3 Selected from alkyl; R 82 H is H.

[0311] In one embodiment of a compound of formula (VII) or formula (VIII), R 81 and R 82 H is H.

[0312] In one embodiment of a compound of formula (VII) or formula (VIII), R 81 Hello, C 1~4 Selected from alkyl and -CF3; R 82 H is H.

[0313] In one embodiment of a compound of formula (VII) or formula (VIII), R 82 Hello, C 1~4 Selected from alkyl and -CF3; R 81 H is H.

[0314] In one embodiment of a compound of formula (VII) or formula (VIII), R 7 R may have any of the values ​​in any one of the paragraphs (65) to (74) above. 7 H, halo and C 1~3 Alkyl may be selected. 7 R may be selected from fluoro and methyl. 7 It may be methyl.

[0315] In one embodiment of a compound of formula (VII) or formula (VIII), which includes any of the embodiments described above, R 81 and R 82 H is; R 7 This is Halo and C 1~3 Alkyl compounds may be selected.

[0316] In one embodiment of a compound of formula (VII) or formula (VIII), which includes any of the embodiments described above, R 9 It may be H.

[0317] In one embodiment of a compound of formula (VIII), which includes any of the embodiments described above, R 10 C1~4 Alkyl or C 3~6 It is a cycloalkyl. For example, R 10 C 1~4 It is alkyl. 10 It may be methyl.

[0318] Compound of formula (IX) In one embodiment, the compound of formula (I) is the compound of formula (IX) as defined above or a pharmaceutically acceptable salt thereof. In the compound of formula (IX), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 X1, X2, X3, m and n are as defined for compounds of formula (I), or unless otherwise specified, have any of the values ​​defined herein, including one or more of (1) to (135) (to the extent that those paragraphs are applicable to compounds of formula (IX)). The following embodiments relate to compounds of formula (IX).

[0319] In one embodiment of the compound of formula (IX), m is 0; X1 is CR 1 And; R 1 These are H, Halo, -CN and C 1~3 Alkyl compounds may be selected.

[0320] In one embodiment of the compound of formula (IX), m is 0; X1 is CR 1 And; R 1 This may be a halo.

[0321] In one embodiment of the compound of formula (IX), m is 0; X1 is CR 1 And; R 1 C 1~3 It may be alkyl.

[0322] In one embodiment of the compound of formula (IX), m may be 0; X1 may be CH.

[0323] In some embodiments of the compound of formula (IX), which include any of the embodiments described above, n may be 0.

[0324] In one embodiment of a compound of formula (VII) or formula (VIII), which includes any of the embodiments described above, n is 0; X2 is N; X3 is CR 33 This may be the case.

[0325] In a certain embodiment of the compound of formula (VII) or formula (VIII), X2 and X3 are CH; n is 0.

[0326] In one embodiment of a compound of formula (IX), which includes any of the embodiments described above, R 7 R may have any of the values ​​in any one of the paragraphs (65) to (74) above. 7 H and C 1~3 Alkyl compounds may be selected.

[0327] In one embodiment of a compound of formula (IX), which includes any of the embodiments described above, R 8 R may have any of the values ​​in any one of the paragraphs (75) to (96) above. 8 These are H, -CN, and -S(O)2R 10 It may be selected from the following.

[0328] In one embodiment of a compound of formula (IX), which includes any of the embodiments described above, R 8 H, -CN, C 1~4 Alkyl, -C 1~4 alkyl-OH, -C 1~4 Alkyl-OMe, -OC 2~4 alkyl-OH, -OC 2~4 Alkyl-OMe, -C(O)NH2, -C(O)N(H)C 1~3Alkyl, -C(O)N(C 1~3 Alkyl)2 and -S(O)2C 1~4 It may be selected from alkyl groups.

[0329] In one embodiment of a compound of formula (IX), which includes any of the embodiments described above, R 8 H, -CN and C 1~4 Selected from alkyl; R 7 H and C 1~3 Alkyl compounds may be selected.

[0330] In one embodiment of a compound of formula (IX), which includes any of the embodiments described above, R 9 It may be H.

[0331] In one embodiment of compounds of formulas (I), (II), (III), and (IV), which includes any of the embodiments described above, formula: [ka] The basis of is [ka] It may be selected from the following.

[0332] In one embodiment of compounds of formulas (I), (II), (III), and (IV), which includes any of the embodiments described above, formula: [ka] The basis of is [ka] It may be selected from the following.

[0333] In one embodiment, the compound of formula (I) is of formula (IIIa): [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein R 7 H, fluoro and C 1~3 Selected from alkyl; R 8 is H or -CN. In this embodiment, R 7 is selected from H, F and methyl, and R 8 R may be -CN. In this embodiment, 7 It is methyl, and R 8 R may be -CN. In this embodiment, 7 and R 8 It is possible that both are H.

[0334] In one embodiment of the compounds of formulas (I), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), and (IX), which include any of the embodiments described above, R 4 and R 5 H is R 6 This may be selected from H and methyl.

[0335] In one embodiment of the compounds of formulas (I), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), and (IX), which include any of the embodiments described above, the base [ka] is, formula [ka] It may be of that nature.

[0336] In one embodiment of the compounds of formulas (I), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), and (IX), which include any of the embodiments described above, the base [ka] is, formula [ka] It may be of that nature.

[0337] In one embodiment of the compounds of formulas (I), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), and (IX), which include any of the embodiments described above, the base [ka] is, formula [ka] It may be of that nature.

[0338] In one embodiment of the compounds of formulas (I), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), and (IX), which include any of the embodiments described above, the base [ka] teeth, [ka] This may be the case.

[0339] In another embodiment, compounds selected from any one of the examples herein, or pharmaceutically acceptable salts or prodrugs thereof, are provided.

[0340] In another embodiment, compounds selected from Table 1 or pharmaceutically acceptable salts or prodrugs thereof are provided. In particular, compounds selected from Table 1 or pharmaceutically acceptable salts thereof are provided.

[0341] [Table 1]

[0342] [Table 2]

[0343] [Table 3]

[0344] [Table 4]

[0345] [Table 5]

[0346] In another embodiment, compounds selected from Table 2 or pharmaceutically acceptable salts or prodrugs thereof are provided. In particular, compounds selected from Table 2 or pharmaceutically acceptable salts thereof are provided.

[0347] [Table 6]

[0348] [Table 7]

[0349] [Table 8]

[0350] Pharmaceutical composition In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0351] Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, MEAulton, Churchill Livingstone, 1988.

[0352] The compositions of the present invention may be in forms suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels or aqueous or oily liquids or suspensions), administration by inhalation (e.g., as finely ground powders or liquid aerosols), administration by airborne inhalation (e.g., as finely ground powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration, or as suppositories for rectal administration).

[0353] The compositions of the present invention are obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0354] An effective amount of the compound of the present invention for use in the treatment of diseases is sufficient to alleviate symptoms in warm-blooded animals, particularly symptoms of human diseases, or to slow the progression of the disease.

[0355] The amount of active ingredient combined with one or more excipients to produce a single dosage form will inevitably vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.1 mg to 0.5 g of the active ingredient (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), combined with an appropriate and convenient amount of excipients that can vary in weight from about 5 to about 98 percent of the total composition.

[0356] The size of the dosage of the compound of the present invention for therapeutic or prophylactic purposes will, naturally, vary according to well-known principles of pharmacopoeia, depending on the nature and severity of the animal's or patient's condition, age and sex, and route of administration.

[0357] When using the compounds of the present invention for therapeutic or preventive purposes, they will generally be administered in divided doses as needed, so as to give a daily dose selected from the applicable range, for example, 0.05 mg / kg to 100 mg / kg, 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, 5 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.1 mg / kg to 2 mg / kg, or 0.1 mg / kg to 1 mg / kg body weight. Generally, when parenteral routes are used, lower doses will be administered. Therefore, for example, in the case of intravenous, subcutaneous, intramuscular, or intraperitoneal administration, doses within the applicable range, such as 0.05 mg / kg to 30 mg / kg, 0.1 mg / kg to 30 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.1 mg / kg to 2 mg / kg, or 0.1 mg / kg to 1 mg / kg body weight, would be commonly used. Similarly, in the case of administration by inhalation, doses within the applicable range, such as 0.05 mg / kg to 25 mg / kg body weight, would be used. Preferably, the compounds of the present invention are administered orally, for example, in the form of tablets or capsules. The daily dose administered orally may be a total daily dose selected from, for example, 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg, 25 mg to 500 mg, 1 mg to 100 mg, 5 mg to 75 mg, or 10 mg to 50 mg. Typically, a unit dosage form would contain about 0.5 mg to 0.5 g of the compound of the present invention. In certain embodiments, the compounds of the present invention are administered parenterally, for example, by intravenous administration. In other specific embodiments, the compounds of the present invention are administered orally.

[0358] The compounds of the present invention may be administered, for example, at dosing intervals of once every hour, once every two hours, once every four hours, once every six hours, once every eight hours, or once every twelve hours. In some embodiments, the compounds may be administered once daily, twice daily, three times daily, four times daily, once every two days, or once a week. Preferably, the compounds of the present invention may be administered once or twice daily.

[0359] Regular administration of the compounds of the present invention may provide a cumulative and sustained analgesic effect. Examples herein demonstrate that a single injection of the compounds of the present invention results in analgesia, but the analgesic effect decreases to baseline levels within a few hours of administration. Repeated regular administration of the compounds of the present invention may provide a cumulative and sustained analgesic effect. The cumulative effect on analgesia provided by the compounds of the present invention may allow the compounds to be administered at doses lower than those required to obtain the complete analgesic effect when administered as a single bolus. Therefore, regular administration of low doses of the compounds of the present invention may provide a wider therapeutic range between analgesia and undesirable side effects that may be associated with higher doses, such as bradycardia or tremor.

[0360] In certain embodiments, the compounds of the present invention provide analgesic ED of the compounds. 50 It is administered regularly to provide a plasma concentration of 10% to 120% of the compound. For example, the compound is used for analgesic ED of the compound. 50 It may be administered in doses that provide 10% to 100%, 10% to 80%, 10% to 60%, 15% to 50%, 20% to 50%, 25% to 50%, or 25% to 45% of the total. The regular dosing interval may be, for example, any of the dosing intervals described above.

[0361] Therapeutic uses and applications In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention for use as a pharmaceutical agent.

[0362] Further aspects of the present invention provide compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention for use in the treatment of diseases or conditions mediated by hyperpolarization-activated cyclic nucleotide-modulated ion channels 2 (HCN2).

[0363] The use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention in the manufacture of agents for the treatment of diseases or conditions mediated by HCN2 is also provided.

[0364] A method is also provided for treating a disease or condition mediated by HCN2 in a subject in need thereof, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the subject; or (ii) a pharmaceutical composition of the present invention.

[0365] Diseases mediated by HCN2 may be, for example, any of the diseases disclosed herein.

[0366] The compounds of the present invention are HCN2 inhibitors useful in the treatment of diseases in which inhibition of HCN2 ion channels is beneficial. As described in the background of the invention, which is incorporated into the main description, HCN4 is highly expressed in cardiac tissue and is a major regulator of cardiac pacemaking. Inhibition of HCN4 induces bradycardia and HCN4 deletion systemically or locally in the heart in mice, and is lethal. Therefore, compounds that significantly inhibit HCN4 in addition to HCN2 would not be suitable as long-term treatments, for example, as analgesics used for the long-term treatment of pain. Preferred compounds of the present invention selectively inhibit HCN2 rather than HCN4. HCN2-selective compounds are expected to reduce or eliminate the risk of undesirable cardiac side effects associated with the use of the compounds of the present invention as agents for the treatment of HCN2-mediated diseases. In preferred embodiments, the compounds of the present invention are measured in the HCN4 assay described herein (see Example 50) of the same compound. 50The IC in the HCN2 assay described herein (see Example 50) is at least 2 times lower, for example, at least 5 times, at least 10 times, at least 20 times, or at least 30 times lower. 50 This indicates.

[0367] The HCN1 channel is also expressed in cardiac tissue and is associated with cardiac function. Therefore, preferred compounds of the present invention selectively inhibit HCN2 rather than HCN1. In one embodiment, the IC of the compound of the present invention is measured in the HCN1 assay described herein (see Example 50) of the same compound. 50 The IC in the HCN2 assay described herein (see Example 50) is at least 2 times lower, for example, at least 5 times, at least 10 times, or at least 20 times lower. 50 This indicates.

[0368] To evaluate the selectivity of the compound, IC for the compound was performed in an HCN assay. 50 When comparing values, the same assay protocol will determine the IC value for the compound. 50 It should be used to generate values. For example, both ICs 50 The values ​​should be measured using the PatchXpress protocol described in Example 50A, or both should be measured using the Sophion Qube protocol described in Example 50B.

[0369] Voltage-dependent Na + Channel Na v 1.5 is mainly found in the myocardium. It is essential for initiating myocardial action potentials in the heart and for the conduction of electrical impulses and the sustainment of action potentials. In preferred embodiments, the compound of the present invention is Na v 1.5 selectively inhibits HCN2. In one embodiment, the compound of the present invention is Na as described herein. v 1.5 IC of the same compound measured in assay (see Example 50) 50The IC in the HCN2 assay described herein (see Example 50) is at least 2 times lower, for example, at least 5 times, at least 10 times, at least 20 times, or at least 50 times lower. 50 This shows the IC for HCN2. Preferably, 50 This was measured using the Sophion Qube protocol described in Example 50B, and Na v IC for 1.5 50 The value is determined using the Sophion Qube protocol described in Example 52B.

[0370] It is well known that drugs that inhibit hERG potassium channels in the heart can result in delayed ventricular repolarization (QT interval prolongation). Preferred compounds of the present invention have a low hERG load. In one embodiment, the IC of the compound of the present invention is measured in the hERG assay described herein (see Example 51). 50 At least twice, for example, at least five times, at least ten times, or at least twenty times lower, the IC in the HCN2 assay described herein. 50 This shows the IC for HCN2 and hERG. Preferably, the IC for HCN2 and hERG. 50 These are measured using the Sophion Qube protocol described in Examples 50B and 51B, respectively.

[0371] Therefore, in preferred embodiments, the compounds of the present invention have a high therapeutic range between the concentrations required for the inhibition of HCN2 and ion channels related to cardiac function. In some embodiments, the compounds of the present invention are HCN4, HCN1, Na v 1.5 or one or more hERGs are selective to HCN2. In certain embodiments, preferred compounds of the present invention selectively inhibit HCN2 more than HCN4 and / or HNC1. In further specific embodiments, preferred compounds of the present invention selectively inhibit HCN2 more than HCN4.

[0372] HCN2 channels are widely expressed in the brain, and significant inhibition of HCN2 in the brain can induce undesirable central nervous system (CNS) side effects such as tremors or ataxia. In preferred embodiments, the compounds of the present invention are peripherally restricted HCN2 inhibitors such that, when present in therapeutically effective concentrations in peripheral tissues, only low levels of the compound are present in the brain at concentrations below those required to induce undesirable CNS-related side effects. In some embodiments, the compounds of the present invention are substrates for the transporter P-glycoprotein (P-gp). P-gp substrates are generally effluxed in the brain endothelium. Therefore, compounds that are P-gp substrates are expected to exhibit low concentrations in brain tissue. In some embodiments, the compounds of the present invention have a high efflux ratio when measured in the MDCK-MDR1 permeability assay described herein (see Example 53). The MDCK-MDR1 assay described in Example 53, performed in the absence and presence of P-gp inhibitors, can be used to identify compounds with peripherally restricted potentials. A net elimination value > 5 (i.e., the elimination ratio without the inhibitor divided by the elimination ratio with the inhibitor) indicates a compound that is a substrate for the transporter P-gp and therefore is more likely to be restricted from the central nervous system (i.e., a compound with low central nervous system permeability). In some embodiments, compounds of the present invention having low central nervous system permeability have a net elimination of 5 or more, for example, 10 or more, 15 or more, or 20 or more, when measured in the MDCK-MDR1 permeability assay described herein. Compounds of the present invention that exhibit low central nervous system permeability after administration are referred to herein as “peripheral restriction compounds” or “peripheral restriction HCN2 inhibitors.”

[0373] In the following sections of this application, the compounds of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of a particular disease or condition are referred to. Any reference herein to a compound for a particular use should be understood to also be intended to refer to (i) the use of the compound of the present invention or pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of that disease or condition; and (ii) a method of treating a disease or condition in a subject, comprising administering a therapeutically effective amount of the compound of the present invention or pharmaceutically acceptable salt thereof to the subject.

[0374] The diseases or conditions mediated by HCN2 may be any of the diseases or conditions listed in this application.

[0375] pain In one embodiment, the compounds of the present invention are intended for use in the treatment or prevention of pain, including, but not limited to, NP and IP in general.

[0376] neuropathic pain In some embodiments, the compounds of the present invention are for use in the treatment or prevention of neuropathic pain. In some embodiments, the compounds of the present invention are for use in the treatment or prevention of peripheral neuropathic pain. Examples of NPs include, but are not limited to, pain-related diabetic neuropathy (PDN), postherpetic neuralgia (PHN), cancer-related pain, chemotherapy-induced pain including chemotherapy-induced peripheral neuropathy, postoperative pain (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, or phantom limb pain), trigeminal neuralgia, complex regional pain syndrome (CRPS), opioid-resistant pain, neuropathic pain associated with pudendal neuralgia and low back pain, post-traumatic nerve injury (e.g., cervical sprain due to a car accident), and neuropathic pain selected from carpal tunnel syndrome.

[0377] In one embodiment, the compounds of the present invention are used to treat neuropathic pain related to or caused by: neuropathy, spinal and peripheral nerve surgery, spinal cord injury, chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, neuralgia (e.g., trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and burning pain), lupus, HIV infection, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, sciatica, temporomandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, fractures, oral neuropathic pain, Charcot pain, complex regional pain syndromes I and II (CRPS). It is intended for use in the treatment or prevention of VIT, nerve root disorders, Guillain-Barré syndrome, paresthesia femoral neuralgia, burning oral syndrome, optic neuritis, post-febrile neuritis, migratory neuritis, segmental neuritis, Gomball neuritis, neuritis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythroneuritis, Sruder's neuralgia, sprenopalatin neuralgia, supraorbital neuralgia, vulvovaginal pain, or Vidian neuralgia. In one embodiment, the compound of the present invention is intended for use in the treatment of postherpetic neuralgia.

[0378] In one embodiment, the compounds of the present invention are intended for use in the prevention or alleviation of one or more symptoms of NP, such as paresthesia (spontaneous or induced burning pain, often accompanied by superimposed elements of electric shock pain), deep pain, throbbing pain, hyperesthesia, hyperalgesia, allodynia, and hyperalgesia.

[0379] Preferred compounds treat neuropathic pain (especially peripheral neuropathic pain) while maintaining the perception of acute pain.

[0380] inflammatory pain In some embodiments, the compounds of the present invention are for use in the treatment or prevention of inflammatory pain. In some embodiments, the pain is chronic inflammatory pain. In some embodiments, the pain is acute inflammatory pain. In some embodiments, the compounds of the present invention are for use in the treatment or prevention of inflammatory pain, particularly chronic inflammatory pain, resulting from or associated with one or more of the following: inflammatory bowel disease, visceral pain, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, arthralgia, abdominal pain, chest pain, labor pains, musculoskeletal disorders, skin diseases, toothache, fever, burns, sunburn, animal or insect bites or stings, neurogenic bladder, interstitial cystitis, urinary tract infections, rhinitis, dermatitis including contact dermatitis and atopic dermatitis, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual cramps, endometriosis, headache due to sinusitis, tension headache, or arachnoiditis.

[0381] In one embodiment, the compounds of the present invention are for use in the treatment of inflammatory hyperalgesia, including inflammatory somatic hyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesia may be characterized by the presence of an inflammatory hyperalgesic state in which hypersensitivity to thermal, mechanical, and / or chemical stimuli is present. Inflammatory visceral hyperalgesia may also be characterized by the presence of an inflammatory hyperalgesic state in which increased visceral irritability is present.

[0382] Emery et al. (2011, 2012), cited above, showed that selective deletion of HCN2 in mouse NaV1.8-expressing sensory neurons resulted in loss of pain perception due to inflammatory stimuli, but maintained the response to acute pain in the absence of inflammatory stimuli. Therefore, preferred compounds treat inflammatory pain while maintaining the perception of acute pain.

[0383] Tinnitus As described in the background of the invention and as shown in the examples, the inventors have shown for the first time that tinnitus can be treated with HCN2 inhibitors in an animal model. The examples suggest that the observed effects are applicable to any HCN2 inhibitor and are not limited to the compounds of the present invention.

[0384] In one embodiment of the present invention, an HCN2 inhibitor is provided for use in the treatment of tinnitus or related disorders. In a preferred embodiment, the HCN2 inhibitor is the compound of the present invention. Thus, the compound of the present invention is provided for use in the prevention or treatment of tinnitus or related disorders.

[0385] Ivabradine is a peripherally restricted compound with pan-HCN inhibitory activity. The examples herein demonstrate that the compound successfully treated tinnitus despite being peripherally restricted. Similar results were obtained using a peripherally restricted and selective HCN2 inhibitor compound (compound 476 in Figure 7). Therefore, the experiments suggest that tinnitus can be treated without the need for central nervous system penetration, thereby avoiding undesirable side effects that may be associated with HCN2 inhibition in the central nervous system, such as tremor or ataxia.

[0386] Therefore, peripheral restriction HCN2 inhibitors for use in the treatment of tinnitus or related disorders are also provided. In one embodiment, the peripheral restriction HCN2 inhibitor is a peripheral restriction HCN2 inhibitor, such as ivabradine. In a preferred embodiment, the peripheral restriction HCN2 inhibitor is the peripheral restriction compound of the present invention.

[0387] Tinnitus can occur as objective tinnitus or subjective tinnitus. Subjective tinnitus is the most common type of tinnitus. Also known as sensorineural tinnitus, subjective tinnitus is audible only to the person affected. Objective tinnitus, on the other hand, can be perceived by others and is usually caused by myoclonus or vascular disease, but in some cases, tinnitus is caused by spontaneous oscillations in the ear. In a preferred embodiment, an HCN2 inhibitor (preferably a compound of the present invention) is intended for use in the treatment of subjective tinnitus. Tinnitus can be acute, but in a preferred embodiment, tinnitus is chronic tinnitus, for example, tinnitus that lasts for more than two weeks, more than one month, or more than six months.

[0388] In one embodiment, an HCN2 inhibitor (preferably a compound of the present invention) is intended for use in the treatment or prevention of tinnitus caused by or associated with one or more of the following: exposure to loud noises; age-related hearing loss (hearing loss); ear or head injury, ear infection; tumors affecting the auditory nerve; Meniere's disease; cardiovascular disease, cerebrovascular disease; hyperthyroidism; hypothyroidism; drug therapy (e.g., side effects of salicylates (including mesalamine or aspirin), especially when taken in high doses), quinine antimalarial agents, aminoglycoside antibiotics, chemotherapy (including, but not limited to, platinum cytotoxic agents (e.g., cisplatin, carboplatin, and oxaliplatin)) or loop diuretics (e.g., furosemide, ethacrine, and torsemide); or auditory impairment (e.g., hyperacusis, sound distortion, phonophobia, phonophobia, and central auditory processing disorder).

[0389] In one embodiment, an HCN2 inhibitor (preferably the compound of the present invention) is for use in the treatment or prevention of tinnitus, Meniere's disease, or hyperacusis. In one embodiment, an HCN2 inhibitor is for use in the treatment or prevention of tinnitus or Meniere's disease. In a specific embodiment, a compound of the present invention is provided for use in the treatment or prevention of tinnitus.

[0390] Migraine The debilitating pain of migraines imposes a considerable personal and economic burden. The actual or potential potential of medications as treatments for migraines is demonstrated, among other things, by the triptan family, the "gepanto" family of CGRP receptor antagonists, and monoclonal antibodies against CGRP. All have considerable drawbacks, including the promotion of medication overuse headache with triptans, hepatotoxicity with gepanto, and the need for regular infusions of monoclonals. However, a significant proportion of migraine sufferers do not achieve relief with these treatments. These still require new treatments for migraines.

[0391] Triptans are agonists at the 5HT1B / D receptor, binding to Gi / o and thus inhibiting cAMP5 production (Alexander et al., Br.J.Pharmacol.174 Suppl.1,S17-S129, (2017)). CGRP receptors, which have emerged as a significant mediator of migraine, bind to Gs and thus increase cAMP (Alexander et al., cited above). These studies suggest that cAMP in trigeminal nociceptive afferent nerves stimulating the meninges and dura mater may be a significant downstream mediator of migraine (Schytz et al., Curr.Opin.Neurol.23,259-265, (2010)).

[0392] As described herein, HCN2 ion channel isoforms whose activation is enhanced by cAMP have been shown to promote firing in nociceptive afferent nerves, and as a result, they have been shown to be important ultimate effectors of pain in animal models of nerve injury pain, chemotherapy-induced pain, and pain-causing diabetic neuropathy ((Tsantoulas, et al., Sci Transl Med 9, eaam6072, (2017); Tsantoulas et al., Biochem J 473, 2717-2736, 2016); Young et al., Pain 155, 1708-1719, (2014); and Emery et al., Science 333, 1462-1466, (2011)). Therefore, HCN2 ion channels may be important downstream mediators of migraine-related pain. HCN2 inhibitors may be useful in the treatment or prevention of migraine, in particular in the treatment or prevention of migraine-related pain.

[0393] In certain embodiments, an HCN2 inhibitor is provided for use in the prevention or treatment of migraines. In certain embodiments, an HCN2 inhibitor is provided for use in the treatment or prevention of pain caused by migraines. In preferred embodiments, the HCN2 inhibitor is the compound of the present invention. Thus, the compound of the present invention is provided for use in the prevention or treatment of migraines. The compound of the present invention is also provided for use in the prevention or treatment of pain caused by migraines.

[0394] Treatment of specific pain syndromes and conditions In certain embodiments, the compounds of the present invention are intended for use in the treatment of conditions selected from painful diabetic neuropathy; migraine, rheumatoid arthritis (RA), osteoarthritis (OA), pain associated with long-term opioid use (opioid-induced hyperalgesia, OIH), cancer-related bone pain, and fibromyalgia (FMS, fibromyalgia syndrome).

[0395] subject The compounds of the present invention may be used for the treatment of human or animal subjects suffering from any of the medical conditions disclosed herein. Subjects may be warm-blooded mammals such as livestock (e.g., cattle, sheep, or pigs) or companion animals or pets (e.g., dogs, cats, or horses). Preferably, the subject is human.

[0396] Combination therapy The therapeutic methods or compounds of the present invention may be applied as monotherapy or in combination with further active agents for use in treating diseases mediated by HCN2 as defined herein.

[0397] For example, if the condition is pain (e.g., NP or IP), the compounds of the present invention may be used in combination with another analgesic. Examples of analgesics include, but are not limited to, opioids (e.g., morphine and other opioid receptor agonists; nalbufine or other mixed opioid agonist / antagonist; or tramadol); nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., selective COX2 inhibitors such as aspirin, ibuprofen, naproxen, or celecoxib); paracetamol; baclofen, pregabalin, gabapentin, tricyclic antidepressants (e.g., clomipramine or amitriptyline), or local anesthetics (e.g., lidocaine), or two or more combinations thereof.

[0398] Combination therapy as defined herein can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the compounds of the present invention within the therapeutically effective dosage range described herein and other pharmaceutically active agents within their approved dosage ranges.

[0399] Where the term “combination” is used herein, it should be understood to refer to simultaneous, separate, or sequential administration. In one embodiment of the present invention, “combination” refers to simultaneous administration. In another embodiment of the present invention, “combination” refers to separate administrations. In a further embodiment of the present invention, “combination” refers to sequential administration. When the administrations are sequential or separate, any delay in administering the second component should not impair the beneficial effect of the combination.

[0400] In some embodiments in which combination therapy is used, the amounts of the compound of the present invention and other pharmaceutically active agents, when combined, are therapeutically effective in treating a targeted disorder in a patient. In this regard, a combined amount is a “therapeutic effective amount” if, when combined, it is sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder; cure the disorder; halt, completely halt or slow the progression of the disorder; or reduce the risk of the disorder worsening. Typically, such amounts can be determined by those skilled in the art, for example, by starting from the dosage ranges described herein for the compound of the present invention and the approved or otherwise disclosed dosage ranges for the other pharmaceutically active compounds.

[0401] A further aspect of the present invention provides a pharmaceutical product comprising a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof, and a further active agent, for the treatment of pain (e.g., NP or IP). The further active agent may be an analgesic as defined herein.

[0402] In one embodiment, a pharmaceutical product is provided comprising a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof, and a further active agent, for the treatment of a disease modulated by HCN2. The further active agent may be an analgesic as defined herein.

[0403] A further aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of pain (e.g., NP or IP) simultaneously with, or separately from, analgesics as defined herein.

[0404] synthesis It should be understood that in the description of the synthesis method and the synthesis method mentioned below used to prepare the starting materials, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, and duration of the experiment and workup procedures, can be selected by those skilled in the art.

[0405] Those skilled in organic synthesis will understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0406] The necessary starting materials are obtained by standard procedures in organic chemistry. The preparation of such starting materials is described below, along with representative process forms, and in the accompanying examples. Alternatively, the necessary starting materials may be obtained by procedures similar to those shown, which are within the scope of the skills of those skilled in organic chemistry.

[0407] It will be understood that during the synthesis of the compounds of the present invention in the processes defined below, and during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. Those skilled in the art of chemistry will understand when such protection is necessary and how such protecting groups may be established and subsequently removed.

[0408] For examples of protecting groups, see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature as suitable for the removal of the protecting group in question or known to those skilled in the art of chemistry, such method being selected to remove the protecting group with minimal disturbance to other groups in the molecule.

[0409] Therefore, if the reactant contains groups such as amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions referred to herein.

[0410] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, e.g., alkanoyl groups, e.g., acetyl or trifluoroacetyl; alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl; and aroyl groups, e.g., benzoyl. The deprotection conditions for the above protecting groups inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups, e.g., alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with a suitable base, e.g., alkali metal hydroxides, e.g., lithium or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, can be removed by hydrogenation with a catalyst such as palladium carbon or by treatment with a Lewis acid, e.g., BF3.OEt2. A suitable alternative protecting group for the primary amino group is, for example, an alkylamine, such as dimethylaminopropylamine, or a phthaloyl group, which can be removed by treatment with hydrazine.

[0411] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups, such as acetyl, alloyl groups, such as benzoyl, or arylmethyl groups, such as benzyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. For example, acyl groups, such as alkanoyl or alloyl groups, can be removed by hydrolysis with suitable bases such as alkali metal hydroxides, such as lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation with a catalyst such as palladium-carbon.

[0412] Suitable protecting groups for the carboxyl group include, for example, esterifying groups that can be removed by hydrolysis with a base such as sodium hydroxide, such as methyl or ethyl groups, or by treatment with an acid such as an organic acid such as trifluoroacetic acid, such as t-butyl groups, or by hydrogenation with a catalyst such as palladium carbon, such as benzyl groups.

[0413] Resins can also be used as protective groups.

[0414] Common synthesis routes The compound of formula (I) can be prepared according to scheme 1. [ka]

[0415] The intermediate hydrazone (3) can be prepared at room temperature to reflux temperature of the solvent by the reaction of a suitable aldehyde or ketone with (1) a suitable hydrazine in a solvent such as an alcohol (methanol or ethanol) or DMF, (2) optionally in the presence of a base such as cesium carbonate or potassium carbonate. Conversion to the indazole alcohol analog (6) can be achieved by reduction to an alcohol followed by cyclization, or by cyclization first followed by reduction. Reduction from ester (3) to alcohol (4) can be carried out at a temperature of -78°C to room temperature in a solvent such as diethyl ether or THF, under various conditions known to those skilled in the art, such as the use of DIBAL or lithium aluminum hydride. Cyclization to indazole can be achieved at a temperature of room temperature to 100°C by treating 2-fluorohydrazone (4) with a base such as potassium tert-butoxide in a polar solvent such as DMF or NMP. Next, oxidation from alcohol (4) to aldehyde (5) can be achieved using conditions known to those skilled in the art. For example, oxidation can be carried out at room temperature in DCM under Dess-Martin-Periodinane conditions or in the presence of a trialkylamine base, such as triethylamine, in a solvent such as DCM using oxalyl chloride and DMSO under Swan conditions.

[0416] The conversion from aldehyde (7) to imine (8) can be achieved by treatment with a suitable chiral single enantiomer of (S)-2-methylpropane-2-sulfinamide in a chlorinated solvent such as DCM, in the presence of a base such as cesium carbonate, at reflux temperature of the solvent. Alternatively, the reaction with (S)-2-methylpropane-2-sulfinamide can be carried out at room temperature to reflux temperature of the solvent, in a suitable solvent such as ethanol or THF, in the presence of, for example, titanium ethoxide. At temperatures of -78°C to 0°C, the reaction of the generated single enantiomer of sulfinamide (8) in a solvent such as THF with an anion generated from an organolithium reagent such as appropriately substituted 2-alkylpyridine and n-butyllithium, lithium diisopropylamide, or lithium hexamethyldisilazide preferentially yields the desired diastereomer isomer of intermediate (9), which can be purified by chromatography to remove undesirable by-product diastereomers. Next, the target compound of formula (I) is obtained as a single enantiomer (10) by deprotection under acidic conditions using, for example, HCl or trifluoroacetic acid in a solvent such as DCM, ethyl acetate methanol, or dioxane.

[0417] Those skilled in the art can use various bases, for example, R, R 2 or R 3 It will be recognized that interconversions can occur at various stages of synthesis and that protection of various functional groups may be necessary to complete synthesis.

[0418] An alternative synthetic method for the compound of formula (I) via the same intermediate aldehyde (7) is described in Scheme 2. [ka]

[0419] Intermediate indazole (5) (wherein X 2 or X 3The compound (where X is N) can be prepared by the reaction of an N-unsubstituted indazole (11) with a 2-halosubstituted carboxylic acid ester (12) (for example, where X is F or Cl) in a solvent such as THF or DMF at a temperature of 0°C to room temperature in the presence of a strong base such as sodium hydride. Removal of undesirable positional isomers can be achieved by chromatography. Alternatively, X 2 and X 3 If X is carbon, then X is bromine or iodine, and the reaction may be carried out under copper catalytic conditions, for example, using copper(I) iodide or copper(I) oxide, in a solvent such as DMF or dioxane, at a temperature from room temperature to reflux temperature of the solvent, in the presence of a base such as potassium phosphate, potassium hydroxide or cesium carbonate and an amine such as dimethylethylenediamine or 1,2-cyclohexanediamine. Those skilled in the art will recognize that there are several other conditions that can be used for the coupling of a haloester and an indazole to produce a type (5) intermediate.

[0420] The conversion from ester (5) to aldehyde (7) can be achieved either directly or in two steps. Direct conversion from ester to aldehyde can be achieved at a temperature of -78°C to room temperature in a solvent such as DCM using a mild reducing agent such as DIBAL. Alternatively, ester (5) can be reduced to alcohol (6) at a temperature of -78°C to room temperature in an ether solvent such as diethyl ether or THF using stronger conditions such as lithium aluminum hydride. Next, oxidation from alcohol (6) to aldehyde (7) can be achieved using conditions known to those skilled in the art. For example, oxidation can be achieved at room temperature in DCM using Dess-Martin-Periodinane conditions, or in the presence of a trialkylamine base, such as triethylamine, in a solvent such as DCM using oxalyl chloride and DMSO under Swan conditions.

[0421] Once the aldehyde (7) is obtained, the conversion to the compound of formula (I) can be achieved using the same method as described above in Scheme 1. [Examples]

[0422] Abbreviation: The following abbreviations are used. DCM: Dichloromethane DIBAL: Diisobutylaluminum hydride DMF: N,N-dimethylformamide DMP: Des Martin Periodine DMSO: Dimethyl sulfoxide EGTA: Ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid FCC: Flash Column Chromatography HATU:O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid HPLC: High-Performance Liquid Chromatography IPA: 2-propanol LDA: Lithium diisopropylamide MDAP: Automated purification using mass spectrometry. Min: minutes MP-Carbonate: Polymer-bonded tetraalkylammonium carbonate (macroporous) NMP: N-methylpyrrolidinone RT: retention time TBME: tert-butylmethyl ether TFA: Trifluoroacetic acid THF: Tetrahydrofuran

[0423] In the following procedure, references to intermediates / example numbers after each starting material are usually given. This is provided solely as an aid to those skilled in the art of chemistry. Where the use of “similar” or “similar” procedures is mentioned, such procedures may include minor modifications, e.g., reaction temperature, amounts of reagents / solvents, reaction time, workup conditions, or chromatographic purification conditions, as will be understood by those skilled in the art.

[0424] NMR spectra were obtained using a Varian Unity Inova 400 spectrometer with a 5 mm inverse-detector triple-resonance probe operating at 400 MHz, a Bruker Avance DRX 400 spectrometer with a 5 mm inverse-detector triple-resonance TXI probe operating at 400 MHz, a Bruker Avance DPX 300 spectrometer with a standard 5 mm dual-frequency probe operating at 300 MHz, or a Bruker Fourier 300 spectrometer with a 5 mm dual-frequency probe operating at 300 MHz. Shifts relative to tetramethylsilane (δ=0 ppm) are shown in ppm. J values ​​are shown in Hz throughout. NMR spectra were assigned using CMC-Assist Version 2.3 or SpinWorks version 3.

[0425] The liquid chromatography-mass spectrometry (LCMS) method used is as follows:

[0426] [Table 9]

[0427] [Table 10]

[0428] [Table 11]

[0429] The MDAP method used was as follows:

[0430] MDAP method (standard-acidic): Agilent Technologies 1260 Infinity purification system with XSELECT CSH Prep C18 column (19 × 250 mm, 5 μm OBD) maintained at room temperature. Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% formic acid in acetonitrile Flow rate: 20ml / min Gradient program: 10% to 95%, 22 min, focusing on a specific, focused gradient. Sample: Injection of a 20-60 mg / mL solution in DMSO (+ optional formic acid and water).

[0431] MDAP method (basic): Agilent Technologies 1260 Infinity purification system with XBridge Prep C18 OBD column (19 x 250 mm, 5 μm OBD) maintained at room temperature. Mobile phase A: 0.1% aqueous ammonia Mobile phase B: 0.1% ammonia in acetonitrile Flow rate: 20ml / min Gradient program: 10% to 95%, 22 min, focusing on a specific, focused gradient. Sample: Injection of a 20-60 mg / ml solution in DMSO + any formic acid and water.

[0432] Example 1: (S)-1-[2-(5-bromo-1H-indazole-1-yl)phenyl]-2-(pyridine-2-yl)ethane-1-amine hydrochloride [ka] Intermediate 1A: Methyl 2-[2-(5-bromo-2-fluorobenzylidene)hydrazinyl]benzoate [ka] A mixture of 5-bromo-2-fluorobenzaldehyde (4.32 g), methyl 2-hydrazinyl benzoate (prepared according to Australian Journal of Chemistry vol.69(11)1268, 4.32 g), and cesium carbonate (6.95 g) in DMF (80 mL) was stirred overnight at room temperature. The mixture was poured into water being stirred at high speed, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound as a yellow solid (7.0 g). 1 H NMR (400MHz, DMSO-d6) 11.20 (1H, s), 8.32 (1H, s), 8.07 (1H, dd, J=2.5, 6.6Hz), 7.88-7.78 (2H, m), 7.59-7.53 (2H, m), 7.27 (1H, dd, J=8.8, 10.4Hz), 6.92-6.87 (1H, m), 3.88 (3H, s).

[0433] Intermediate 1B: {2-[2-(5-bromo-2-fluorobenzylidene)hydrazinyl]phenyl}methanol [ka] Lithium aluminum hydride (0.397 g) was gradually added to a stirred, cooled solution of methyl 2-[2-(5-bromo-2-fluorobenzylidene)hydrazinyl]benzoate (intermediate 1A, 3.5 g) in dry THF (40 mL) while maintaining the temperature below 5°C. Upon completion of the addition, the temperature was raised to room temperature, the mixture was stirred for 4.5 hours, and then cooled again to 0°C. The reaction mixture was quenched by adding water (0.4 mL), followed by 15% aqueous sodium hydroxide solution (0.4 mL), and finally water (1.2 mL), and then filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC elution with 0-30% ethyl acetate in petroleum ether to obtain the title compound as an orange solid (2.0 g). LCMS (Method 3) RT 3.82 m / z 305 / 307[MH + -18]

[0434] Intermediate 1C: [2-(5-bromo-1H-indazole-1-yl)phenyl]methanol [ka] Potassium tert-butoxide (0.47 g) was added to a solution of {2-[2-(5-bromo-2-fluorobenzylidene)hydrazinyl]phenyl}methanol (intermediate 1B, 0.542 g) in NMP (7 mL), the resulting mixture was stirred, and heated overnight at 100°C. After cooling, the mixture was added to water, the pH was adjusted to approximately 5 by adding potassium bisulfate, and then extracted with ethyl acetate. The organic layer was washed with water, dried, filtered (MgSO4), and the filtrate was concentrated under reduced pressure. The crude product was purified by FCC elution with 0-50% TBME in petroleum ether, in combination with the second experiment using {2-[2-(5-bromo-2-fluorobenzylidene)hydrazinyl]phenyl}methanol (intermediate 1B, 0.581 g), to obtain the title compound (0.198 g). LCMS (Method 3) RT 3.32 m / z 285 / 287[MH + -18]

[0435] Intermediate 1D: 2-(5-bromo-1H-indazole-1-yl)benzaldehyde [ka] DMP (0.257 g) was added to a solution of [2-(5-bromo-1H-indazole-1-yl)phenyl]methanol (intermediate 1C, 0.153 g) in DCM (4 mL), and the mixture was stirred overnight at room temperature under argon. Sodium thiosulfate aqueous solution was added, the mixture was extracted with DCM, washed with saturated sodium bicarbonate solution and brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as a brown solid (0.198 g). LCMS (Method 3) RT 3.67 m / z 301 / 303[MH + ]

[0436] Intermediate 1E: (S,E)-N-[2-(5-bromo-1H-indazole-1-yl)benzylidene]-2-methylpropane-2-sulfinamide [ka] A mixture of 2-(5-bromo-1H-indazole-1-yl)benzaldehyde (intermediate 1D, 0.198 g), (S)-2-methylpropane-2-sulfinamide (0.095 g), and cesium carbonate (0.257 g) in DCM (5 mL) was stirred and heated overnight under gentle reflux. The resulting mixture was concentrated under reduced pressure, and the residue was separated into water and ethyl acetate. The layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC elution with 0-30% ethyl acetate in petroleum ether to obtain the title compound (0.124 g). 1 H NMR (400MHz, CDCl3) 8.40 (1H, s), 8.25 (1H, dd, J=1.3, 8.0Hz), 8.19 (1H, d, J=0.9Hz), 7.96-7.95 (1H, m), 7.67 (1H, ddd, J=7.6, 7.6, 1.5Hz), 7.60-7.57(1H, m), 7.57-7.53(1H, m), 7.47(1H, dd, J=1.7, 9.0Hz), 7.25-7.23(1H, m), 1.21(9H, s).

[0437] Intermediate 1F: (S)-N-{(S)-1-[2-(5-bromo-1H-indazole-1-yl)phenyl]-2-[pyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide [ka] n-butyllithium (2.5 M in hexane, 0.1 mL) was added to a stirred, chilled solution of 2-methylpyridine (0.024 mL) in THF (1 mL) while maintaining the temperature below -70°C. Upon completion of the addition, the mixture was stirred at -78°C for 15 minutes, and then a solution of (S,E)-N-[2-(5-bromo-1H-indazole-1-yl)benzylidene]-2-methylpropane-2-sulfinamide (intermediate 1E, 0.045 g) in THF (1 mL) was added. The mixture was stirred at -78°C for 30 minutes, and then warmed to -30°C. Saturated ammonium chloride was added, and the mixture was warmed to room temperature and separated into water and ethyl acetate. The layers were separated, the aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC (Fiber Culling) elution with 0-100% ethyl acetate in petroleum ether, followed by 0-2% methanol in ethyl acetate, to obtain the title compound (0.041 g). 1 H NMR (400MHz, CDCl3) 8.42 (1H, dd, J=0.8, 4.8Hz), 8.20 (1H, d, J=1.0Hz), 7.97 (1H, d, J=1.3H z), 7.68(1H, dd, J=1.5, 7.8Hz), 7.48-7.42(3H, m), 7.40(1H, dt, J=1.2, 7.5Hz), 7.31(1H, dd , J=1.6, 8.1Hz), 7.22(1H, d, J=8.9Hz), 7.06(1H, ddd, J=1.1, 4.9, 7.5Hz), 6.78(1H, d, J=7.6 Hz), 5.56 (1H, d, J=6.8Hz), 4.67-4.60 (1H, m), 3.11 (1H, m), 2.94-2.87 (1H, m), 0.97 (9H, s).

[0438] Example 1: (S)-1-[2-(5-bromo-1H-indazole-1-yl)phenyl]-2-(pyridine-2-yl)ethane-1-amine hydrochloride [ka] Hydrogen chloride (4M, 0.18 mL) in dioxane was added to a solution of (S)-N-{(S)-1-[2-(5-bromo-1H-indazole-1-yl)phenyl]-2-[pyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide (intermediate 1F, 0.04 g) in methanol (0.5 mL). The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by MDAP under acidic conditions, the purified material was dissolved in methanol, and MP-carbonate was added. The mixture was allowed to stand for 1 hour, then filtered, and the solid was washed with methanol. The filtrate was concentrated under reduced pressure, the residue was dissolved in dioxane, treated with hydrogen chloride (4M) in dioxane, and concentrated under reduced pressure. The residue was dissolved again in water and freeze-dried to obtain the title compound as a white solid (0.02 g). 1 H NMR (400MHz, DMSO-d6)8.79(3H, br s), 8.32(1H, d, J=0.9Hz), 8.17-8.13(1H, m), 8.12-8.06(2H, m), 7.72-7.62(2H, m), 7.55(1H, dt, J=1.2, 7.8Hz), 7.48(1H, dd, J=1.7, 8 .8Hz), 7.43(1H, dd, J=1.2, 7.9Hz), 7.23-7.16(1H, m), 7.08(2H, d, J=8.8Hz), 4.77-4.66(1H, m), 3.46-3.40(1H, m), 3.39-3.30(1H, m). LCMS (Method 1) RT 3.22 m / z 393 / 395[MH + ]

[0439] Example 2: (S)-6-{2-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-aminoethyl}-5-methylpyridine-2-carbonilicate hydrochloride [ka] Intermediate 2A: Ethyl 3-(1H-indazole-1-yl)pyridine-2-carboxylate [ka] Sodium hydride (60% oil dispersion, 0.4 g) was gradually added at 0°C to a chilled solution of 1H-indazole (1.18 g) in DMF (20 mL). The resulting mixture was stirred in an ice bath until foaming ceased. The chilled bath was removed, and ethyl 3-fluoropyridine-2-carboxylate (1.52 g) was added. The resulting mixture was stirred at room temperature for 6 hours, then heated at 70°C for 2.5 hours. After cooling, the mixture was diluted with water and brine, extracted with ethyl acetate, washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC elution with 0-50% ethyl acetate in pentane to obtain the title compound (0.81 g). 1 H NMR (400MHz, CDCl3) 8.77(1H, dd, J=1.5, 4.7Hz), 8.23-8.23(1H, s), 8.05(1H, dd, J=1.5, 8.1Hz), 7.83-7.81(1 H, m), 7.63 (1H, dd, J=4.7, 8.1Hz), 7.44-7.42 (2H, m), 7.28-7.23 (1H, m), 4.15-4.09 (2H, m), 0.99-0.95 (3H, m).

[0440] Intermediate 2B: 3-(1H-indazole-1-yl)pyridine-2-carboxyaldehyde [ka] 18 mL of DIBAL (1 M solution in DCM) was added dropwise to a stirred, cooled solution of ethyl 3-(1H-indazole-1-yl)pyridine-2-carboxylate (intermediate 2A, 3.45 g) in DCM (77 mL) while maintaining the temperature below -60°C. The mixture was stirred further at -78°C for 1.5 hours, and then methanol (5 mL) was added. The resulting mixture was stirred again at -78°C for 2.5 hours, and then warmed to room temperature. It was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by FCC elution with 0-100% ethyl acetate in DCM to obtain the title compound as a yellow oil, which solidified upon standing (2.3 g). 1H NMR (400MHz, CDCl3) 10.07 (1H, s), 8.91 (1H, dd, J=1.4, 4.5Hz), 8.30 (1H, s), 8.07 (1H, dd, J=1.5, 8.1Hz), 7.88 -7.85(1H, m), 7.70(1H, dd, J=4.6, 8.1Hz), 7.50-7.45(1H, m), 7.38(1H, dd, J=0.6, 8.5Hz), 7.33-7.28(1H, m).

[0441] Intermediate 2C: (S,E)-N-{[3-(1H-indazole-1-yl)pyridine-2-yl]methylene}-2-methylpropane-2-sulfinamide [ka] It is prepared by starting with 3-(1H-indazole-1-yl)pyridine-2-carboxyaldehyde (intermediate 2B) and (S)-2-methylpropane-2-sulfinamide and proceeding in the same manner as intermediate 1E. 1 H NMR (400MHz, CDCl3) 8.91 (1H, dd, J=1.5, 4.6Hz), 8.58 (1H, s), 8.27-8.27 (1H, m), 7.98 (1H, dd, J=1.6, 8.1Hz), 7.8 4-7.81 (1H, m), 7.61 (1H, dd, J=4.6, 8.1Hz), 7.45-7.40 (1H, m), 7.33-7.28 (1H, m), 7.27-7.25 (1H, m), 1.16 (9H, s).

[0442] Intermediate 2D: (S)-N-{(S)-1-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-[6-bromo-2-methylpyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide [ka] LDA (2M heptane, ethylbenzene, 1 mL in THF) was added dropwise to a stirred, cooled solution of 6-bromo-2,3-dimethylpyridine (0.4 g) in THF (8 mL) while maintaining the temperature below -60°C. Upon completion of the addition, the mixture was stirred at -78°C for 1 hour, and then added by cannula to a pre-cooled (-78°C) solution of (S,E)-N-{[3-(1H-indazole-1-yl)pyridine-2-yl]methylene}-2-methylpropane-2-sulfinamide (intermediate 2C, 0.25 g) in THF (4 mL). The resulting mixture was stirred at -78°C for 1 hour, and then warmed to room temperature. It was separated into ethyl acetate and water, the organic layer was dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC elution with 0-5% methanol in DCM to obtain the title compound (0.305 g). 1 H NMR (400MHz, CDCl3) 8.75-8.72 (1H, m), 8.23 ​​(1H, s), 7.84-7.81 (1H, m), 7. 71-7.68(1H, m), 7.52-7.43(2H, m), 7.41-7.37(1H, m), 7.29-7.23(1H, m), 7.06-7.05(2H, m), 5.28-5.24(1H, m), 5.02-4.95(1H, m), 3.18(1H, dd, J=5 .9, 13.4Hz), 3.09 (1H, dd, J=9.1, 13.8Hz), 1.77 (3H, s), 1.06-1.05 (9H, s).

[0443] Intermediate 2E: (S)-N-{(S)-1-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-[6-cyano-2-methylpyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide [ka] A mixture of (S)-N-{(S)-1-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-[6-bromo-2-methylpyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide (intermediate 2D, 0.305 g), zinc cyanide (0.21 g), and tetrakis(triphenylphosphine)palladium (0.139 g) in DMF (5 mL) was degassed and heated in a sealed vial at 90°C for 2 hours. After cooling, the mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (0.27 g). 1 H NMR (400MHz, CDCl3) 8.75-8.72 (1H, m), 8.24 (1H, s), 7.86-7.83 (1H, m), 7.7 4-7.70(1H, m), 7.50-7.47(2H, m), 7.41(1H, dd, J=4.4, 8.0Hz), 7.37-7.34( 1H, m), 7.30-7.27(2H, m), 5.24-5.19(1H, m), 5.09-4.98(1H, m), 3.28(1H, d d, J=5.9, 14.0Hz), 3.19 (1H, dd, J=8.7, 14.0Hz), 2.03 (3H, s), 1.05 (9H, s).

[0444] Example 2: (S)-6-{2-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-aminoethyl}-5-methylpyridine-2-carbonilicate hydrochloride [ka] The preparation proceeds in the same manner as in Example 1, but starting with (S)-N-{(S)-1-[3-(1H-indazole-1-yl)pyridine-2-yl]-2-[6-cyano-2-methylpyridine-2-yl]ethyl}-2-methylpropane-2-sulfinamide (intermediate 2E), it is dissolved in acetonitrile, treated with a 0.1 M aqueous HCl solution, and converted to the HCl salt by freeze-drying. 1H NMR (400MHz, DMSO-d6) 8.87 (1H, dd, J=1.4, 4.7Hz), 8.61 (3H, s), 8.38-8.37 (1 H, m), 8.07(1H, dd, J=1.4, 8.1Hz), 7.89-7.86(1H, m), 7.72(1H, dd, J=4.7, 8.1H z), 7.50-7.46(1H, m), 7.43-7.39(1H, m), 7.36-7.34(1H, m), 7.31-7.26(1H, m ), 7.23-7.20(1H, m), 5.30-5.24(1H, m), 3.27-3.23(2H, m), 1.94-1.93(3H, m). LCMS (Method 1) RT 2.84 m / z 355[MH + ]

[0445] The compounds in Table 3 were prepared using the same methods as those described for Examples 1 and 2.

[0446] [Table 12]

[0447] [Table 13]

[0448] [Table 14]

[0449] [Table 15]

[0450] [Table 16]

[0451] [Table 17]

[0452] Table 18

[0453] Table 19

[0454] Table 20

[0455] Table 21

[0456] Table 22

[0457] Table 23

[0458] Table 24

[0459] Table 25

[0460] Table 26

[0461] Table 27

[0462] Table 28

[0463] Biological assays The biological effects of the compound can be evaluated using one or more of the assays described herein.

[0464] Example 50: Assay for HCN1, HCN2, and HCN4 Example 50A, Use of PatchXpress 7000A The following solutions were used to record the HCN current.

[0465] [Table 29]

[0466] For HCN1 and HCN2, the pulse protocol involved stepping from a holding potential of -30mV to -110mV over 2 seconds to induce a current (see Figure 1A). The membrane voltage was then stepped back down to -30mV over a further 8 seconds. This sequence was repeatedly induced every 10 seconds throughout the experiment, starting before the drug (control A) and during the cumulative addition of five increasing compound concentrations, followed by cesium chloride (CsCl, 3mM) at a 100% inhibitory concentration.

[0467] For HCN4, the pulse protocol involved stepping from a holding potential of -30mV to -130mV over 4 seconds to induce a current (see Figure 1B). The voltage protocol then involved stepping the membrane voltage back down to -30mV, with a 14-second interval between initiations, starting before the drug (control A), and then cumulatively adding increasing compound concentrations, followed by cesium chloride (CsCl, 3mM) at a 100% inhibitory concentration.

[0468] The peak inward current measured at the end of pulses to -110mV (HCN1 and HCN2) or -130mV (HCN4) was measured, and the HCN current was calculated by subtracting the leakage current. The HCN current amplitude was measured after each control or compound addition and normalized against the control amplitude (control A).

[0469] All experiments were conducted at room temperature (approximately 22°C).

[0470] Each test compound concentration was applied to cells over a period of 7 minutes, at which point the next cumulative concentration was applied. 3 mM CsCl was applied to each cell over 2 minutes at the end of each experiment (control B) to determine the 100% inhibition level of the HCN current.

[0471] Example 50B, Use of Sophion Qube The following solutions were used to record the HCN current.

[0472] [Table 30]

[0473] For HCN1 and HCN2, the cells were held at -30mV, then stepped to -110mV for 2 seconds, and then stepped back to -30mV, representing one experimental sweep. This voltage protocol was applied every 20 seconds over the duration of the experiment. Both vehicle (0.3% DMSO) and complete blockade (3mM CsCl) addition periods were applied for 10 experimental sweeps each. Compound addition periods were applied for 30 sweeps.

[0474] For HCN4, cells were held at -30mV, then stepped to -130mV for 4 seconds, and then stepped back to -30mV, representing one experimental sweep. This voltage protocol was applied every 20 seconds over the duration of the experiment. Both vehicle (0.3% DMSO) and complete blockade (3mM CsCl) addition periods were applied for 10 experimental sweeps each. Compound addition periods were applied for 30 sweeps.

[0475] The current induced by stepping to -110mV (HCN1 and HCN2) or -130mV (HCN4) was measured for the analysis of percentage inhibition by the test compounds. The current amplitude was measured by subtracting criterion A from criterion B, along with the inhibition calculated by normalizing for vehicle addition (0.3% DMSO) and the complete inhibition by 3mM CsCl in the same well (see Figure 2).

[0476] Efficacy of test compounds that inhibit HCN ion channels (IC) 50 The reaction was determined from concentration-response curves generated from up to eight test compound concentrations, with a maximum of eight replicates per concentration. The compounds were applied to the wells for a total of 600 seconds.

[0477] Example 51: Assay for hERG Example 51A, Using IonWorks Quattro The solution used to record the hERG current was as follows:

[0478] [Table 31]

[0479] Electrophysiological recordings were performed from human embryonic kidney (HEK) cell lines that stably express full-length hERG channels. Single-cell ion current was measured using Molecular Devices' IonWorks Quattro at room temperature (approximately 22°C) in a perforated patch clamp configuration (100 μg ml). -1 The measurement was taken using amphotericin.

[0480] The cells were held at a holding potential of -70mV for 30 seconds, then stepped to +40mV for 1 second. Following this, a 1-second hyperpolarization step to -30mV was performed to induce an hERG tail current. This sequence was repeated five times at a frequency of 0.25Hz (see Figure 3). The current was measured from the tail step in the fifth pulse, and the holding current was referenced. The compounds were then incubated for 6–7 minutes before a second measurement of the hERG signal using the same pulse train.

[0481] The potency (IC50) of the test compound that inhibits hERG channels was determined from concentration-response curves generated from up to eight test compound concentrations, with up to four replicates per concentration.

[0482] Example 51B, Use of Sophion Qube The solution used to record the hERG current was as follows:

[0483] [Table 32]

[0484] The cells were held at a voltage of -80mV, then stepped to +40mV over 2 seconds, and then stepped back to -40mV over another 2 seconds, representing one experimental sweep. This voltage protocol was applied every 15 seconds over the duration of the experiment. Both the vehicle and the first compound addition period were applied for 10 sweeps. A second compound addition period was applied for 20 sweeps. The compound concentration was added to the test well twice to ensure complete exchange of the test compound with the external buffer. In total, the compound was applied to the wells over a period of 450 seconds.

[0485] The peak-tail current induced by the step to -40mV was measured for the analysis of percentage inhibition by the test compound. The peak-tail current was first normalized for vehicle addition (0.3% DMSO) in the same well.

[0486] The potency (IC50) of the test compound that inhibits hERG channels was determined from concentration-response curves generated from up to eight test compound concentrations, with up to four replicates per concentration.

[0487] Example 52: hNa v Assay for 1.5 Example 52A, Using IonWorks Quattro Na v 1.5 The solution used to record the current was as follows:

[0488] [Table 33]

[0489] Electrophysiological recording, full length hNa V The procedure was performed using human embryonic kidney (HEK) cell lines that stably express 1.5. Population patch-clamp measurements were performed using IonWorks Quattro from Molecular Devices at room temperature (approximately 22°C) using a perforated patch-clamp configuration (100 μg ml). -1 The procedure was performed using amphotericin. The voltage protocol is shown in Figure 4. The current was first measured under control (before compound addition) conditions. Next, the compound was added using the same pulse train as hNa V 1.5 The signal was incubated for 5–7 minutes before the second measurement. The current was measured from the depolarization step in the 15th pulse and referenced to the holding current.

[0490] Example 52B, Use of Sophion Qube The cells were held at -100mV, followed by a depolarization process to -10mV over 100ms, and then stepped back up to -100mV, representing one experimental sweep. This voltage protocol was applied at 0.1Hz and 4Hz to obtain hNa v1.5 The potential for both sustained and use-dependent blockade was evaluated for each channel. The vehicle and compound addition duration were applied as a series of 20 depolarizations at a frequency of 4 Hz to evaluate sustained blockade (20 sweeps) and to test use-dependent blockade (20 depolarizations).

[0491] For sustained blockade (0.1 Hz), the peak current induced by the step to -10 mV was measured for the analysis of percentage inhibition by the test compound. For use-dependent blockade (4 Hz), the peak current induced in the 20th depolarization step to -10 mV was measured for the analysis of percentage inhibition by the test compound. The peak currents were first normalized for vehicle addition (0.3% DMSO) in the same well. hNa v 1.5 Efficacy of test compounds that inhibit channels (IC 50 The ) was determined from concentration-response curves generated from up to eight test compound concentrations, with a maximum of four replicates per concentration, and used for use-dependent blockade.

[0492] Example 53: MDCK assay A bidirectional MDCK permeability assay was performed using MDCK-MDR1 cells (Solvo Biotechnology) seeded at 2.35 × 10⁵ cells per well in a 24-well Transwell plate. These cells were cultured at 37°C for 3 days under 5% CO₂ and used in a confluent monolayer. The test compound (10 μM, 0.1% DMSO final, n=2) was added to the donor compartment of the Transwell plate assembly in assay buffer (Hanks equilibrium salt solution supplemented with 25 mM HEPES, adjusted to pH 7.4) for both apical-to-basolateral (A>B) and basolateral-to-apical (B>A) measurements. A series of parallel incubations were performed in the presence of the transporter inhibitor elacridal (5 μM) added to both compartments in the Transwell plate. Incubation was performed at 37°C, and samples were removed from both the donor and acceptor chambers at T=0 and 1 hour for recovery evaluation. The compounds were analyzed by mass spectrometry (LC-MS / MS) including an analytical internal standard. The apparent permeability (Papp) value was determined from the following relation: Papp = [Compound acceptor T = end] × V acceptor / ([Compound donor T = 0] × V donor) / incubation time × V donor / area × 60 × 10⁻⁶ cm / s In the formula, V is the volume of each Transwell compartment (125 μL at the apex and 600 μL at the sides and bottom), and the concentration is the relative MS reaction (normalized to an internal standard) to the compound in the donor chamber before incubation and in the acceptor chamber at the end of incubation. Area = Area of ​​cells exposed for drug transfer (0.33 cm²).

[0493] The efflux ratio (PappB>A / PappA>B) was calculated for each compound from the average Papp value in each direction. The MDCK-MDR1 cell line was engineered to overexpress the efflux transporter, MDR1 (P-glycoprotein), and the finding that it exhibits good permeability B>A but low permeability A>B suggests that the compound is a substrate for this transporter. The efflux ratio was calculated in the same way as in the implementation performed in the presence of the inhibitor. Net efflux is the ratio of efflux in the absence of the inhibitor to efflux in the presence of the inhibitor. A net efflux value > 5 (i.e., the efflux ratio without the inhibitor divided by the efflux ratio with the inhibitor) indicates a compound that is a substrate for the transporter P-gp and therefore would have a higher probability of being restricted from the central nervous system (i.e., restricted to the periphery).

[0494] Lucifer Yellow (LY) was added to the apical buffer in all wells to assess cell layer viability. Since LY cannot freely permeate the lipid-soluble barrier, high levels of LY transport are observed, with LY Papp > 10 × 10⁻⁶. -6 A cell layer with a density of cm / s indicates rejection due to low well integrity. Note that a defect in the integrity of one well does not affect the effectiveness of the other wells on the plate.

[0495] Compound recovery from the wells was determined by MS reactions (normalized to an internal standard) in the donor and acceptor chambers at the end of incubation, compared to the reaction in the donor chamber before incubation. Recovery rates <50% suggest problems with the solubility, stability, or binding of the compound in the assay, which can reduce the reliability of the results.

[0496] Biological data Table 4 shows the ICs for HCN2 and HCN using the PatchXpress protocol (PX) for the compounds being tested. 50 The value is shown in μM units.

[0497] [Table 34]

[0498] Table 5 shows the ICs for HCN2 and HCN using the Sophion Qube protocol (SQ) for the compounds being tested. 50 The value is shown in μM units.

[0499] [Table 35]

[0500] Example 54: Effect of pharmacological blockade of HCN2 ion channels on tinnitus Tinnitus in guinea pigs was monitored using gap induction inhibition in the Acoustic Startle Assessment Test (GPIAS) (see Figure 5). When tinnitus was present, the GPIAS score was reduced; see Berger, J. I et al. Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs. Hearing Research, (2017) and Coomber, B. et al. Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig. Eur J Neurosci 40, 2427-2441, (2014).

[0501] In Figure 5, auditory stimuli (above) and the corresponding auricular reflexes (below) are shown in freely moving guinea pigs. Stimuli with and without gaps are shown in a random order. Traces contaminated by movement (upper trace in the "no gap" section) were removed before analysis.

[0502] Tinnitus was induced in humans within 1-2 hours by high doses of salicylate. A similar short-term tinnitus model was implemented in guinea pigs by intraperitoneal (ip) injection of salicylate. In all animals, salicylate caused behavioral inhibition of GPIAS (see bar 2 in Figure 6). Blockade of HCN ion channels with the non-selective inhibitor ivabradine (equally blocking HCN1-4) improved GPIAS (see bar 3 in Figure 6). Therefore, HCN ion channel blockade was found to improve the behavioral signs of tinnitus in this short-term (salicylate) model.

[0503] Salicylate (350 mg / kg, intraperitoneal (ip)) impaired behavioral gap detection 2 hours after salicylate administration (see bar 2 in Figure 6). Gap detection was restored by blocking HCN channels with ivabradine (5 mg / kg, subcutaneous (sc)).

[0504] Mild unilateral noise exposure was found to reduce GPIAS in approximately 40% of guinea pigs, an observation similar to the effects of noise in humans, where noise exposure causes tinnitus in some, though not all, subjects. The noise exposure model is more clinically significant than the salicylate model because it is similar to the common causes of tinnitus in humans. A second important point is that salicylate-induced tinnitus improves rapidly after salicylate exposure, while salicylate-induced tinnitus is long-term.

[0505] The reduction in GPIAS observed after noise exposure (see bar B in Figure 7) was found to be rapidly and completely improved by ivabradine-mediated HCN ion channel blockade, which equally blocks all four HCN ion channel isoforms (see bar C in Figure 7). GPIAS returned after drug washout (see bar D in Figure 7). Therefore, HCN ion channel blockade was found to eliminate the behavioral manifestations of tinnitus.

[0506] A peripherally restricted and HCN2-selective compound ("Compound 476" in Figure 7), which is chemically unrelated to ivabradine and outside the scope of the claims, also induced a complete improvement in "tinnitus" behavior (see bar E in Figure 7). In a control experiment with noise-exposed guinea pigs that did not exhibit behavioral evidence of tinnitus, ivabradine had no effect on GPIAS (n=3, results not shown). Similar results obtained in short-term salicylate and long-term noise exposure models suggest that tinnitus is initiated and maintained by the activity of HCN2 ion channels. Bar A: Untreated guinea pigs showed a significant reduction in acoustic startle responses after short gaps in continuous noise. Bar B: After unilateral noise exposure (NE, 110 dB, 1 hour, 8 weeks prior to the test), approximately 40% of the guinea pigs developed reduced GPIAS. • Bar C: The non-selective HCN inhibitor ivabradine (5 mg / kg, subcutaneous (sc)) completely resolves GPIAS. Dark gray bar: Reduced GPIAS returns after drug washout (1-2 days). • Compounds exhibiting higher selectivity for HCN2 than HCN1 (28x) and HCN4 (63x) completely restored GPIAS at the same dose (0.5 mg / kg, subcutaneous (sc)) that achieved complete blockade of neuropathic pain.

[0507] In a control experiment using noise-exposed guinea pigs that did not exhibit behavioral tinnitus, ivabradine had no effect on gap detection (not shown).

[0508] Example 55: Evaluation of central nervous system penetration of the HCN blocker ivabradine Ivabradine was assayed in guinea pig plasma, brain (somatosensory cortex), and auditory nerves 30 minutes after injection (the time used in Example 130).

[0509] Ratio of total concentrations in preliminary experiments on plasma: Brain:Auditory nerve was 1:0.12:0.57 (n=2). The small amount detected in the brain (12% of plasma concentration) is mainly explained by the presence of ivabradine in the cerebral vascular supply. Therefore, as in other species, ivabradine is strongly excluded from the guinea pig brain due to its hydrophilicity and Pgp substrate activity; see Young, GT, Emery, EC, Mooney, ER, Tsantoulas, C. & McNaughton, PA Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarization-activated cyclic nucleotide-gated ion channels. Pain 155, 1708-1719, (2014).

[0510] The ratio of 0.57 between auditory nerve and total plasma concentration indicates that ivabradine is not eliminated from the auditory nerve and is therefore utilized in the plasma concentration of ivabradine. The difference from a value of 1 can be explained by the difference in binding to proteins in plasma and auditory nerve. Thus, it was found that the HCN blocker ivabradine penetrates the auditory nerve but not the central nervous system.

[0511] Example 56: Effects of HCN2 gene deletion or pharmacological blockade on auditory threshold In this example, the effects of HCN2 gene deletion or pharmacological blockade on the auditory brainstem response (ABR) threshold to pulsed sounds with frequencies of 3 kHz to 42 kHz were evaluated. The results are shown in Figure 8 for WT mice and sox10-Cre + / - / fHCN2 littermates (auditory targeted HCN2 deletion) did not show significant differences in ABR threshold or latency. Similar results were obtained in adult mice treated with the non-selective HCN blocker ivabradine and a chemically unrelated HCN2 selective blocker (20 mg / kg intraperitoneal (ip)). No significant difference in hearing was observed in mice with overall HCN2 gene deletion, however, in this case, HCN2 - / -Since the mice die within 3-4 weeks, their hearing was compared to that of 2-week-old wild littermates.

[0512] Mice with auditory-targeted HCN2 deletion (upper white line in Figure 8) and wild littermates (lower black line in Figure 8) showed no significant difference in either the threshold (Figure 8) or response latency (data not shown, latency of clicks and P1 and N1 waves measured at 12 kHz and 18 kHz). Therefore, deletion of HCN2 expressed in spiral ganglion neurons does not affect normal hearing threshold or response latency. Bars indicate standard deviation (SD) (n=6).

[0513] These results indicate that HCN2 is not involved in normal hearing and is activated only in pathological situations, such as after noise exposure.

[0514] Example 57: Mechanical analgesic effect of a compound in a mouse neuropathic pain model tested using von Frye filaments. The compounds from Example 2 and Example 4 were tested in a mouse neuropathic pain model using WT Black6 mice. The model used was similar to the one described in Seltzer Z, Dubner R, & Shir Y (1990), A novel behavioural model of neuropathic pain disorders produced in rats by partial sciatic nerve injury, Pain 43:205-218). Further details of the experimental procedure used are described in Young GT et al. (2014), Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarization-activated cyclic nucleotide-gated ion channels; Pain 155:1708-1719; and Tsantoulas C et al., (2017), Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci Transl Med 9:eaam6072.

[0515] The test compound was administered intraperitoneally (IP) to mice 5 days after surgery for partial sciatic nerve injury, and data from 3-4 mice were averaged. Mechanical pain threshold was measured using the "up-down" method with a manual von Floy filament applied to the hind limb on the operated side. The test compound was compared to intraperitoneal (IP) injection of 5 mg / kg ivabradine and vehicle.

[0516] The compound in Example 2 provided complete analgesia at 0.2 mg / kg intraperitoneal (ip) (Figure 9, "883")

[0517] The compound in Example 4 produced maximum analgesia at 2 mg / kg intraperitoneal (ip) (Figure 12 (A), "797") and 10 mg / kg (Figure 12 (B), "797").

[0518] No hyperalgesia was observed in the contralateral (unsurgered) hind limb of the mouse (see the dotted line in Figure 12).

[0519] Example 58: Bradycardia test The test compound was administered intraperitoneally (ip) to awake, behaving Black6 mice, along with a vehicle-only control arm. The mice's heart rate was measured using a MouseOx pulse oximeter.

[0520] The compound of Example 4 is 19-fold hyperselective to HCN2 than to HCN4 in the PatchXpress protocol (PX) assay described herein. As shown in Example 57, the compound of Example 4 provided maximum analgesia at a dose of 2 mg / kg. At this dose, the compound produced minimal bradycardia in mice, which was significantly lower than that of ivabradine administered at a dose of 5 mg / kg intraperitoneal (ip) (Figure 13).

[0521] The compound from Example 2 was administered to awake, behaving Black6 mice at doses ranging from 0.05 mg / kg to 2 mg / kg. The effect of the compound from Example 2 on heart rate is shown in Figure 11, compared to ivabradine administered at a dose of 5 mg / kg intraperitoneally (ip) and a vehicle control.

[0522] The compound of Example 2 is 21-fold selective to HCN2 than HCN4 in the PatchXpress protocol (PX) assay described herein. As shown in Example 57 and Figure 9, the compound of Example 2 provided complete analgesia at a dose of 0.2 mg / kg intraperitoneal (ip). At this dose, the compound produced minimal bradycardia in the mice tested (see Figure 11, Panel (A)).

[0523] In contrast, ivabradine blocks pain, but because it does not distinguish between HCN2 and HCN4, there is a small therapeutic range between analgesia and bradycardia in Black6 mice (Figure 10). The data shown in Figure 10 are based on inflammatory pain measured in a formalin model performed in Black6 mice. Mouse heart rates were measured using a MouseOx pulse oximeter in awake and behaving mice (data published from Young GT et al. (2014), Pain 155:1708-1719).

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, X １ is N or CR １ And; R １ is selected from H, halo, -CN, C １～６ alkyl, C １～６ haloalkyl, -OR Ｂ１ , C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl and C ３～６ cycloalkyl-C １～６ alkyl-, and R １ any alkyl, alkenyl, alkynyl or cycloalkyl group in R is optionally substituted with 1 to 4 substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl and -OR Ｂ２ ; R ２ Each time it appears independently, Halo, C １～６ Alkyl and C １～６ Selected from haloalkyls; X ２ is N or CR ３２ And; X ３ is N or CR ３３ And; R ３２ and R ３３ These are independently H, Halo, -CN, and C. １～６ Alkyl, C １～６ Haloalkyl, -NR Ａ３ R Ａ３ and -OR Ｂ３ Selected from; R ３ Each instance of these appears independently as Halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, -NR Ａ３ R Ａ３ and -OR Ｂ３ Selected from; R ４ , R ５ and R ６ These are H and C, respectively, independently. １～４ Selected from alkyl groups, or R ５ and R ６ C ３～６ Forms a cycloalkyl group; R ７ H, Halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, -C(O)NR Ａ４ R Ａ４ , -N(R Ａ４ ) C(O)R Ｂ４ and -C(O)R Ｂ４ Selected from; and R ８ H, Halo, -CN, Nitro, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, -OR １０ , -NR １０ R １１ , -S(O) ｘ R １０ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０Ａ , -C(O)NR １０ R １１ , -N(R １１ ) C(O)R １０ , -N(R １１ ) C(O)NR １０ R １１ , -N(R １１ ) C(O)OR １０ , -N(R １１ ) SO ２ R １０ , -SO ２ NR １０ R １１ , C ３～６ Selected from cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl group has 1 to 4 R １２ The group is optionally substituted with a group, and the phenyl or heteroaryl group has 1 to 4 R groups. １３ It is optionally substituted in the base; R ８１ and R ８２ These are H, Halo, -CN, and C, respectively, independently. １～４ Alkyl, C １～４ Haloalkyl, -OH, and -OR Ｂ８ Selected from; R ９ H, halo, -CN and C １～６ Selected from alkyl groups; R １０ , each occurrence independently, is selected from H, C １～６ alkyl, C １～６ haloalkyl and C ３～６ cycloalkyl; said alkyl or cycloalkyl group is substituted with 1 to 4 R １４ groups optionally substituted; R １０Ａ is C １～６ alkyl, C １～６ haloalkyl and C ３～６ selected from cycloalkyl; said alkyl or cycloalkyl group is substituted with 1 to 4 R １４ optionally substituted with a group; R １１ These appear independently, each time H and C appear. １～６ Selected from alkyl groups; or R １０ and R １１ Together with the nitrogen to which they are bound, they form a 4-7 membered heterocycline, and the heterocycline is a halo, =O,C １～４ Alkyl, C １～４ Haloalkyl and -OR Ｂ７ Optionally substituted with one or two substituents selected from; R １２ and R １４ Each of these appears independently, representing Halo, =O, -CN, Nitro, and C. １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, -OR Ｂ５ , -NR Ａ５ R Ａ５ , -S(O) ｘ R Ｂ５ , -C(O)R Ｂ５ , -NR Ａ５ C(O)R Ｂ５ , -C(O)NR Ａ５ R Ａ５ , -NR Ａ５ SO ２ R Ｂ５ and -SO ２ NR Ａ５ R Ａ５ Selected from; R １３ Each of these appears independently as Halo, -CN, Nitro, and C. １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, -OR Ｂ６ , -NR Ａ６ R Ａ６ , -S(O) ｘ R Ｂ６ , -C(O)R Ａ６ , -NR Ａ６ C(O)R Ｂ６ , -C(O)NR Ａ６ R Ａ６ , -NR Ａ６ SO ２ R Ｂ６ , -SO ２ NR Ａ６ R Ａ６ Selected from; R Ｂ１ These appear independently, each time H and C appear. １～６ Selected from alkyl groups; R Ｂ３ Each of these appears independently, with H and C. １～６ Alkyl and C １～６ Selected from haloalkyls; R Ｂ２ , R Ｂ４ , R Ｂ５ , R Ｂ６ , R Ｂ７ Each of these appears independently, with H and C. １～４ Alkyl and C １～４ Selected from haloalkyls; R Ｂ８ Each instance of it appearing independently is C １～４ Alkyl and C １～４ Selected from haloalkyls; R Ａ３ , R Ａ４ , R Ａ５ and R Ａ６ These appear independently, each time H and C appear. １～４ Selected from alkyl groups; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, or 2; and x is an integer that is independently selected from 0, 1, 2, and 3 each time it appears; however, (i) X １ If X is N, ２ CR ３２ and X ３ CR ３３ And; (ii) X １ CR １ And R １ If X is -CN, ２ CR ３２ and X ３ CR ３３ And; (iii)X １ CR １ And R １ ga-CF ３ If R ８ is, -SO ２ Me not; and (iv) X ２ and X ３ (It is not possible for both to be N.) A compound of or a pharmaceutically acceptable salt thereof.

2. R ７ H, halo and C １～４ A compound according to claim 1, selected from alkyl groups.

3. R ８ H, Halo, -CN, C １～４ Alkyl, C １～４ Haloalkyl, -C １～４ Alkyl-OR Ｂ５ -OH, -OC １～４ Alkyl, -OC ２～４ Alkyl-OR Ｂ５ , -C(O)C １～４ Alkyl, -S(O) ２ C １～４ Alkyl, -C(O)NH ２ , -C(O)N(H)C １～４ Alkyl and -C(O)N(C) １～４ Alkyl) ２ A compound according to claim 1 or 2, selected from the above.

4. R ８ H, -CN and -S(O) ２ C １～４ Selected from alkyl groups (optionally, R ８ -CN and -S(O) ２ A compound according to claim 1 or 2, selected from Me.

5. R ８ H, -CN and -S(O) ２ C １～４ Selected from alkyl; and R ７ H, halo and C １～４ Selected from alkyl, however, R ７ and R ８ The compound according to claim 1, wherein both atoms are not H.

6. R ７ is selected from fluoro and methyl, and R ８ H, -CN, C １～４ Alkyl, -C １～３ Alkyl-OH, -C １～３ Alkyl-OMe and -S(O) ２ C １～４ Selected from alkyl groups (optionally, R ８ H, -CN, C １～３ Alkyl and -S(O) ２ C １～３ A compound according to claim 1, selected from alkyl groups.

7. R ８１ and R ８２ These are H, Halo, and C, which are independent. １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ Alkyl and -OC １～４ A compound according to any one of claims 1 to 6, selected from haloalkyls.

8. R ８１ is a halo (e.g., F), and R ８２ The compound according to any one of claims 1 to 6, wherein is H.

9. base 【Chemistry 2】 teeth, 【Transformation 3】 (In the formula, ＊ (This indicates the bond point to the rest of the molecule.) A compound according to claim 1, selected from the following.

10. X ２ CR ３２ and X ３ CR ３３ (Optionally, R ３２ and R ３３ The compound according to any one of claims 1 to 9, wherein (is H).

11. X ２ N is N, and X ３ CR ３３ The compound according to any one of claims 1 to 9.

12. R ３３ H, halo and C １～３ Selected from alkyl groups (optionally, R ３３ This is Halo and C １～３ The compound according to claim 11, selected from alkyl groups.

13. X １ The compound according to any one of claims 1 to 10, wherein is N.

14. X １ CR １ And R １ H, Halo, -CN, C １～４ Alkyl, C １～４ Haloalkyl and -OR Ｂ１ Selected from, R １ The alkyl group in the above is -OR Ｂ２ The compound according to any one of claims 1 to 12, which is optionally substituted with

15. X １ CR １ And R １ H, Halo, -CN, C １～３ Alkyl and C １～３ A compound according to any one of claims 1 to 12, selected from haloalkyls.

16. X １ The compound according to any one of claims 1 to 12, wherein is CH.

17. The compound according to any one of claims 1 to 16, wherein n is 0.

18. The compound according to any one of claims 1 to 17, wherein m is 0.

19. R ９ H and C １～４ Selected from alkyl groups (optionally, R ９ The compound according to any one of claims 1 to 18, wherein (is H).

20. R ４ and R ５ H is H, and R ６ is H or C １～３ It is alkyl (optionally, R ４ , R ５ and R ６ The compound according to any one of claims 1 to 19, wherein (is H).

21. base 【Chemistry 4】 The formula is: 【Transformation 5】 It is such that, optionally, the base 【Transformation 6】 teeth, 【Transformation 7】 The compound according to any one of claims 1 to 20.

22. The compound is 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical agent.

25. A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions mediated by hyperpolarizing activated cyclic nucleotide-modulated ion channels 2 (HCN2).

26. The disease or condition mediated by HCN2 is pain, for example, neuropathic pain or inflammatory pain (for example, the pain is peripheral neuropathic pain), the compound for use according to claim 25.

27. A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, for use in the treatment of tinnitus or related disorders.

28. An HCN2 inhibitor for use in the treatment of migraines, The HCN2 inhibitor is an HCN2 inhibitor which is a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

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