Azaindazole derivatives useful as HCN2 modulators

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, (I) can inhibit HCN2 and are expected to have utility as therapeutic agents, for example, for treating inhibiting, or ameliorating pain, such as, inflammatory and / or neuropathic pain, central nervous system (CNS) and psychiatric disorders, mood disorders, and tinnitus. The disclosure also provides pharmaceutical compositions which comprise the compounds disclosed herein or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of, pain, such as, inflammatory and / or neuropathic pain, central nervous system (CNS) and psychiatric disorders, mood disorders, and tinnitus, and for preparing pharmaceuticals for this purpose.

Description

25835 AZAINDAZOLE DERIVATIVES USEFUL AS HCN2 MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 586,337 filed September 28, 2023, the entire contents of which are incorporated by reference herein. FIELD OF THE INVENTION

[0002] The present disclosure relates to certain azaindazole compounds that inhibit hyperpolarization activated cyclic-nucleotide modulated ion channel (HCN channel) activity, and selective to HCN2 isoform, pharmaceutical compositions comprising such compound, and methods for using the compounds for treating, inhibiting, or ameliorating pain, such as, inflammatory and / or neuropathic pain, central nervous system (CNS) disorders, mood disorders, and tinnitus. BACKGROUND OF THE INVENTION

[0003] Nociception is the sensory nervous system’s process to detect potentially harmful stimuli to the body resulting from the internal or external stimuli, such as extreme temperatures or tissue injury, and is generated by the activation of nociceptors and their pathways. The nociceptors transmit information to the brain where the perception of acute pain is generated. These receptors can be found on the skin, joints, viscera, and muscles. Nociception is an important sense that warns an individual against present or imminent damage resulting in an acute pain signal. However, in patients with chronic pain, this warning signal persists in the absence of any genuine threat and can impose major limitations on lifestyle and working patterns.

[0004] Inflammatory pain (IP) results from the increased sensitivity of peripheral nociceptive sensory fibers produced by the action of inflammatory mediators released from damaged, inflamed, or stressed tissues onto nociceptive (pain-sensing) nerve terminals. IP may be chronic or acute. Acute IP is associated with the immediate inflammatory response following tissue damage or injury and includes, for example, post-operative pain, dental pain and injury such as sprains or muscle tears. In general, acute IP resolves as the injury heals. However, IP can also be chronic. Chronic IP is a feature of many medical conditions, for example infection, injury, osteoarthritis and rheumatoid arthritis.

[0005] IP is typically treated with non-steroidal anti-inflammatory drugs (NSAIDs) or in more severe cases with opioids, both of which are effective and associated with major side effects.Undesirable side-effects related to NSAIDs include gastric and renal complications, together with an increased incidence of myocardial infarction. Side effects associated with opioids include constipation and CNS side effects, for example cognitive impairment, sedation, and addiction. Moreover, even at normal doses opiates promote respiratory depression and are the cause of many premature deaths.

[0006] Neuropathic pain (NP) is a form of chronic pain caused by damage to and / or dysfunction of sensory nerves of the peripheral or sympathetic nervous system, for example a lesion or disease of the somatosensory system, including peripheral fibers (Aβ, Aδ and C fibers) and central neurons. The damage to the somatosensory system results in disorderly transmission of sensory signals to the brain and triggers the generation of pain. Symptoms of neuropathic pain include abnormal sensation of painful and other stimuli, known as dysesthesia (e.g. hyperesthesia, hyperalgesia, allodynia (pain due to a non-noxious stimulus), and hyperpathia) and / or ongoing pain, typically sensed as deep and aching pain. NP is often long-lasting and typically persists after apparent resolution of the primary cause.

[0007] An estimated 50 million patients world-wide suffer from chronic non-malignant pain, defined as pain of greater than 3 months' duration that is not related to cancer. Neuropathic pain affects about 8% of people in the Western World sometime during their life.

[0008] In Small Fiber Sensory Neuropathy (SFSN), the small sensory cutaneous nerves are affected. (See, Small Fiber Sensory Neuropathy (hopkinsmedicine.org)). Examples of SFSN are outlined as follows. Painful diabetic neuropathy (PDN), the pain resulting from nerve damage caused by Type 1 and Type 2 diabetes, is a major patient burden which is rapidly growing with the increasing incidence of obesity and has no highly efficacious treatment options at this stage. Post-herpetic neuralgia (PHN), a long-lasting pain following a Herpes zoster (shingles) eruption, is also a significant problem, particularly amongst the elderly. Pain caused either by cancer or by the chemotherapeutic agents used to treat it (chemotherapy-induced peripheral neuropathy, CIPN) imposes an additional patient burden, and the ability of patients to tolerate the neuropathic pain induced by chemotherapy is often a limiting factor in treatment. Post-operative neuropathic pain sometimes occurs following surgical procedures causing patients chronic pain that may persist long after the surgical wound has healed.

[0009] In addition to these specific small fiber neuropathies, there are also idiopathic forms of painful small fiber neuropathies where the cause is unknown. In addition to these major patient groups there are many rarer but excruciating neuropathic pain conditions such as trigeminal neuralgia, complex regional pain syndrome (CRPS) and pudendal neuralgia. In addition, many clinicians believe, on the basis that drugs used to treat neuropathic pain have some efficacy inthese conditions, that there is a neuropathic pain component in many common conditions involving nerve damage or compression, such as lower back pain, nerve damage following traumatic injury (e.g. whiplash injury in car crash), fibromyalgia and carpal tunnel syndrome.

[0010] Existing therapies for NP, such as gabapentinoids, serotonin norepinephrine reuptiake inhibitors (SNRI) and tricyclic antidepressants, have poor efficacy, with as many as 70% of patients reporting limited or no relief and with the number needed to treat to obtain 50% relief in a single patient (NNT) typically in the range 7-10 (Finnerup, N. B. et al., 2015, Lancet Neuro / . 14, 162-173). There are also numerous side effects associated with existing therapies for NP.

[0011] There remains a need for new treatments for pain, particularly IP and NP.

[0012] The Hyperpolarization activated, Cyclic-Nucleotide (HCN) modulated ion channels comprise four isoforms, HCN 1, 2, 3 and 4, which carry an inward current called Ih (also known as If, Iqor It) activated by hyperpolarization in the range of membrane potentials between -60 and -90mV (Kaupp & Seifert (2001) "Molecular diversity of pacemaker ion channels." Annu. Rev. Physiol.63: 235-257.

[0013] The HCN isoforms perform an important pacemaker function in both cardiac and nervous tissue. HCN4 is considered the major regulator of cardiac rhythmicity. Inducible deletion of cardiac HCN4 causes a progressive decrease in heart rate which is fatal in mice after a few 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, the sine-atrial 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. Mo / . Cell. Cardiol.51, 997-1006, 2011.

[0014] HCN1 and HCN2 are the predominant isoforms expressed in both brain and somatosensory neurons (Ludwig et al., 2003, ibid). NP has traditionally been attributed to sensitization and / or remodeling of the CNS. However, in more recent work it has been shown using peripherally restricted blockers of HCN ion channels and by recordings of activity in single nociceptors (pain sensitive nerve fibers) that pain continues to have its origin in repetitive firing of peripheral nociceptors even long after the initial injury has apparently resolved. These findings suggest that peripherally restricted blockers of HCN ion channels would provide 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.

[0015] The negative membrane potential range of activation of HCN ion channels means that they are hardly activated at the resting membrane potential of nerve fibers, which seldom is more negative than -60mV. However, many inflammatory mediators, amongst them the potent pro- inflammatory agents PGE2 and bradykinin, bind to Gs-coupled GPCRs which thus activate adenylate cyclase and so cause an increase in cAMP (cyclic adenosine monophosphate), which in turn binds directly to a site in the C-terminal domain of HCN ion channels. The voltage range of activation of the HCN2 and HCN4 isoforms, but not HCN1 and HCN3, is shifted in the positive direction by increased intracellular cAMP. The inward current passing through activated HCN2 ion channels in nociceptive nerve fibers therefore triggers repetitive firing, resulting in a sensation of pain 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 Ihcurrently in nociceptors following neuronal damage or inflammation, though other studies have failed to find a change in expression or even found a decrease (reviewed in Tsantoulas, C., et al. (2016), ibid).

[0017] It has been shown that HCN2 is expressed in nociceptive (pain-sensitive) neurons, and that modulation of the voltage-dependence of HCN2 by inflammatory mediators such as PGE2 is a major contributor to IP. It has also been shown in mouse models for inflammatory pain (including pain elicited by injection of PGE2, carrageenan and formalin) that blockage and / or targeted genetic deletion of HCN2 provides analgesia (Emery et al.2011, ibid).

[0018] In a study in a chronic constriction injury (CCI) mouse model of NP in which HCN2 had been genetically deleted from nociceptors, the mice showed no sign of NP following a nerve lesion (Emery et al., 2011 ibid.). Subsequent studies have shown that ivabradine, a non-selective blocker of HCN ion channels, is an effective analgesic in a variety of mouse models of neuropathic pain, including nerve injury, cancer chemotherapy and diabetic neuropathy models (Young et al., 2014, ibid; Tsantoulas et al., 2017, ibid).

[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 blockers used were peripherally restricted and the targeted genetic deletion was restricted to peripheral nociceptive neurons. In mouse models global genetic deletion of all HCN2, in contrast, caused epilepsy, failure to gain weight and early death (Ludwig et al. Int. J. Mol. Sci.2015 Jan; 16(1): 1429-1447). Thus, a peripherally restricted HCN2 blocker is expected to provide an effective analgesic for NP and IP while also avoiding CNS mediated side effects which may be associated with blocking HCN2 channels in the brain. The avoidance or minimization of CNS side-effects would also address a major problem with other analgesics such as opioids and gabapentinoids.Selective HCN2 blockers may also avoid some or all of the undesirable gastric, renal and cardiac side effects associated with NSAIDS or the constipation caused by opiates.

[0020] Experiments (Tsantoulas C et al.2017 ibid) have shown that ivabradine and nociceptor- targeted genetic deletion of HCN2 both give complete analgesia in a mouse model of diabetic neuropathy, which closely mimics the human condition. These experiments demonstrate that neuropathic pain is primarily peripheral in origin, because in each case the intervention was peripheral, as ivabradine is peripherally restricted and the HCN2 genetic deletion was targeted to peripheral nociceptors.

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

[0022] The non-selective and peripherally restricted HCN blocker, ivabradine, has been approved by the FDA to treat symptoms associated with stable angina and heart failure. HCN4 and HCN 1 channels, the targets of ivabradine in these conditions, are critical for the regulation of heart rate, and the mode of action of ivabradine is to cause bradycardia by blocking HCN4 and HCN1, and thereby to reduce the oxygen demand of the heart. Thus, although the studies described above have shown that ivabradine provides an analgesic effect on NP, the compound is not suitable as an analgesic in the clinic, because of its effects on cardiac pacemaking associated with HCN4 and / or HCN1 inhibition. Accordingly, preferred analgesics targeting HCN2 ion channels for the treatment of, for example, pain should not interact to any significant extent with HCN4 and / or HCN 1 to avoid or minimize cardiac side-effects such as bradycardia.

[0023] HCN inhibitors have been shown useful for the treatment of cognitive and psychiatric disorders. Bartels, B, et al., discloses a class of HCN inhibitors for the use in the treatment, prevention and / or delay of the progression of central nervous system (CNS) disorders including cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders such as depression.

[0024] There remains a need for HCN channel inhibitors, particularly compounds which selectively inhibit HCN2 channels.

[0025] Tinnitus is the conscious perception of sound heard in the absence of physical sound sources external to the body. Tinnitus commonly manifests itself as ringing, buzzing, whistling or hissing sounds in the ear. Tinnitus is estimated to occur in 25.3% of American adults with 7.9%experiencing it frequently (Shargorodsky et al., Prevalence and characteristics of tinnitus among US adults. Am. J. Med.2010 Aug;123(8):711-8).

[0026] There are no drug therapies currently approved by the FDA for the treatment of tinnitus and there is, therefore, an unmet medical need for an effective treatment of the condition. It has been found that HCN2 inhibitors can be effective in the treatment of tinnitus. McNaughton, P.et al., has shown that the peripherally restricted HCN blocker, ivabradine and peripherally restricted HCN2 inhibitors provide an effective treatment for tinnitus in an in-vivo model for the condition. (See, WO 2022 / 185058). These results suggest that a peripherally restricted HCN2 inhibitor may provide an effective treatment of tinnitus and related conditions such as Meniere's disease with the additional benefit of a reduced risk of CNS related side-effects resulting from HCN2 inhibition in the brain. SUMMARY OF THE DISCLOSURE

[0027] The present disclosure provides certain compounds that inhibit hyperpolarization activated cyclic-nucleotide modulated ion channel (HCN channel) activity. These compounds can be valuable pharmaceutically active compounds for the treatment of pain including, inflammatory pain (IP) such as chronic IP and acute IP; and neuropathic pain (NP) such as painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), and chemotherapy-induced peripheral neuropathy (CIPN). Additionally, HCN channel inhibitors may be useful for treating tinnitus, CNS and psychiatric disorders including cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders such as depression.

[0028] Accordingly, in another aspect, the present disclosure provides a method for treating pain (e.g., inflammatory pain (IP) such as chronic IP and acute IP; and neuropathic pain (NP) such as painful diabetic neuropathy (PDN), dysesthesia (e.g. hyperesthesia, hyperalgesia, allodynia, and hyperpathia), post-herpetic neuralgia (PHN), chemotherapy-induced peripheral neuropathy (CIPN), trigeminal neuralgia, complex regional pain syndrome (CRPS), post- operative neuropathy, pudendal neuralgia, small fiber sensory neuropathy (SFSN), lower back pain, nerve damage following traumatic injury, fibromyalgia, and carpal tunnel syndrome) comprising administering a therapeutically effective amount of the compound of the disclosure to a subject in need thereof. In some embodiments, the administration comprises an oral administration of the compound.

[0029] Non-limiting examples of inflammatory pain (IP) such as chronic IP and acute IP include infection, osteoarthritis, rheumatoid arthritis, post-operative pain, dental pain, and muscle pain due to injury.25835

[0030] In one aspect, the present disclosure provides compounds of Formula (I) , salts.processes for preparing compounds of the disclosure and pharmaceutical compositions which comprise compounds of the disclosure and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION Compounds of the Disclosure

[0032] In one embodiment, the present disclosure provides a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof: (I)wherein:R1 is C1-10alkyl, heteroaryl(C0-10alkyl), (C3-12)cycloalkyl(C0-10alkyl), or (C3-12)heterocycloalkyl(C0-10 alkyl), wherein R1is substituted by 0, 1, 2, or 3 R1asubstituents each independently selected from C1-6alkyl, cyano, halo, and hydroxy;R2 is C1-10alkyl, C1-10alkyloxy, (C1-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxycarbonyl(C0-10alkyl), (C1-6alkyl)carbonyloxy(C0-10alkyl), or (C0-6alkyl)hydroxy(C1-10alkyl); andW is selected from:

[0033] In a first embodiment of the invention, is C1-6alkyl, heteroaryl(C0-6alkyl), (C3-12)cycloalkyl(C0-6alkyl), or (C3-12)heterocycloalkyl(C0-6alkyl), wherein R1 is substituted by0, 1, 2, or 3 R1asubstituents each independently selected from C1-6 alkyl, cyano, halo, andhydroxy, and the other groups are as provided in the general Formula (I) above.

[0034] In a second embodiment of the invention, R1 is C1-6alkyl, heteroaryl(C0-6alkyl), or(C3-12)cycloalkyl(C0-6alkyl), wherein R1 is substituted by 0, 1, 2, or 3 R1a substituents eachindependently selected from C1-6alkyl, cyano, and halo, and the other groups are as provided inthe general Formula (I) above.

[0035] In a third embodiment of the invention, R1is methyl, ethyl, propyl, isobutyl, butyl,pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, (2-ethyl)butyl, pyrrolyl(C0-6alkyl), furanyl(C0-6alkyl), thienyl(C0-6alkyl), imidazolyl(C0-6alkyl), furazanyl(C0-6alkyl), oxazolyl(C0-6alkyl,oxatriazolyl(C0-6alkyl), isoxazolyl(C0-6alkyl), thiazolyl(C0-6alkyl, isothiazolyl(C0-6alkyl,pyrazolyl(C0-6alkyl), triazolyl(C0-6alkyl), tetrazolyl(C0-6alkyl), oxadiazolyl(C0-6alkyl),isoxazolinyl(C0-6alkyl), pyranyl(C0-6alkyl), pyridyl(C0-6alkyl), pyrazinyl(C0-6alkyl),triazinyl(C0-6alkyl), pyridazinyl(C0-6alkyl), pyrimidyl(C0-6alkyl), cyclobutyl(C0-6alkyl),cyclopropyl(C0-6alkyl), cyclopentyl(C0-6alkyl), oxetanyl(C0-6alkyl), piperidyl(C0-6alkyl),pyrrolidinyl(C0-6alkyl), piperazinyl(C0-6alkyl), morpholinyl(C0-6alkyl), thiomorpholinyl(C0-6alkyl), thiazolidinyl(C0-6alkyl), 1,4-dioxanyl(C0-6alkyl), tetrahydrofuranyl(C0-6alkyl),tetrahydrothiophenyl(C0-6alkyl), piperidinyl(C0-6alkyl), or azetidinyl(C0-6alkyl), wherein R1is substituted by 0, 1, 2, or 3 R1asubstituents each independently selected from C1-6alkyl, cyano, and halo, and the other groups are as provided in the general Formula (I) above.

[0036] In a fourth embodiment of the invention, R1is isobutyl, neopentyl, 2,2-dimethylbutyl,pent-3yl, (2-ethyl) butyl, pyrrolyl(C0-4alkyl), furanyl(C0-4alkyl), imidazolyl(C0-4alkyl),furazanyl(C0-4alkyl), oxazolyl(C0-6alkyl,) isoxazolyl(C0-6alkyl), thiazolyl(C0-6alkyl),isothiazolyl(C0-6alkyl), pyrazolyl(C0-6alkyl), oxadiazolyl(C0-6alkyl), oxazolinyl(C0-6alkyl),pyrimidyl(C0-6alkyl), cyclobutyl(C0-6alkyl), or cyclopropyl(C0-6alkyl), wherein R1 issubstituted by 0, 1, 2, or 3 R1asubstituents each independently selected from C1-6alkyl, cyano, and halo, and the other groups are as provided in the general Formula (I) above.

[0037] In a fifth embodiment of the invention, each R1aindependently is selected from methyl,ethyl, propyl, isopropyl, butyl, cyano, fluoro, and chloro, and the other groups are as provided in the general Formula (I) above, or as in the first through fourth embodiments.

[0038] In a sixth embodiment of the invention, each R1aindependently is selected frommethyl, cyano, fluoro, and chloro, and the other groups are as provided in the general Formula (I) above, or as in the first through fourth embodiments.

[0039] In a seventh embodiment, R2 is C1-6alkyl, C1-6alkyloxy, (C1-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxycarbonyl(C0-6alkyl), (C1-6alkyl)carbonyloxy(C0-6alkyl), or (C0-6alkyl)hydroxy(C1-6alkyl), and the other groups are as provided in the general Formula (I) above,or as in the first through sixth embodiments.

[0040] In an eighth embodiment, R2is methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, 3-methoxy-3methylbutyl, 2-methoxycarbonyl-2-methyl-4yl, 2-methylbutyl, 2-methylbut-4yl, 2- methylprop-3yl, 2-methoxypropy-3yl, 2-hydroxy-2-methylbut-4yl, 2-methoxyethyl, or 2- hydroxybut-4yl, and the other groups are as provided in the general Formula (I) above, or as in the first through sixth embodiments.

[0041] In a ninth embodiment of the invention, R2is isobutyl, 3-methoxy-3-methylbutyl, 2-methoxycarbonyl-2-methyl-4yl, 2-methylbutyl, 2-methylbut-4yl, 2-methylprop-3yl, 2- methoxypropy-3yl, 2-hydroxy-2-methylbut-4yl, 2-methoxyethyl, or 2-hydroxybut-4yl, and the other groups are as provided in the general Formula (I) above, or as in the first through sixth embodiments.

[0042] In a tenth embodiment of the invention, W is25835 ,wherein W is substituted by 0, 1, 2 or 3 R4C1-6alkyl, cyano, and halo, and the other groupsor as in the first through ninth embodiments.

[0043] In an eleventh embodiment of the invention, W is ,wherein W is substituted by 0, 1, 2 or 3 R46alkyl, cyano, and halo, and the other groupsare as provided in the general Formula (I) above, or as in the first through ninth embodiments.

[0044] In a twelfth embodiment of the invention W is selected from: , wherein W is substituted by 0, 1, 2 or 3 R4substituents eachfrom C1-6alkyl, cyano, and halo, and the other groups are as provided inthe general Formula (I) above, or as in the first through ninth embodiments.

[0045] In a thirteenth embodiment of the invention, each R4substituent is independentlyselected from methyl, ethyl, propyl, cyano, chloro, and fluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0046] In a fourteenth embodiment of the invention, each R4substituent is independentlyselected from cyano, chloro, and fluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0047] Non-limiting examples of the Compounds of Formula I include compounds 1 through 106 or a pharmaceutically acceptable salt thereof, as set forth in the Examples: N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide;25835 N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; methyl 4-(3-(3,3-dimethylbutanamido)-5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4- b]pyridin-1-yl)-2,2-dimethylbutanoate; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide;25835 N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]thiazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide;25835 N-(5-(6-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide; N-(5-(6-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d]thiazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)isothiazole- 5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide;25835 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3- yl)cyclobutanecarboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; (R)-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; (S)-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)isoxazole-5- carboxamide; 2-cyclopropyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)propenamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-2,2-dimethylcyclopropane-1-carboxamide; (S)-N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2- dimethylcyclopropane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2- dimethylcyclopropane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-methyl-1H- pyrazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)isothiazole-4- carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)furan-3- carboxamide;25835 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)thiazole-5- carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylpentanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3-methylisoxazole-4-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-4-methyloxazole-5-carboxamide; 3,3-difluoro-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pyrimidine-5-carboxamide; 3-fluoro-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-2,2-dimethylpropanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclopropane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)isothiazole-4-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)furan-3-carboxamide; 2-ethyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)butanamide; 3-ethyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pentanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutanecarboxamide;25835 1-cyano-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-difluoro-1-methylcyclobutane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-4-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)furan-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3-ethylpentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylpentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3-methylisoxazole-4-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-4-methyloxazole-5-carboxamide; 3,3-difluoro-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)isothiazole-4-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)furan-3-carboxamide; 3-ethyl-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutanecarboxamide;25835 1-cyano-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutane-1-carboxamide; 3,3-difluoro-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)cyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; or N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide. Definitions

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0049] As used throughout this disclosure, “a compound of the disclosure”, “a compound of the present disclosure” and “a compound disclosed herein” are used interchangeably and to be understood to include the disclosed compounds of Formula (I). The compounds of Formula (I) can form salts which are also within the scope of the present disclosure. Reference to a compound of the disclosure (or compound of Formula (I)) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to an amino group, pyrrolidine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0050] The term “C0” or “C0” or “C0” as employed in expressions such as “C0-6alkyl” and“C0-6alkyl” means a direct covalent bond; or when the term appears at the terminus of asubstituent, C0-6alkyl means hydrogen or C1-6alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms25835 Qsadjacent thereto are connected directly by a bond. For example, in the , Qwherein s is an integer equal to zero, 1 or 2, the structurewhen s is zero.

[0051] The term “alkyl”, as well as other groups having“alk”, such as alkoxy, dialkylamino, and trialkylammonium, and the like, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 10 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 10 carbon atoms. In different embodiments, an alkyl groupcontains from 1 to 6 carbon atoms (C1-6alkyl) or from about 1 to about 4 carbon atoms (C1-C4alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

[0052] “Alkoxy”, “alkyloxy” and “alkyl–O–” are used interchangeably and refer to an alkyl (carbon and hydrogen chain) group linked to oxygen (R–O). Non-limiting examples of alkoxy are methoxy (CH3O–), ethoxy (CH3CH2O–) and propoxy (CH3CH2CH2O–).

[0053] “Celite®” (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0054] “Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl, biphenyl, and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0055] “Bicyclic ring system” refers to two joined rings. The rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”, i.e., share only a single atom.

[0056] “Carbonyl” means a functional group composed of a carbon atom double-bonded to an oxygen atom (C=O).

[0057] “Cycloalkyl” or “C3-12cycloalkyl” means any univalent non-aromatic radical derivedfrom a monocyclic, bicyclic, tricyclic or tetracyclic ring system having 3 to 12 ring carbons atoms. These non-aromatic radicals, which have 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms may be fully saturated, or partially unsaturated. Unless stated specifically in the specification, the cycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Here, the point of attachment for a “cycloalkyl” to the rest25835 of the molecule is on the saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems, where two rings share two atoms (e.g., decalin), spiro ring systems where two rings share one atom (e.g., spiro[4.5]decanyl) and bridged groups (e.g., norbornyl).

[0058] Additional examples within the above meaning include, but are not limited to univalent radicals of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, [1.1.1]-bicyclo pentane, bicyclo[3.1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0059] The term “C3-8cycloalkyl” (or “C3-C8cycloalkyl” or “C3-8cycloalkyl”) means a cyclicring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C3-7cycloalkyl”, “C3-6cycloalkyl”, “C5-7 cycloalkyl” and the like have analogous meanings.

[0060] “Halogen” or “halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro (–F) or chloro (– Cl).

[0061] The term “heteroaryl”, as used herein, represents a stable monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 carbon atoms and containing at least one ring heteroatom selected from nitrogen (N), sulfur (S) (including S=O and SO2) and oxygen (O), wherein at least one of the heteroatoms containing rings is aromatic. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, isothiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, and isoquinolinyl, and oxazolyl. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0062] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl,25835

[0063] Examples of six membered heteroaryl groups include but are not limited to pyranyl, pyridyl, pyrazinyl, triazinyl, pyridazinyl, and pyrimidyl.

[0064] The term “heterocycloalkyl” as used herein refers to a stable and non-aromatic(including not fully aromatic, e.g., one double bond) 3- to 12-membered ring (i.e., C3-12heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six ring heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 12” or “3-12” refers to each integer in the given range. For example, “3 to 12 ring atoms” means that the heterocycloalkyl group may consist

[0065] of 3 ring atoms, 4 ring atoms, 5 ring atoms, etc., up to and including 12 ring atoms. In some embodiments, it is a 5 to 10 ring heterocycloalkyl. In some embodiments, it is a 4 to 10 ring heterocycloalkyl. In some embodiments, it is a 3 to 10 ring heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide (S=O) or S-dioxide (SO2). One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of a molecule through any atom of the ring(s).

[0066] In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms present in the ring system.

[0067] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, piperidinyl, 3-azabixyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 2,3-dihydro-1H-indenyl, dihydro-1H-indenyl, 3H- spiro[benzofuran-2’,4’-piperidinyl, 2,3-dihydro-1H-pyrrolo[3,2,1-ij][1,6]naphthyridinyl, 3,4,6,7-25835 tetrahydro-5H-imidazo[4,5-c]pyridyl, 3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridyl, hexahydro-2H- pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, bicyclo[2,2,1]heptenyl, 2',3'-dihydro- 1'H-spiro[piperidine-4,4'-quinazolin], octahydropyrrolo[3,4-b][1,4]oxazinyl, (diazabicyclo[2.2.1]heptanyl), 2,5-diazabicyclo[2.2.1]heptanyl, tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, dihydro- 5H-pyrrolo[3,4-d]thiazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]thiazolyl, dihydro-5H-pyrrolo[3,4- d]oxazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]oxazolyl, dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, 6,7- dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, benzo[d]imidazolyl, 1H-enzo[d]imidazolyl, diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and pyrrolidinone, and oxides thereof and all isomers thereof. In one embodiment of the invention, heterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, azetidinyl.

[0068] The term “oxy” means an oxygen (O) atom.

[0069] The term “thio” means a sulfur (S) atom.

[0070] By “pharmaceutically acceptable” is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0071] When any variable (e.g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0072] When any ring atom is specified as being optionally substituted with, or in a specified form, for example, sulfur (S) substituted with oxo groups, or nitrogen (N) in the form of a N- oxide, this does not preclude the substitution of any ring atom with the other listed optional substituents when not substituted with oxo groups or in the form of a N-oxide.

[0073] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0074] By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention are limited to stable compounds embraced by Formula I.25835

[0075] The term “compound” refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with an organic solvent.

[0076] The term “in substantially purified form,” as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term “in substantially purified form” also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, reversed- phase preparative HPLC, recrystallization, and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

[0077] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0078] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0079] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is preceded by the adjacent functionality toward the point ofattachment. For example, a “(C1-5alkyl)carbonylamino(C1-6alkyl)” substituent is equivalent toO -C1-6alkyl-HNC1-5 alkyl.

[0080] Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “Me”, “–Me”, “CH3”,“–CH3” or using a straight line representing the presence of the methyl group, e.g." ",i.e., have equivalent meanings.

[0081] For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where ris the integer 2, Riis a defined variable, and Rjis a defined variable, the value of Rimay differin each instance in which it occurs, and the value of Rjmay differ in each instance in which it25835occurs. For example, if Riand Rjare independently selected from the group consisting ofH3CH2C CH3methyl, ethyl, propyl and butyl, then (CRiRj)2.

[0082] Unless expressly stated to the contrary,example, a heteroaromatic ring described as means the ring can contain, 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms,and 4 heteroatoms. Similarly, C1-6or C1-6 or C1-C6 when used with a chain, for example an alkylchains means that the chain can contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all ranges contained therein including C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C6, C5-C6, and all other possible combinations.

[0083] In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, RA, R2b, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0084] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

[0085] When any variable (e.g., R1a) occurs more than one time in any constituent or inFormula (I) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents,e.g., R1a, are to be chosen in conformity with well-known principles of chemical structureconnectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, heteroaryl ring, or saturated heteroaryl ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient25835 to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0086] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0087] The wavy line , as used herein, indicates a point of attachment to the rest of the compound.

[0088] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present disclosure.

[0089] In the compounds of the disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well-known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0090] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present disclosure is acidic (or has a functional group which may be anionic), its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Examples of suitable inorganic cations include, but are not limited to,alkali metal ions such as Li+, Na+, and K+, alkaline earth metal cations such as Ca2+, andMg2+, and other cations such as Al3+and Zn2+. Examples of suitable organic cations include,but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions. Examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, triethylamine and ethylenediamine. When a compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non- toxic acids, including inorganic acids and organic acids. Example of such acid addition salts include salts formed from hydrohalic acids (e.g., hydrochloric, hydrobromic, hydroiodic), formic acid, acetic acid, capric acid, and citric acid. Salts containing acetate, formate, caprate, chloride, or sodium salts are typical for use with the compounds of the present disclosure. In some embodiments, salts of compounds of the present disclosure can be formed by exchange well- known to those of ordinary skill in the art, such as by anion exchange, e.g., replacement of trifluoroacetate ions with chloride ions.

[0091] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as, but not limited to, acetic acid or acetonitrile. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0092] Any pharmaceutically acceptable pro-drug modification of a compound of this disclosure which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0093] The present disclosure also relates to processes for the preparation of the compounds of Formula (I) which are described in the following Examples and by which the compounds of the disclosure are obtainable.

[0094] “Treatment” and “treating” refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.

[0095] “Preventing” or “prophylaxis” as used herein, refers to reducing the likelihood of contracting disease or disorder described herein, or reducing the severity of a disease or disorder described herein.

[0096] The terms “therapeutically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for treatment” or “an effective dose” are intended to mean thatamount of a compound of the disclosure that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a compound of the disclosure that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a compound of the disclosure that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. Dosages of the Compounds of the Present Disclosure

[0097] The dosage regimen utilizing a compound of the present disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an immunological condition, and a prophylactically effective amount, e.g., for prevention of an immunological condition.

[0098] While individual needs vary, determination of optimal ranges of effective amounts of the compound of the present disclosure is within the skill of the art. For administration to a human in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical dosages of the compounds of the present disclosure can be about 0.05 mg / kg / day to about 1000 mg / kg / day. Such doses may be administered in a single dose or may be divided into multiple doses. Pharmaceutical Compositions

[0099] The compounds of the disclosure and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and particularly to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term “subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition.25835

[0100] Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of or desire treatment for an existing disease or medical condition or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of the disease or medical condition. As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0101] The present disclosure therefore also provides the compounds of the disclosure and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for selectively modulating the activity of HCN2, and in particular, their use in the therapy and prophylaxis of the below- mentioned diseases or disorders as well as their use for preparing medicaments for these purposes. In certain embodiments, the compounds of the disclosure and their pharmaceutically acceptable salts selectively inhibit HCN2.

[0102] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of the disclosure and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives. Thus, the present disclosure provides, for example, said compound and its pharmaceutically acceptable salts for use as pharmaceutical compositions which comprise as active component an effective dose of the compound of the disclosure and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the below- mentioned diseases or disorders, e.g., inflammatory pain (IP) (including Acute IP, Chronic IP), postoperative pain, neuropathic pain (NP), painful diabetic neuropathy, tinnitus, trigeminal neuralgia, complex regional pain syndrome (CRPS), pudendal neuralgia, chronic lower back pain, nerve damage following traumatic injury, fibromyalgia, Migraine, painful chemotherapy- induced peripheral neuropathy (CIPN), pain associated with cancer, opioid resistant pain, rheumatoid arthritis (RA), osteoarthritis (OA), pain associated with long-term use of opioids (Opioid-induced hyperalgesia, OIH), cancer-associated bone pain,) and carpal tunnel syndrome, CNS and psychiatric disorders including cognitive impairments associated with schizophrenia (CIAS) , early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders such as depression; as well as their use for preparing medicaments for these purposes.25835

[0103] In some embodiments of the invention, a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, may be used in the therapy or prophylaxis of neuropathic pain (NP). No limiting examples of NP include painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), pain associated with cancer, chemotherapy induced pain (chemotherapy-induced peripheral neuropathy), post-operative pain, trigeminal neuralgia, complex regional pain syndrome (CRPS), opioid resistant pain, pudendal neuralgia, neuropathic pain associated with lower back pain, sciatica, nerve damage following traumatic injury and carpal tunnel syndrome.

[0104] In some embodiments of the invention, a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, may be used in the therapy or prophylaxis of inflammatory pain (IP) including chronic inflammatory pain and acute inflammatory pain. Afflictions associated with IP, include inflammatory bowel disease, visceral pain, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, animal or insect mite / sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, dermatitis (atopic and contact), pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, sinus headache, tension headache, inflammatory hyperalgesia (such as, somatic and visceral hyperalgesia), or arachnoiditis.

[0105] In some embodiments of the invention, a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, may be used in the therapy or prophylaxis of tinnitus and / or migraines.

[0106] In some embodiments of the invention, a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, may be used in the therapy or prophylaxis of CNS and psychiatric disorders including cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders such as depression.

[0107] In some embodiments of the invention, a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, may be used in the therapy or prophylaxis of cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and depression.

[0108] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or25835 suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example, subcutaneously, intramuscularly, or intravenously in the form of solutions or suspension for injection or infusion.

[0109] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0110] The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I). The compound of Formula (I) can be used in combination with any suitable pharmaceutical carrier or excipient. Such pharmaceutical compositions comprise a therapeutically effective amount of one or more compounds of Formula (I), and pharmaceutically acceptable excipient(s) and / or carrier(s). The specific pharmaceutic composition will suit the mode of administration. In particular aspects, the pharmaceutical acceptable carrier may be water or a buffered solution.

[0111] Excipients included in the pharmaceutical compositions have different purposes depending, for example on the nature of the drug, and the mode of administration. Examples of generally used excipients include, without limitation: saline, buffered saline, dextrose, water-for- infection, glycerol, ethanol, and combinations thereof, stabilizing agents, solubilizing agents and surfactants, buffers and preservatives, tonicity agents, bulking agents, lubricating agents (such as talc or silica, and fats, such as vegetable stearin, magnesium stearate or stearic acid), emulsifiers, suspending or viscosity agents, inert diluents, fillers (such as cellulose, dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate), disintegrating agents (such as crosslinked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose), binding agents (such as starches, gelatin, cellulose, methyl cellulose or modified cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, sugars such as sucrose and lactose, or sugar alcohols such as xylitol, sorbitol or maltitol, polyvinylpyrrolidone and polyethylene glycol), wetting agents, antibacterials, chelating agents, coatings (such as a cellulose film coating, synthetic polymers, shellac, corn protein zein or other polysaccharides, and gelatin), preservatives (including vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, cysteine, methionine, citric acid and sodium citrate, and synthetic preservatives, including methyl paraben and propyl paraben), sweeteners, perfuming agents, flavoring agents, coloring agents, absorption enhancers, administration aids, and combinations thereof.25835

[0112] Carriers are compounds and substances that improve and / or prolong the delivery of an active ingredient to a subject in the context of a pharmaceutical composition. Carriers may serve to prolong the in vivo activity of a drug or slow the release of the drug in a subject, using controlled-release technologies. Carriers may also decrease drug metabolism in a subject and / or reduce the toxicity of the drug. Carriers can also be used to target the delivery of the drug to particular cells or tissues in a subject. Common carriers (both hydrophilic and hydrophobic carriers) include fat emulsions, lipids, PEGylated phospholipids, PEGylated liposomes, PEGylated liposomes coated via a PEG spacer with a cyclic RGD peptide, liposomes and lipospheres, microspheres (including those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, protein-DNA complexes, protein conjugates, erythrocytes, vesicles, nanoparticles, and side chains for hydrocarbon stapling. The aforementioned carriers can also be used to increase cell membrane permeability of the compounds of Formula (I). In addition to their use in the pharmaceutical compositions of the present disclosure, carriers may also be used in compositions for other uses, such as research uses in vitro (e.g., for delivery to cultured cells) and / or in vivo.

[0113] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions). Suitable excipients for tablets or hard gelatin capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatin capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols and sugars. For the preparation of suspensions oils, e.g., vegetable oils, may be used to provide oil-in- water or water-in-oil suspensions. Excipients which promote absorption from the gastrointestinal tract, e.g., permeation enhancers, such as sodium caprate can be included. In certain situations, delayed release preparations may be advantageous and compositions which can deliver the compounds of the present disclosure in a delayed or controlled release manner may also be prepared. Prolonged gastric residence brings with it the problem of degradation by the enzymes present in the stomach and so enteric-coated capsules may also be prepared by standard techniques in the art where the active substance for release lower down in the gastro-intestinal tract.

[0114] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a25835 prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6):318 (1986).

[0115] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

[0116] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0117] Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

[0118] Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.

[0119] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0120] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solution which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Excipients which may be used for injectable solutions include water-for-injection, alcohols, polyols, glycerin and vegetable oils, for example. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water or saline for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders,25835 granules and tablets. The pharmaceutical compositions may contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts (substances of the present disclosure may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents or antioxidants. They may also contain therapeutically-active agents in addition to the compounds of the present disclosure. Methods of Using the Compounds of the Disclosure

[0121] The present application also provides methods of using the compounds of the disclosure (or their pharmaceutically acceptable salts) or pharmaceutical compositions containing such compounds to treat disease conditions, including but not limited to, conditions implicated by HCN2.

[0122] In some embodiments, the present disclosure provides a method of treating pain and other HCN2-driven diseases, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the HCN2-driven pain is inflammatory pain. In some embodiments, the HCN2-driven pain is neuropathic pain. In some embodiments, the HCN2- driven pain comprises both neuropathic pain and inflammatory pain. Non-limiting examples of inflammatory pain (IP) such as chronic IP and acute IP include infection, osteoarthritis, rheumatoid arthritis, post-operative pain, dental pain, and muscle pain due to injury. In some embodiments the HCN2-driven disease is tinnitus. In some embodiments, the HCN2-driven inflammatory pain disease is rheumatoid arthritis. In some embodiments, the HCN2-driven pain disease is migraine. In some embodiments of the invention, the HCN2-driven disease is CNS and psychiatric disorders including cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders such as depression.

[0123] In some embodiments, the present disclosure provides a method of treating an inflammatory pain, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0124] In some embodiments, the present disclosure provides a method of treating an acute inflammatory pain, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the25835 foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0125] In some embodiments, the present disclosure provides a method of treating a chronic inflammatory pain, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0126] In some embodiments, the present disclosure provides a method of treating a neuropathic pain, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0127] In some embodiments, the present disclosure provides a method of treating painful diabetic neuropathy, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0128] In some embodiments, the present disclosure provides a method of treating tinnitus, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0129] In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0130] In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0131] In some embodiments, the present disclosure provides a method of treating a CNS or a psychiatric disorder selected from CIAS, EIEE, autism and depression, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.25835

[0132] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.

[0133] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven diseases selected from inflammatory pain, neuropathic pain, tinnitus, and migraine,.

[0134] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven CNS and psychiatric disorders selected from (CIAS), (EIEE), schizophrenia, autism (sensory sensitivity), and depression.

[0135] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven diseases selected from inflammatory pain.

[0136] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven diseases selected from neuropathic pain.

[0137] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven diseases that is tinnitus.

[0138] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven diseases that is migraine. Combination Therapies

[0139] One or more additional pharmacologically active agents may be administered in combination with a compound of the disclosure. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including prodrugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula I, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents.

[0140] For example, for the treatment of pain, a compound of the present invention may be used in combination with another analgesic agent. Non-limiting, illustrative examples of analgesic agents include: an opioid such as morphine, nalbuphine, and tramadol; an opiate such as oxycontin, Hysigla, Zohydro, Xtampza, Oxaydo, and Nucynta; non-steroidal anti- inflammatory agents (NSAIDs) such as aspirin, naproxen, ibuprofen, or a COX2 inhibitor such as celecoxib; paracetamol; baclofen, pregabalin, gabapentin, clomipramine, amitriptyline, lidocaine; or a combination of any of the above listed analgesic agents.METHODS OF SYNTHESIS General Procedures

[0141] The compounds of the present invention can be prepared according to the procedures of the following schemes (Scheme A -Scheme D) and specific examples, or modifications thereof, using readily available starting materials, appropriate materials and reagents and conventional synthetic procedures and are further exemplified by the following specific examples. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following schemes. The examples also include methods for testing such compounds in biophysical, biochemical, and cellular assays. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure.

[0142] Unless otherwise specifically indicated, all reagents are commercially available, known in the literature, or readily synthesized by one skilled in the art. The general route applied to the synthesis of compounds of Formula I is described in the Schemes that follow. In some instances, the order of carrying out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies familiar to one skilled in the art of organic synthesis and solid phase peptide synthesis may be employed to facilitate the reaction, to improve yield and purity, or to avoid unwanted reaction products.

[0143] All reagents and solvents were purchased from commercial sources and used without further purification unless otherwise noted. All temperatures are in degrees Celsius (°C), and ambient temperature or room temperature (RT) is 20 °C. Most compounds were purified by reversed-phase preparative high-performance liquid chromatography (HPLC) or medium- pressure liquid chromatography (MPLC) on silica gel. The course of the reactions was followed by liquid chromatography / mass spectrometry (LC-MS) or Ultra performance liquid chromatography / mass spectrometry (UPLC-MS); electrospray ionization (ESI); UV detection at 254 nm). Proton, fluorine, and carbon magnetic resonance (1H,19F and13C NMR) spectra were recorded on a 300, 400, 500, or 600 MHz Varian or Bruker spectrometer, and chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in hertz. Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usuallyperformed with pre-coated TLC plates (E. Merck, Darmstadt, Germany), silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS). Instrumentation

[0144] Reverse phase chromatography was carried out on a GILSON®GX-281 liquid handler (Gilson Incorporated, Middleton, WI) equipped with a column selected from the following: Phenomenex™ Synergi™ C18 (150mm x 30mm x 4 micron, (Phenomenex™, Torrance, CA)), YMC-Actus Pro C18 (150mm x 30mm x 5 micron), (YMC CO,. LTD. Koyoto, JP)), Xtimate®C18 ((150mm x 25mm x 5 micron) Welch Materials, West Haven, CT)), Waters™ XSELECT C18 ((150mm x 30mm x 5 micron), Waters Corporation, Milford, MA)). Conditions included either high pH (0-100% acetonitrile / water eluent comprising 0.1% v / v 10mM NH4CO3 or 0.05% NH4OH) or low pH (0-95% acetonitrile / water eluent comprising 0.1% v / v TFA) and are noted for some examples.

[0145] SFC chiral resolution was carried out on a Sepiate Prep SFC 100 (Sepiatec GmBH, Berlin, Germany), Multigram®II (MG II) (Thar Instruments, Inc. (Now Waters Corporation, Waters Corporation, Milford, MA)), THAR80 prep SFC (Thar Instruments, Inc. (Now Waters Corporation, Waters Corporation, Milford, MA)) , or a Waters™ SFC (80, 200, or 350).

[0146] LC / MS determinations were carried out on a Waters™ Classing Aquity system equipped with TUV and MS detectors and a Waters™ SQD mass spectrometer, a Shimadzu 20 UV 254 and 220nM with Shimadzu 2010 or 2020 (Shimadzu Scientific Instruments, Columbia, MD) mass spectrometer, or an Agilent 1200 HPLC (Agilent Technologies, Schaumburg, IL) equipped with DAD / ELSD (Diode Array Detector / Evaporative Light Scattering Detector) and G6110 MSD (Agilent Technologies) using one of the following conditions: 1) Ascentis®Express C18 (3 x 50 mm) 2.7μm column (Millipore Sigma, St. Louis, MO), using mobile phase containing A: 0.05% TFA in water and B: 0.05% TFA in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 6 min at a flow rate of 1.8 mL / min, UV detection at 210 nm; 2) Waters™Aquity BEH C18, (1.0 x 50 mm) 1.7 μm column (Waters Corporation, Milford, MA), using mobile phase containing A: 0.05% TFA in water and B: 0.05% TFA in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 2 min at a flow rate of 0.3 mL / min, UV detection at 215 nm; 3) Agilent YMC-J'Sphere H- 80 ((3 x 50 mm) 5μm, (YMC CO,. LTD. Koyoto, JP)) column using mobile phase containing A: 0.1% TFA in water and B: acetonitrile with a gradient from 95:5 (A:B) to 0:100 (A:B) over 3.6 min and 0:100 (A:B) for 0.4 min at a flow rate of 1.4 mL / min, UV detection at 254 and 220 nm and Agilent 1100 quadrupole mass spectrometer; 4) an Agilent TC-C18 (2.1 x 50 mm) 5μm column using mobile phase containing A: 0.0375% TFA in25835 water and B: 0.01875% TFA in acetonitrile with a gradient from 90:10 (A:B) for 0.4 min to 90:10 to 0:100 (A:B) over 3 min and 10:90 (A:B) for 0.6 min at a flow rate of 0.8 mL / min, UV detection at 254 and 220 nm and Agilent 6110 quadrupole mass spectrometer.

[0147] Proton or 1H NMR was acquired using a Varian Unity-Inova 400 MHz NMR spectrometer equipped with a Varian 400 ATB PFG 5mm (Varian, Inc., Palo Alto, CA), Nalorac DBG 400-5 or a Nalorac IDG 400-5 probe (Nalorac Corporation, Martinez, CA), a Varian- 400MHz MR spectrometer equipped with an Auto X ID PFG Probe 5mm, a Varian 400MHz VNMRS spectrometer equipped with a PFG 4Nuc Probe 5 mm, or a AVANCE III 500MHz spectrometer (Bruker Corporation, Billerica, MA) equipped with a PABBO Probe (Bruker Corporation) 5 mm in accordance with standard analytical techniques, unless specified otherwise, and results of spectral analysis are reported. Chemical shift (δ) values are reported in delta (δ) units, parts per million (ppm). Chemical shifts for1H NMR spectra are given relative to signals for residual non-deuterated solvent (CDCl3 referenced at δ 7.26 ppm; DMSO d-6 referenced at δ 2.50 ppm and CD3OD referenced at δ 3.31 ppm). Multiples are reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlap of nonequivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[0148] Unless otherwise indicated, when ratios of compounds (such as for examples solvents) are given, the ratio is on a volume-to-volume basis. For example, solvent gradient ranging from 100% hexanes to 50% EtOAc / hexanes means a gradient starting from a mixture of 100 parts by volume of hexanes varying to mixture of 50 parts by volume ethyl acetate to 50 parts by volume of hexanes.

[0149] The term “w / w” means weight of compound to total weight. For example, NaH 60% w / w means 60 parts by weight NaH to 100 parts total weight.

[0150] The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable Intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates and examples. Asymmetric methodologies (e.g. chiral catalysis, auxiliaries, biocatalytic process) may be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions depends upon the nature of the intended25835 product. In the examples, chemical synthesis schemes are provided for reagents and intermediates which were not commercially available. Abbreviations

[0151] Abbreviations and acronyms employed herein include the following: AcOH = acetic acid min = minute BAST = bis(2-methoxyethyl)aminosulfur mL = milliliters25835 HATU = 1-[bis(dimethylamino)- sol = solution methylene]-1H-1,2,3-triazolo[4,5- b] ridinium-3-oxidehexa-fluoro hos hate REAScheme A3- amide A-7 from a 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine A-1. A-1 is mixed with NaH and a substituted bromide such as A-2 in DMF to afford a 5-bromo-1-N-substituted-pyrazolo[3,4- b]pyridin-3-amine such as A-3. The latter is then coupled with an acid or an acid chloride such as A-4 using TCFH and N-methyl imidizole to afford a 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-25835 amide such as A-5. Then a Suzuki coupling of A-5 with a boronic acid such as A-6, cesium carbonate, and PdCl2dppf affords a 1H-pyrazolo[3,4-b]pyridin-3-amide such as A-7. Scheme B 3-amide B-7 from 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine B-1. B-1 is coupled with an acid or an acid chloride such as B-2 using TCFH and N-methyl imidizole to afford a 5-bromo-1H- pyrazolo[3,4-b]pyridin-3-amide such as B-3. Then B-3 is mixed with NaH and a substituted bromide such as B-4 in DMF to afford a 5-bromo-1-N-substituted-pyrazolo[3,4-b]pyridin-3- amide such as B-5. Subsequently, a Suzuki coupling of B-5 with a boronic acid such as B-6, cesium carbonate, and PdCl2dppf affords a 1H-pyrazolo[3,4-b]pyridin-3-amide such as B-7. Scheme C25835

[0154] Scheme C illustrates the procedure for the formation of a 1H-pyrazolo[3,4-b]pyridin-3- amide C-7 from 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine C-1. C-1 is mixed with NaH and substituted with a bromide such as C-2 in DMF to afford a 5-bromo-1-N-substituted- pyrazolo[3,4-b]pyridin-3-amine such as C-3. Subsequently, C-3 is coupled with a boronic acid such as C-4, cesium carbonate, and PdCl2dppf to afford a 1-N-substituted-pyrazolo[3,4- b]pyridin-3-amine such as C-5. The latter is coupled with an acid or an acid chloride such as C-6 using TCFH and N-methyl imidizole to afford an 1H-pyrazolo[3,4-b]pyridin-3-amide such as C- 7. Scheme D

[0155] Scheme D illustrates the procedure for the formation of a 1H-pyrazolo[3,4-b]pyridin-3- amide D-8 from 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine D-1. D-1 is mixed with NaH and a substituted bromide such as D-2 in DMF to afford a 5-bromo-1-N-substituted-pyrazolo[3,4- b]pyridin-3-amine such as D-3. The latter is then coupled with an acid or an acid chloride such as D-4 using TCFH and N-methyl imidizole to afford a 5-bromo-1H-pyrazolo[3,4-b]pyridin-3- amide such as D-5. D-5 is then converted to boronic ester D-6. D-6 then undergoes a Suzuki coupling with a bromide such as D-7, cesium carbonate, and PdCl2dppf to afford a 1H- pyrazolo[3,4-b]pyridin-3-amide such as D-8. EXAMPLE 1 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide (1)25835

[0156] Step A: 4-(3-amino-5-1-yl)-2-methylbutan-2-ol (1-a) 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (547 mg, 2.57 mmol) was dissolved in DMF (8 mL). Sodium hydride (154 mg, 3.85 mmol) was added into reaction mixture at 0°C, and stirred for 30 min. at room temperature.4-Bromo-2-methylbutan-2-ol (542 mg, 3.08 mmol) was slowly added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was cooled, aqueous ammonium chloride (20 %, 20mL) was added and the mixture was extracted with ethyl acetate (3x30 mL). The combined organic fractions were washed with brine (saturated, 3x20 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure to give 4-(3-amino-5-bromo-1H-pyrazolo[3,4-b]pyridin- 1-yl)-2-methylbutan-2-ol (1-a). LCMS (ES, m / z): 298.8 [M+H]+.

[0157] Step B: N-(5-bromo-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide (1-b) Pivaloyl chloride (0.2 mL, 0.368 mmol) was added to 4-(3-amino-5-bromo-1H-pyrazolo[3,4- b]pyridin-1-yl)-2-methylbutan-2-ol (1-a, 110 mg, 0.368 mmol) and DIEA (0.193 mL, 1.103 mmol) in Dioxane (10 mL) at room temperature. The mixture was stirred for 2h. The solvent was evaporated under reduced pressure. The mixture was cooled, and aqueous potassium carbonate (20 %, 20 mL) was added. The mixture was extracted with ethyl acetate (3x20 mL). The combined organic fractions were washed with brine (saturated, 15 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure to give N-(5-bromo-1-(3-hydroxy-3- methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (1-b). LCMS (ES, m / z): 383.2 [M+H]+.

[0158] Step C: N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide (1), TFA N-(5-bromo-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (1-b, 57 mg, 0.149 mmol) was dissolved in tetrahydrofuran (10 mL) . PdCl2(dppf) (10.88 mg, 0.015 mmol), Cs2CO3 (1M in water 0.149 mL, 0.149 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (37.0 mg, 0.223 mmol) were added into the reaction mixture, and stirred at 70°C for 2 h. The25835 mixture was cooled, diluted with ethyl acetate (25 mL), washed with brine (saturated, 3 x 15 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18) Waters™ SunFire 18X150mm (Waters Corporation, Milford, MA), eluting with Acetonitrile / Water + 0.1% TFA, from 5 to 100%, wavelength 254mm, to give N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pival amide (1) TFA. LCMS (ES, m / z): 425.4 [M+H]+.

[0159] The compounds of Examples 2 through 55 depicted in Table 1 were prepared in an analogous fashion to that described for Example 1 but using the appropriate commercially available starting material and intermediates. NameCalc’d Observ Chiral on ns le25835 Example StructureNameCalc’d Observ ed Chiral on ns25835 ple StructureCalc Observ ExamName’d ed Chiral on ns ve lk- 4.6 m, % k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve lk- 4.6 m, % k ve lk- 250 + A) k ve lk- 250 + A) k ve lk- 250 + A) k ve lk- 250 + A) k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve H, 0 + A) k ve H, 0 + A) k ve H, 0 H) k ve H, 0 + A) k ve H, 0 + A) k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve H, 0 + A) k ve H, 0 + A) k ve H, 0 + A) k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve H, 0 H) k ve 4.6 m, % k ve H, 0 + A) k ve H, 0 + A) k25835 StructureCalc’d Observ ExampleNameed Chiral on ns ve H, 0 + A) k ve H, 0 + A) k25835 ample StructureCal Observ ExNamec’d ed Chiral on ns ve H, 0 + A) k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve H, 0 H) k ve H, 0 H) k ve H, 0 + A) k ve H, 0 + A) k25835 Example StructureNameCalc’d Observ ed Chiral on ns ve H, 0 H) k ve H, 0 H) kExamples 56 and 57 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide SFC peak1 (56 faster peak) and N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3- hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide SFC peak2 (57 slower peak) slow peak (57)

[0160] Step A: N-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide, HCl (56 / 57-a)25835 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (0.984 g, 4.62 mmol), Et3N (1.288 mL, 9.24 mmol) and pivaloyl chloride (0.682 mL, 5.54 mmol) were dissolved in THF (15 mL). The reaction mixture at room temperature was stirred for 2 h. The mixture was cooled, diluted with water (10 mL), filtered, and the solid was washed with 10 mL ethyl acetate to give N-(5-bromo-1H- pyrazolo[3,4-b]pyridin-3-yl)pivalamide, HCl (56 / 57-a). LCMS (ES, m / z): 296.8 [M+H]+. Step B: N-(5-bromo-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide N-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (0.51 g, 1.716 mmol) was dissolved in DMF (5 mL). Sodium hydride (0.103 g, 2.57 mmol) was added into reaction mixture at 0 °C, then stirred at 0 °C for 30 min, then warmed up to room temperature.4-bromobutan-2-ol (0.315 g, 2.060 mmol) was slowly added to reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was cooled, aqueous ammonium chloride (20 %, 15 mL) was added and the mixture was extracted with ethyl acetate(3x15 mL). The combined organic fractions were washed with brine (15 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to give N-(5-bromo-1-(3-hydroxybutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pivalamide (56 / 57-a). LCMS (ES, m / z): 368.9 [M+H]+.

[0161] Step C: N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl)pivalamide (56 / 57-b) N-(5-bromo-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (56 / 57-a, 390 mg, 1.056 mmol) was dissolved in Tetrahydrofuran (20 mL), PdCl2(dppf) (77 mg, 0.106 mmol), Cs2CO3(1 N in water, 2.112 mL, 2.112 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (210 mg, 1.267 mmol) were added into reaction mixture, and stirred at 70 °C for 2 h. The reaction mixture was a slurry. The solid was filtered to give N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3- hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (56 / 57-b). LCMS (ES, m / z): 411.4 [M+H]+.

[0162] Step D: N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide SFC peak1 (faster peak) and N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3- hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide SFC peak2 (slower peak) For a pair of enantiomers, the faster-eluting diastereoisomer is always listed first. The enantiomeric pure title compounds were obtained by chiral preparative SFC (Column: AS-H, 21 x 250mm Co-Solvent: 10% IPA + 0.2% DIPA, UV Wavelength: 210 nm). The fast er-eluting enantiomeric pure of N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide(peak 1, 56) was obtained as a solid. LCMS (ES, m / z): 411.4 [M+H]+. (faster peak, 56). The slower-eluting enantiomeric pure of N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-25835 hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide(peak 2, 57) was obtained as a solid. LCMS (ES, m / z): 411.4 [M+H]+. (slower peak, 57)

[0163] The compounds of Examples 58 and 59 depicted in Table 2 were prepared in an analogous fashion to that described for Examples 56 and 57 but using the appropriate commercially available reagents and intermediates. TABLE 2 Chiral Calc’d Observed Ex. Compound Name Separation 1 - 1 -xamp e 60 N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide (60)

[0164] Step A: 4-(3-amino-yl)-1H-pyrazolo[3,4-b]pyridin-1- yl)-2-methylbutan-2-ol (60-a) 4-(3-amino-5-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylbutan-2-ol (132 mg, 0.441 mmol) was dissolved in THF (3 mL). PdCl2(dppf) (42 mg, 0.057 mmol), Cs2CO3 (1M in water, 0.5 mL, 0.500 mmol) and 2-(4-fluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.571 mmol) were added into the reaction mixture at 70 °C and stirred overnight. The25835 mixture was cooled, aqueous ammonium chloride (20 %, 15 mL) was added, and the mixture then was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel ISOLUTE®Flash Si (40 g prepacked, Biotage, LLC, Charlotte, NC) eluting with EtOAc / MeOH from 0 to 10% to give 4-(3-amino-5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)- 2-methylbutan-2-ol (60-a). LCMS (ES, m / z): 359.2 [M+H]+.

[0165] Step B: N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-3,3-dimethylbutanamide (60), TFA 4-(3-amino-5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2- methylbutan-2-ol (25 mg, 0.070 mmol, 60-a), 1-methylimidazole (20.05 mg, 0.244 mmol) and 3,3-dimethylbutyric acid(12.15 mg, 0.105 mmol) were dissolved in acetonitrile (0.5 mL). TCFH (29.4 mg, 0.105 mmol) in acetonnitrle (0.1 mL) was added into reaction mixture at room temperature and stirred overnight. The residue was purified by preparative HPLC reverse phase Waters™ SunFire 18X150mm (Waters Corporation, Milford, MA), eluting with Acetonitrile / Water + 0.1% TFA from 20 to 100%, wavelength 254nm, to give N-(5-(4- fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide (60), TFA. LCMS (ES, m / z): 457.3 [M+H]+.

[0166] The compounds of Examples 61 to 103 depicted in Table 3 were prepared in an analogous fashion to that described for Example 60 but using the appropriate commercially available reagents and intermediates. Table 3. Calc’d Ob- Chiral on - le25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation - ve 1, 0 H) k ve H, 0 + A) kCalc’d O Chiral Ex. CompoundNameb- [M+H] served Separation -Calc’d O Chiral Ex. CompoundNameb- [M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -25835 Calc’d Ob- Chiral Ex. CompoundName[M+H] served Separation -N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (104)

[0167] Step A: N-(1-2-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pivalamide (104-a) A solution of N-(5-bromo-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (16.5 g, 46.7 mmol), bis(pinacolato)diboron (13.05 g, 51.4 mmol), and potassium acetate (13.75 g, 140 mmol) in dry DMF (280 mL) was purged with N2. [1,1'-bis(diphenyphosphino)ferrocene] dichloropalladium (II) (2.051 g, 2.80 mmol) was added to the solution and purged again with N2. The solution was heated at 90 °C for 2 h under N2 and cooled to the room temperature. The mixture was cooled, diluted with ethyl acetate (500 mL x 2), washed with water (500 mLx2), brine (200 mL), dried (Na₂SO₄), and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 80g, eluting with EtOac / Hexane 0-65% to give N-(1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pivalamide (104-a).25835

[0168] Step B: N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1- isobutyl-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide (104) N-(1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide (42 mg, 0.105 mmol, (104-a)), potassium carbonate (0.126 mL, 2.5 M in water, 0.315 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.68 mg, 10.49 µmol), were added to a vial with 5-bromo-7-fluoro-1,3-benzoxazole (27.2 mg, 0.126 mmol) in dioxane (1.049 mL). The reaction vial was flushed with N2 and stirred at 65°C for 1 hr. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), washed with water (5 mL), dried (Na₂SO₄), filtered. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel RediSep Rf Gold®(24 g, Teledyne ISCO, Lincoln, NE), eluting with EtOAc / Hexane 0-80% to give N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1- isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide (104). LCMS (ES, m / z): 410.3 [M+H]+.

[0169] The compounds of Examples 105 and 106 depicted in Table 4 were prepared in an analogous fashion to that described for Example 104 but using the appropriate commercially available reagents and intermediates. Table 4. Calc’d Observ Chiral N tion - le25835 BIOLOGICAL ASSAYS

[0170] Qube® Ion Channel Automated Patch-Clamp Electrophysiology Experimental Procedure Whole-cell currents were recorded from recombinant cell lines stably expressing human HCN1, HCN2, HCN3 or HCN 4 channels using the Qube®automated patch-clamp technology (Sophion Bioscience, Inc., Bedford, MA). Cells were sealed on a planar substrate using the multi-hole technology.

[0171] Experiments were performed at room temperature (25-29oC). The following solutions were used: Internal solution: 110 mM KF, 20 mM KCl, 10 mM NaCl, 2 mM MgCl2, 11 mM EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid) , 10 mM HEPES, pH 7.35. External Solution: 150 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 12 mM Dextrose, pH 7.3.

[0172] Compounds were prepared as 10 mM DMSO stock solutions.10-point compound titrations were generated using the Echo acoustic liquid handling instrument (Beckman Coulter Life Sciences, Indianapolis, IN) and glass coated 384 well plates. The final DMSO concentration in the assay was 0.3%.

[0173] Cells were held at -40 mV. HCN1, HCN2 and HCN3 channel mediated currents were elicited by 2 s (s=seconds) test pulses to -120 mV. HCN4 currents were elicited by 4 s test pulses to -140 mV.

[0174] A train of test pulses was applied at 0.05 Hz before compound addition. Cells in each Qchip well were incubated in compound for 5 minutes. Subsequently, currents during a train of test pulses (0.05 Hz) were measured until reaching steady state in compound. Current amplitudes were measured at the end of the 2s or 4s test pulse in control conditions and after compound addition. Current inhibition in compound was measured as current amplitude reduction in compound relative to control currents. For all electrophysiology experiments, offline analysis was used to determine percent current inhibition as a function of drug concentration. IC50 values were derived from four parameter logistic fits to 10-point dose response curves using the Hill equation. Percent inhibition at each compound concentration was determined using the equation: % inhibition of IHCN = 100*(IHCN(control)-IHCN(drug)) / IHCN(control). IC50 values were calculated using a 4-parameter logistic function (Hill equation): f(x) = Imin + (Imax-Imin) / (1+(IC50 / [x])h); IC50 = half maximal inhibitory concentration; Imin = minimal current; Imax = maximal current; h = Hill coefficient.25835

[0175] Table 5 depicts the activity levels of the compounds of Examples 1 through 106 with respect to their inhibition of the HCN1, HCN2, and HCN4 isoforms. Table 5 Biological Activities of Example Compounds 1–106 Example # HCN1_T2_IC50(nM) HCN2_T2_IC50(nM) HCN4_T2_IC50(nM) 1 >33750 421 >3375025835 31 2770 7 568 32 >33750 98 1539025835 67 >33750 134 3769 68 >33750 112 836025835 103 >33750 94 4822 104 >33750 630 >33750

Claims

25835 CLAIMS What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof,, (C3-12)cycloalkyl(C0-10alkyl), or (C3-12)heterocycloalkyl(C0-10alkyl), wherein R1 is substituted by 0, 1, 2, or 3 R1a substituentseach independently selected from C1-6alkyl, cyano, halo, and hydroxy;R2 is C1-10alkyl, C1-10alkyloxy, (C1-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxycarbonyl(C0-10alkyl), (C1-6alkyl)carbonyloxy(C0-10alkyl), or (C0-6alkyl)hydroxy(C1-10alkyl); andW is selected from:, wherein W is substituted by 0, 1, 2 or 3 R4substituents each independentlyalkyl, cyano, and halo.25835 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6alkyl, heteroaryl(C0-6alkyl), (C3-12)cycloalkyl(C0-6alkyl), or (C3-12)heterocycloalkyl(C0-6 alkyl), wherein R1is substituted by 0, 1, 2, or 3 R1asubstituents eachindependently selected from C1-6alkyl, cyano, halo, and hydroxy.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein: R1is methyl, ethyl, propyl, isobutyl, butyl, pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, (2-ethyl)butyl, pyrrolyl(C0-6alkyl), furanyl(C0-6alkyl), thienyl(C0-6alkyl), imidazolyl(C0-6alkyl), furazanyl(C0-6alkyl), oxazolyl(C0-6alkyl, oxatriazolyl(C0-6alkyl), isoxazolyl(C0-6alkyl), thiazolyl(C0-6alkyl, isothiazolyl(C0-6alkyl, pyrazolyl(C0-6alkyl), triazolyl(C0-6alkyl),tetrazolyl(C0-6alkyl), oxadiazolyl(C0-6alkyl), isoxazolinyl(C0-6alkyl), pyranyl(C0-6alkyl),pyridyl(C0-6alkyl), pyrazinyl(C0-6alkyl), triazinyl(C0-6alkyl), pyridazinyl(C0-6alkyl),pyrimidyl(C0-6alkyl), cyclobutyl(C0-6alkyl), cyclopropyl(C0-6alkyl), cyclopentyl(C0-6alkyl), oxetanyl(C0-6alkyl), piperidyl(C0-6alkyl), pyrrolidinyl(C0-6alkyl), piperazinyl(C0-6alkyl), morpholinyl(C0-6alkyl), thiomorpholinyl(C0-6alkyl), thiazolidinyl(C0-6alkyl), 1,4-dioxanyl(C0-6alkyl), tetrahydrofuranyl(C0-6alkyl), tetrahydrothiophenyl(C0-6alkyl),piperidinyl(C0-6alkyl), or azetidinyl(C0-6alkyl), wherein R1is substituted by 0, 1, 2, or 3R1a.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, whereinR2 is C1-6alkyl, C1-6alkyloxy, (C1-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxycarbonyl(C0-6alkyl), (C1-6alkyl)carbonyloxy(C0-6alkyl), or (C0-6alkyl)hydroxy(C1-6alkyl).

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R2ismethyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, 3-methoxy-3methylbutyl, 2- methoxycarbonyl-2-methyl-4yl, 2-methylbutyl, 2-methylbut-4yl, 2-methylprop-3yl, 2- methoxypropy-3yl, 2-hydroxy-2-methylbut-4yl, 2-methoxyethyl, or 2-hydroxybut-4yl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein W is25835 R47. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein W is , wherein W is substituted by 0, 1, 2 or 3 R4 6 alkyl, cyano, and halo.

8. The compound of claim 6 or 7 or a pharmaceutically acceptable salt thereof, wherein eachR1ais independently selected from methyl, ethyl, propyl, isopropyl, butyl, cyano, fluoro, andchloro.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R1a is independently selected from methyl, ethyl, propyl, isopropyl, butyl, cyano, fluoro, and chloro.

10. The compound of claim 1 selected from the group consisting N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide;25835 N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; methyl 4-(3-(3,3-dimethylbutanamido)-5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4- b]pyridin-1-yl)-2,2-dimethylbutanoate; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(4,7-difluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-isopentyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,3- dimethylbutanamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide;25835 N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(4-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d]thiazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-3,3-dimethylbutanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-dimethylbutanamide; N-(5-(6-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(4-chlorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide;25835 N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 2-methylfuran-3-carboxamide; N-(5-(6-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(7-cyanobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pivalamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d]thiazol-6-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)isothiazole- 5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2- methylfuran-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxypropyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-5-carboxamide; N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3- yl)cyclobutanecarboxamide;25835 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; (R)-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; (S)-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxybutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pivalamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylbutanamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)isoxazole-5- carboxamide; 2-cyclopropyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)propenamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-2,2-dimethylcyclopropane-1-carboxamide; (S)-N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2- dimethylcyclopropane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2- dimethylcyclopropane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-methyl-1H- pyrazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)isothiazole-4- carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)furan-3- carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)thiazole-5- carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylpentanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3-methylisoxazole-4-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide;25835 N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-4-methyloxazole-5-carboxamide; 3,3-difluoro-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pyrimidine-5-carboxamide; 3-fluoro-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-2,2-dimethylpropanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclopropane-1-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)isothiazole-4-carboxamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)furan-3-carboxamide; 2-ethyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)butanamide; 3-ethyl-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pentanamide; N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutanecarboxamide; 1-cyano-N-(5-(4-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3,3-difluoro-1-methylcyclobutane-1-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazole-5-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isothiazole-4-carboxamide;25835 N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)furan-3-carboxamide; N-(5-(benzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 3-ethylpentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3,3-dimethylpentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-3-methylisoxazole-4-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-4-methyloxazole-5-carboxamide; 3,3-difluoro-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methylcyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)isothiazole-4-carboxamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)furan-3-carboxamide; 3-ethyl-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pentanamide; N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutanecarboxamide; 1-cyano-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)cyclobutane-1-carboxamide; 3,3-difluoro-N-(5-(7-fluorobenzo[d][1,3]dioxol-5-yl)-1-(3-hydroxy-3-methylbutyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)cyclobutane-1-carboxamide; N-(5-(7-fluorobenzo[d]oxazol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; N-(5-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide; and25835 N-(5-(7-fluorobenzo[d]oxazol-6-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pivalamide, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A method of treating pain and other HCN2-driven diseases comprising administering a therapeutically effective amount a compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said pain and other HCN2- driven diseases is at least one are selected from inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) and psychiatric disorders.

13. The method according to claim 12, wherein said inflammatory pain and neuropathic pain is selected from at least one of infection pain, osteoarthritis, rheumatoid arthritis, post-operative pain, dental pain, and muscle pain due to injury, painful diabetic neuropathy (PDN), dysesthesia, post-herpetic neuralgia (PHN), chemotherapy-induced peripheral neuropathy (CIPN), trigeminal neuralgia, complex regional pain syndrome (CRPS), post-operative neuropathy, pudendal neuralgia, small fiber sensory neuropathy (SFSN), lower back pain, nerve damage following traumatic injury, fibromyalgia, and carpal tunnel syndrome.

14. The method according to claim 12, wherein said central nervous system (CNS) and psychiatric disorders are selected from cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), autism (sensory sensitivity), and mood disorders.

15. The method of any one of claims 12 - 14 wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof is administered orally to the subject.

16. Use of a compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof in therapy.

17. Use of a compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof for treating pain and other HCN2-driven is at least one are selected from inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) and psychiatric disorders.

18. Use according to claim 17, wherein said inflammatory pain and neuropathic pain is selected from at least one of infection pain, osteoarthritis, rheumatoid arthritis, post-operative pain, dental pain, and muscle pain due to injury, painful diabetic neuropathy (PDN), dysesthesia, post-herpetic neuralgia (PHN), chemotherapy-induced peripheral neuropathy (CIPN), trigeminal neuralgia, complex regional pain syndrome (CRPS), post-operative neuropathy, pudendal neuralgia, small fiber sensory neuropathy (SFSN), lower back pain, nerve damage following traumatic injury, fibromyalgia, and carpal tunnel syndrome. selected from ulcerative colitis and Crohn’s disease.

19. Use according to claim 17, wherein said central nervous system (CNS) and psychiatric disorders are selected from cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders.

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