Pyrrolidinyl derivatives useful as HCN1 / HCN 2 modulators

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, (I) can inhibit HCN1 / 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

25863 PYRROLIDINYL DERIVATIVES USEFUL AS HCN1 / HCN 2 MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 600,156, filed November 17, 2023, the contents of each of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to certain pyrrolidine compounds that inhibit hyperpolarization activated cyclic-nucleotide modulated ion channel (HCN channel) activity, and selective to HCN1 / HCN2 isoforms over the HCN4 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 or sensation 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 trigeminalneuralgia, 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 in these 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). HCN1 appears to share a similar qualitative expression pattern as HCN4 in the heart albeit at RNA levels that are only 15% of those of HCN4 (Chandler et al., “Molecular Architecture of the Human Sinus Node: Insights Into the Function of the Cardiac Pacemaker”. Circulation. 119,1562–1575, 2009). 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 findingssuggest 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 Ih currently 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] 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.

[0023] There remains a need for HCN channel inhibitors, particularly compounds which selectively inhibit HCN1 and HCN2 channels.

[0024] 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).

[0025] 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 restrictedHCN2 inhibitors provide an effective treatment for tinnitus in an in-vivo model for the condition (See, WO 2022 / 185058). SUMMARY OF THE DISCLOSURE

[0026] 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.

[0027] 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.

[0028] 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.

[0029] In one aspect, the present disclosure provides compounds of Formula (I) ,and their pharmaceutically acceptable salts.

[0030] The disclosure furthermore provides 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

[0031] In one embodiment, the present disclosure provides a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein:each R1independently is hydrogen, C1-6alkyl, C1-6alkoxy, or halogen; R2is hydrogen or C1-6alkyl; R3is hydrogen or C1-6alkyl; each Rbindependently is hydrogen or C1-4alkyl; R4is selected from phenyl, 2,3-dihydro-1H-indenyl, pyridyl, quinolinyl, isoquinolinyl, naphthalenyl, indazolyl, pyrimidyl, benzo[d]imidazolyl, pyrazinyl, and pyridazinyl; wherein R4is substituted by 0, 1, or 2 R5substituents;each R5independently is selected from (1) halogen, (2) cyano (3) -SO2(C1-4alkyl), (4) -SO2NH2, (5) –(C1-6alkyl)OH (6) C1-6alkyl, (7) C1-6fluoroalkyl, (8) (C1-6alkyloxy(C0-4alkyl),(9) (C1-6fluoroalkyloxy(C0-4alkyl), (10) (C3-12cycloalkyl)oxy(C0-4alkyl), (11) (heterocycloalkyl)oxy(C0-4alkyl), (12) (C3-12cycloalkyl)carbonyl(C0-4alkyl), (13) (heterocycloalkyl)carbonyl(C0-4alkyl), (14) (C1-6alkyl) carbonylamino(C0-4alkyl), (15) (C0-6alkyl)0-2aminocarbonyl(C0-4alkyl), (16) (C3-12cycloalkyl)(C0-4alkyl) and (17) (heterocycloalkyl)(C0-4alkyl), wherein each R5is independently substituted by 0, 1, 2, 3 or 4 R5a; R5aindependently is (1) halogen, (2) hydroxy, (3) C1-6alkyl (4) C1-6fluoroalkyl (5) amino, (6) cyano, (7) =O, (8) C1-6alkoxy, (9) (C3-6cycloalkyl)carbonyl, (10) (heterocycloalkyl)carbonyl, (11) (C1-6alkyl)oxycarbonyl, (12) (C1-6alkyl)carbonyl, (13) (C0-6alkyl)aminocarbonyl, (14) (C0-6alkyl)carbonylamino, (15) (C0-6alkyl)oxycarbonylamino, (16) –(O-C1-6alkyl)m, (17) (C3-6cycloalkyl)-O-(C=O)-, (18) (heterocycloalkyl)-O-(C=O)-, (19) (C3-6cycloalkyl)-O-(C=O)-, and (20) –(C1-6alkyl)OH, wherein R5ais substituted by 0, 1, 2, or 3 R5b; R5bis hydroxy, (C1-4alkoxy), or halogen;W is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, thiadiazolyl, and isothiazolyl; B is O or S n is 0 or 1; z is 0, 1, 2, or 3; and m is 1, 2, or 3.

[0032] In a first embodiment of the invention, R1is methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, (2-ethyl)butyl, fluoro, chloro, bromo, methoxy, ethoxy, or propoxy, and the other groups are as provided in the general Formula (I) above.

[0033] In a second embodiment of the invention, R1is methyl, methoxy, fluoro or chloro, and the other groups are as provided in the general Formula (I) above.

[0034] In a third embodiment of the invention, R2is hydrogen, methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, or (2- ethyl)butyl, and the other groups are as provided in the general Formula (I) above or as in the first through second embodiments.

[0035] In a fourth embodiment of the invention, R2is hydrogen, methyl, ethyl, propyl,isopropyl, isobutyl, butyl, or tert-butyl, and the other groups are as provided in the general Formula (I) above or as in the first through second embodiments.

[0036] In a fifth embodiment of the invention, R2is hydrogen or methyl, and the other groupsare as provided in the general Formula (I) above, or as in the first through second embodiments.

[0037] In a sixth embodiment of the invention, R3is hydrogen, methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, or (2- ethyl)butyl, and the other groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0038] In a seventh embodiment, R3is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, orbutyl, and the other groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0039] In an eighth embodiment, R3is hydrogen or methyl, and the other groups are asprovided in the general Formula (I) above or as in the first through fifth embodiments.

[0040] In a ninth embodiment of the invention, each Rbsubstituent independently is hydrogen,methyl, ethyl, propyl, or isopropyl, and the other groups are as provided in the general Formula (I) above or as in the first through eighth embodiments.25863

[0041] In a tenth embodiment of the invention, each Rbsubstituent independently is hydrogenor methyl, and the other groups are as provided in the general Formula (I) above or as in the first through eighth embodiments.

[0042] In an eleventh embodiment of the invention, R4is phenyl, 2,3-dihydro-1H-indenyl,pyridyl, quinolinyl, isoquinolinyl, naphthalenyl, indazolyl, pyrimidyl, benzo[d]imidazolyl,pyrazinyl, or pyridazinyl; wherein R4is substituted 0, 1, or 2 R5substituents, and the othergroups are as provided in the general Formula (I) above, or as in the first through tenth embodiments.

[0043] In a twelfth embodiment of the invention, R4is phenyl, 2,3-dihydro-1H-indenyl,pyridyl, quinolinyl, indazolyl, pyrimidyl, or pyrazinyl; wherein R4is substituted by 0, 1, or 2 R5substituents, and the other groups are as provided in the general Formula (I) above, or as in the first through tenth embodiments.

[0044] In a thirteenth embodiment of the invention, each R5substituent independently isselected from halogen, cyano -SO2(C1-4alkyl), -SO2NH2, SO2NH(C1-4alkyl), –(C1-6alkyl)OH, C1-6alkyl, C1-4fluoroalkyl, (C1-4alkyloxy(C0-4alkyl), (C1-4fluoroalkyloxy(C0-4alkyl), (C3-6cycloalkyl)oxy(C0-4alkyl), (heterocycloalkyl)oxy(C0-4alkyl), (C3-6cycloalkyl)carbonyl(C0-4alkyl), (heterocycloalkyl)carbonyl(C0-4alkyl), (C1-6alkyl) carbonylamino(C0-4alkyl), (C0-6alkyl)0-2aminocarbonyl(C0-4alkyl), (C3-6cycloalkyl)(C0-4alkyl) and (heterocycloalkyl)(C0-4alkyl), wherein each R5independently is substituted by 0, 1, 2, 3 or 4 R5a, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0045] In a fourteenth embodiment of the invention, each R5substituent independently isselected from fluoro, chloro, cyano -SO2CH3, -SO2C2H5, -SO2NH2, -SO2NH(methyl), hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisobutyl, hydroxytert-butyl, 2- hydroxypropyl, 2-hydroxy butyl, 2-hydroxyisobutyl, 3-hydroxyisopentyl, hydroxypentyl, methyl, ethyl, isobutyl, propyl, isopropyl, butyl, pentyl, trifluoromethyl, trifluoroethyl, 2,2,2- trifluoroethyl, difluoromethyl, difluoroethyl, 2-difluoropropyl, 2,2-difluoropropyl, difluorobutyl, difluoroisobutyl, 3,3-difluorobutyl, methoxy, ethoxy, propoxy, methoxyethyl, ethoxyethyl, difluoromethoxy, trifluoromethoxy, fluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluorobutyl, cyclopropyloxy, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxy, cyclobutyloxymethyl, cyclopentyloxy, 2-azaspiro[3.3]heptyloxy, (2- azaspiro[3.3]heptyloxy)methyl, piperidinyloxy, (piperidinyloxy)methyl, azetidinyloxy, azetidinyloxymethyl, pyrrolidinyloxy, (pyrrolidinyloxy)methyl, oxazolidinyloxy, (oxazolidinyloxy)methyl, piperazinyloxy, (piperazinyloxy)methyl, morpholinyloxy,25863 (morphlinyloxy)methyl, pyrrolidinyloxy, (pyrrolidinyloxy)methyl, aziridinyloxy, (aziridinyloxy)methyl, oxetanyloxy, (oxetanyloxy)methyl, isoxazolidinyloxy, (isoxazolidinyloxy)methyl, cyclopropyloxy, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxy, cyclobutyloxymethyl, cyclopentyloxy 2-azaspiro[3.3]heptylcarbonyl, (2- azaspiro[3.3]heptylcarbonyl)methyl, piperidinylcarbonyl, (piperidinylcarbonyl)methyl, azetidinylcarbonyl, (azetidinylcarbonyl)methyl, pyrrolidinylcarbonyl, (pyrrolidinylcarbonyl)methyl, oxazolidinylcarbonyl, (oxazolidinylcarbonyl)methyl, piperazinylcarbonyl, (piperazinylcarbonyl)methyl, morpholinylcarbonyl, (morphlinylcarbonyl)methyl, pyrrolidinylcarbonyl, (pyrrolidinylcarbonyl)methyl, aziridinylcarbonyl, (aziridinylcarbonyl)methyl, oxetanylcarbonyl, (oxetanylcarbonyl)methyl, isoxazolidinylcarbonyl, (isoxazolidinylcarbonyl)methyl, methylcarbonylamino, methylcarbonylamino, (methylcarbonylamino)methyl, (methylcarbonylamino)ethyl, ethylcarbonylamino, (ethylcarbonylamino)methyl, (ethylcarbonylamino)ethyl, methylaminocabonyl, (methylaminocarbonyl)methyl, ethylaminocarbonyl, (ethylaminocarbonyl)methyl, isopropylaminocarbonyl, (isopropylaminocarbonyl)methyl, tert- butylaminocarbonyl, (tert-butylaminocarbonyl)methyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylmethyl 2-azaspiro[3.3]heptyl, (2-azaspiro[3.3]heptyl)methyl, piperidinyl, piperidinylmethyl, azetidinyl, azetidinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, oxazolidinyl, oxazolidinylmethyl, piperazinyl, piperazinylmethyl, morpholinyl, morphlinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, aziridinyl, aziridinylmethyl, oxetanyl, oxetanylmethyl, isoxazolidinyl, and isoxazolidinylmethyl, wherein each R5independently is substituted by 0, 1, 2, 3 or 4 R5a, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0046] In a fifteenth embodiment of the invention, each R5substituent independently isselected from fluoro, chloro, cyano -SO2CH3, -SO2NH2, hydroxymethyl, hydroxyethyl, 2- hydroxyisobutyl, 3-hydroxyisopentyl, methyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, difluoromethoxy, cyclobutyloxy, cyclopentyloxy, 2- azaspiro[3.3]heptyloxy, azetidinyloxy, azetidinylcarbonyl, (azetidinylcarbonyl)methyl, (methylcarbonylamino)methyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropyl, azetidinylmethyl, pyrrolidinylmethyl, oxazolidinyl, wherein each R5independently is substituted by 0, 1, 2, 3 or 4 R5a, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0047] In a sixteenth embodiment of the invention, each R5asubstituent independently isselected from chloro, fluoro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl,25863 fluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, amino, =O, methoxy, ethoxy, propoxy, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, piperidinycarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, oxazolidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, (tert-butyl)oxycarbonyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, (C0-6alkyl)carbonylamino, –(O-C1-6alkyl)m, cyclopropyl-O-(C=O)-, cyclobutyl-O-(C=O)-, cyclopentyl-O-(C=O)-, hydroxymethyl, and hydroxyethyl, wherein eachR5aindependently is substituted by 0, 1, 2, 3 or 4 R5b, and the other groups are as provided inthe general Formula (I) above, or as in the first through fifteenth embodiments.

[0048] In a seventeenth embodiment of the invention, each R5asubstituent independently isselected from fluoro, hydroxy, methyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, amino, =O, methoxy, piperidinycarbonyl, (tert-butyl)oxycarbonyl, methylcarbonyl, methylaminocarbonyl, _--O-CH2CH2-O-CH2CH2-OCH3, and cyclopropyl-O-(C=O)-, wherein each R5aindependently issubstituted by 0, 1, 2, 3 or 4 R5b, and the other groups are as provided in the general Formula (I)above, or as in the first through fifteenth embodiments.

[0049] In an eighteenth embodiment of the invention, each R5bsubstituent independently isfluoro, chloro, hydoxy, methoxy, or ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through seventeenth embodiments.

[0050] In a nineteenth embodiment of the invention, each R5bsubstituent independently isfluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through seventeenth embodiments.

[0051] In a twentieth embodiment of the invention, W is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,3-thiadiazolyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.

[0052] In a twenty-first embodiment of the invention, W is selected from pyridyl, pyrazinyl, thiazolyl, and 1,2,4-thiadiazolyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.

[0053] In a twenty-second embodiment of the invention, W is thiazolyl, or 1,2,4-thiadiazolyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.25863

[0054] In a twenty-third embodiment of the invention, W is pyridyl, or pyrazinyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.

[0055] In a twenty-fourth embodiment of the invention, B is O, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-third embodiments.

[0056] In a twenty-fifth embodiment of the invention, B is S, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-third embodiments.

[0057] In a twenty-sixth embodiment of the invention, n is 0, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-fifth embodiments.

[0058] In a twenty-seventh embodiment of the invention, n is 1, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-fifth embodiments.

[0059] In a twenty-eighth embodiment of the invention, z is 0, 1, or 2, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-seventh embodiments.

[0060] In a twenty-nineth embodiment of the invention, z is 0 or 1, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-seventh embodiments.

[0061] In a thirtieth embodiment of the invention, m is 1,or 2,and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-nineth embodiments.

[0062] Non-limiting examples of the Compounds of Formula I include compounds 1 through 80 or a pharmaceutically acceptable salt thereof, as set forth in the Examples: N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (R)-N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (S)-N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide;25863 (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide; N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; 3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; (R)-(3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; (S)-(3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide;25863 (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide; N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide; (R)-N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide;25863 (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (S)-N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide;25863 (S)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; tert-butyl-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; tert-butyl (R)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; tert-butyl (S)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; Cyclopropyl-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate;25863 Cyclopropyl (R)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate; Cyclopropyl (S)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate; N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide; (R)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide; (S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide; 6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; (R)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; (S)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; 6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; (R)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; (S)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; 4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; (R)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; (S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; 2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide; (R)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide;25863 (S)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide; 3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; tert-butyl-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; tert-butyl (R)-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; tert-butyl (S)-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; 2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; (R)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; (S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 (R)-N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3-fluoro- 4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; (64) (R)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; (S)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carbothioamide;25863 (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carbothioamide; 3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (R)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol-3- yl)methanone; (R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol- 3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol- 3-yl)methanone; (1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin- 1-yl)methanone; (R)-(1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidin-1-yl)methanone; (S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidin-1-yl)methanone; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone;(R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone; N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2-yl)pyrrolidine-1- carboxamide; (2R)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; (2S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; (4R)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; (4S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3R)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (4R)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (4S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (2R)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (2S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3R)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (R)-(5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (S)-(5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (R)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin- 1-yl)methanone; (R)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone;(S)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone; N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; or (S)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide. Definitions

[0063] 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.

[0064] 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.25863

[0065] The term “C0” or “C0” or “C0” as employed in expressions such as “C0-6 alkyl” and“C0-6alkyl” means a direct covalent bond; or when the term appears at the terminus of asubstituent, C0-6 alkyl means hydrogen or C1-6 alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms 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.

[0066] 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.

[0067] “Amino” means a –NH2 group.

[0068] “Aminocarbonyl” means –C(=O)NH2.

[0069] “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–).

[0070] “Celite®” (Honeywell Fluka™) diatomite is diatomaceous earth and can be referred to as "celite".

[0071] “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.

[0072] “Carbonyl” means a functional group composed of a carbon atom double-bonded to an oxygen atom (C=O).

[0073] “Carbonylamino” means –NHC(=O)H.

[0074] “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 atoms25863 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 rest 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).

[0075] 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.

[0076] The term “C3-8 cycloalkyl” (or “C3-C8 cycloalkyl” 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.

[0077] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted linear and branched alkyl groups, up to perfluoro substituted alkyl. “C1-6 fluoroalkyl” refers to a fluoronated alkyl group containing from 1 to 6 carbon atoms. For example, fluoromethyl, 1,1- difluoroethyl, difluoromethyl, trifluoromethyl or 3,3,4,4,4-pentafluorobutyl are included.

[0078] “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).

[0079] 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., 3 to 12 membered heterocycloalkyl) 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 membered heterocycloalkyl” means that the heterocycloalkyl group may consist 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 membered heterocycloalkyl. In some embodiments, it is a 4 to 10 membered heterocycloalkyl. In some embodiments, it is a 3 to 10 membered 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,25863 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).

[0080] 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.

[0081] 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- 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.

[0082] The term “hydroxy” means -OH.

[0083] The term “oxo” means (=O).

[0084] The term “oxy” means an oxygen (O) atom.25863

[0085] The term “thio” means a sulfur (S) atom.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.25863

[0094] 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.

[0095] 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-HN C1-5 alkyl. of compounds having substituents terminating with a methylgroup may 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.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 itoccurs. For example, if Riand Rjare independently selected from the group consisting ofmethyl, ethyl, propyl and butyl, then (CRiRj)2.

[0096] Unless expressly stated to the contrary,example, a heteroaromatic ring described as containing from “1 to 4 heteroatoms” 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.25863

[0097] 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.

[0098] 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.

[0099] 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 sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0100] 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.

[0101] The wavy line , as used herein, indicates a point of attachment to the rest of the compound.

[0102] 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.

[0103] 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 and25863 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.

[0104] 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.

[0105] 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 the25863 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.

[0106] 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.

[0107] 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.

[0108] “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.

[0109] “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.

[0110] 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 that amount 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

[0111] 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 effective25863 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.

[0112] 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.

[0113] 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 preferably 0.025-7.5 mg / kg / day, more preferably 0.1-2.5 mg / kg / day, and most preferably 0.1-0.5 mg / kg / day (unless specified otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg / day and 2.4 g / day, preferably 2-600 mg / day, more preferably 8-200 mg / day, and most preferably 8-40 mg / kg / day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably between 8 mg and 100 mg, e.g., 8 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg and 100 mg. Advantageously, the compounds may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably between 4 mg and 50 mg, e.g., 4 mg, 5 mg, 10 mg 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 45 mg, and 50 mg. Pharmaceutical Compositions

[0114] 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.

[0115] 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, a25863 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.

[0116] 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 HCN1 / 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 HCN1 / HCN2 over HCN4.

[0117] 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.

[0118] 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, idiopathic small fiber neuropathy, 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.

[0119] 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,25863 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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 or 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.

[0125] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic25863 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.

[0126] 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.

[0127] 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.

[0128] 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 hydrophobic25863 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.

[0129] 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.

[0130] 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 a 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).

[0131] 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 compositions25863 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.

[0132] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0133] 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.

[0134] 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.

[0135] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0136] 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, 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 Disclosure25863

[0137] 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 HCN1 / HCN2.

[0138] In some embodiments, the present disclosure provides a method of treating pain and other HCN1 / 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 HCN1 / HCN2-driven pain is inflammatory pain. In some embodiments, the HCN1 / HCN2-driven pain is neuropathic pain. In some embodiments, the HCN1 / 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 HCN1 / HCN2-driven disease is tinnitus. In some embodiments, the HCN1 / HCN2-driven inflammatory pain disease is rheumatoid arthritis. In some embodiments, the HCN1 / HCN2-driven pain disease is migraine. In some embodiments of the invention, the HCN1 / 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.

[0139] 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.

[0140] 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 the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0141] 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 the25863 foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.

[0149] 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 HCN1 / HCN2-driven diseases selected from inflammatory pain, neuropathic pain, tinnitus, and migraine.25863

[0150] 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 HCN1 / HCN2-driven CNS and psychiatric disorders selected from (CIAS), (EIEE), schizophrenia, autism (sensory sensitivity), and depression.

[0151] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN1 / HCN2-driven diseases selected from inflammatory pain.

[0152] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN1 / HCN2-driven diseases selected from neuropathic pain.

[0153] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN1 / HCN2-driven diseases that is tinnitus.

[0154] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCN1 / HCN2-driven diseases that is migraine. Combination Therapies

[0155] 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.

[0156] 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

[0157] The compounds of the present invention can be prepared according to the procedures of the following schemes (Scheme A and Scheme B) and specific examples, or modifications25863 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.

[0158] 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.

[0159] 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) usually performed 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).25863 Instrumentation

[0160] 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.

[0161] 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).

[0162] 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 in 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.25863

[0163] Unless specifically mentioned, separation columns referenced generally as AD, AS, OD, OJ type columns can be obtained from various commercial manufacturers generally known to those skilled in the art, such as, for example, Waters Corporation, Millipore Sigma, Agilent, Varian.

[0164] 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).

[0165] 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.

[0166] 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.

[0167] 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 intended25863 product. In the examples, chemical synthesis schemes are provided for reagents and intermediates which were not commercially available. Abbreviations Abbreviations and acronyms employed herein include the following: AcOH = acetic acid min = minute BAST = bis(2-methoxyethyl)aminosulfur mL = milliliters25863 K2CO3= potassium carbonate TCHF = Chloro-N,N,N',N'- tetramethylformamidinium Hexafluoro hos hate REScheme AA-2 Ar O OM1 HOMsCl Ar15utilizing nucleophilic acyl (A-1) substitution with a variety of organometallic nucleophiles (A-2) to give ketone intermediate A-3. Intermediate A-3 may be converted to tertiary alcohol A-4 by25863 treating with Grigard reagent, MeMgBr. Mesylation of tertiary alcohol A-4 and subsequent elimination under excess Et3N conditions yields olefin intermediate A-5. An 1, 3 dipolar cycloaddition under acidic conditions affords the pyrolidine core intermediate A-6, A-6 can be deprotected by 1-chloroethyl chloroformate to give intermediate A-7. Intermediate A-7 may be reacted with isocyanates directly or amines utilizing urea coupling conditions (using triphosgene or CDI as coupling regents) to deliver compounds of formula A-8. Alternatively, amide coupling of intermediate A-7 with an acid using a reagent such as N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) provides compounds of formula A- 9. Scheme BB-3 S Ar O TMPZnCl.LiCl O N O Cl1Phutilizing a Negishi coupling of intermediate B-1 with suitable aryl bromide to give intermediate B-2 which can be deprotoned by NaH and nucleophilic aromatic substitution yields intermediate B-4. B-4 is then subject to a LAH reduction of amide to afford intermediate B-5 which can be deprotected by 1-chloroethyl chloroformate to give intermediate B-6. Intermediate B-6 may then be reacted with isocyanates directly or amines utilizing urea coupling conditions (using triphosgene or CDI as coupling regents) to deliver compounds of formula B-7. Alternatively, one can utilize an amide coupling of intermediate B-6 with an acid with a reagent such as N,N,N',N'-25863 tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) to provide compounds of formula B-9. INTERMEDIATES

[0170] Intermediate I-1 2-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)thiazole hydrochloride (I-1) 1 Step 1: morpholino(thiazol-2-yl)

[0171] A solution of morpholine Et3N (4.25 ml, 30.5 mmol) in DCM (5 ml) was slowly added to a solution of thiazole-2-carbonyl chloride (3 g, 20.33 mmol) in DCM (30 ml) at 0 °C. After addition, the mixture was stirred under nitrogen atmosphere at 0 °C for 1 hour, then warmed to rt for 1 hour. The resulting mixture was then partitoned between ethyl acetate and saturated aqueous NaHCO3. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-70% ethyl acetate / hexane) to give compound I-1a. LCMS m / z (M+H): calculated 199.2, observed 199.1. Step 2: (3-fluoro-4-methylphenyl)(thiazol-2-yl)methanone (I-1b)

[0172] 0.5M (3-fluoro-4-methylphenyl)magnesium bromide in THF (3.76 ml, 1.879 mmol) was added to a cold (0 °C) solution of morpholino(thiazol-2-yl)methanone (266 mg, 1.342 mmol) in anhyrous THF (8 ml). The mixture was stirred under nitrogen atmosphere at 0 °C for 2 hours, quenched with aqueous saturated NH4Cl and then extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound I-1b. LCMS m / z (M+H): calculated 222.2, observed 222.2. Step 3: 1-(3-fluoro-4-methylphenyl)-1-(thiazol-2-yl)ethan-1-ol (I-1c)

[0173] 3.4 M methylmagnesium bromide in THF (0.86 ml, 2.93 mmol) was added to a cold (0°C) solution of (3-fluoro-4-methylphenyl)(thiazol-2-yl)methanone (I-1b, 324 mg, 1.464 mmol) in andyrous THF (10 ml). The mixture was stirred under nitrogen atmosphere at 0 °C for 1 hour, quenched with aqueous saturated NH4Cl, and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrtaed in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-60% ethyl acetate / hexane) to give compound I-1c. LCMS m / z (M+H): calculated 238.3, observed 238.2.25863 Step 4: 2-(1-(3-fluoro-4-methylphenyl)vinyl)thiazole (I-1d)

[0174] Et3N (0.90 ml, 6.42 mmol) and MsCl (0.33 ml, 4.28 mmol) was added to a solution of 1-(3-fluoro-4-methylphenyl)-1-(thiazol-2-yl)ethan-1-ol (I-1c, 254 mg, 1.070 mmol) in DCM (10 ml) at 0 °C. The mixture was stirred under nitrogen atmosphere at 0 °C for 1 hour, warmed to rt and stirred overnight. The reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / hexane) to give compound I-1d. LCMS m / z (M+H): calculated 220.3, observed 220.2. Step 5: 2-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)thiazole (I-1e)

[0175] N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (0.43 ml, 1.687 mmol) and TFA (0.026 ml, 0.337 mmol) was added to a solution of 2-(1-(3-fluoro-4- methylphenyl)vinyl)thiazole (I-1d,185 mg, 0.844 mmol) in THF (6 ml) was added. After stirring at rt for 3 hours, additional N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (0.43 ml, 1.687 mmol) was added to the mixture. The resulting mixture was stirred at rt for additional 4 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound I-1e. LCMS m / z (M+H): calculated 353.5, observed 353.2. Step 6: 2-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)thiazole hydrochloride (I-1)

[0176] A tube was sealed with chloromethyl chloroformate (0.038 ml, 0.426 mmol), 2-(1- benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)thiazole (I-1e, 50 mg, 0.142 mmol) and DCE (0.5 ml). The mixture was heated to 60 °C and stirred for 1 hour, followed by addition of MeOH (2 ml). The reaction was heated to 90 °C, stirred for 2 hours and concentrated in vacuo. The residue was washed with diethyl ether, filtered to give the intermediate I-1. LCMS m / z (M+H): calculated 263.3, observed 263.5.

[0177] Intermediates I-2 through I-5 depicted in Table 1 were prepared in an analogous fashion to that described for intermediate I-1 but using the appropriate commercially available starting material and reagents. Table 1: Intermediate Compound Name Calc’d Observed25863 Intermediate Compoun Name Calc’d Observed Number d [M+H]+[M+H]+5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-6) 6 Step 1: (3-fluoro-4-methylphenyl)(I-6a)

[0179] 2-fluoro-4-iodo-1-methylbenzene (2.15 g, 9.10 mmol) was dissolved in anhyrous THF (20 ml) and cooled to -78 °C. Subsequently, 1.3M isopropylmagnesium chloride lithium chloride complex solution in THF (7.00 ml, 9.10 mmol) was added. The mixture was stirred under nitrogen atmosphere at -78 °C for 1 hour and then ethyl 1,2,4-thiadiazole-5-carboxylate (1.00 g, 6.07 mmol) was added. After stirring at -78 °C for 30 minutes, the reaction was quenched with aqueous saturated NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound I- 6a. LCMS m / z (M+H): calculated 223.2, observed 223.1. Step 2: 1-(3-fluoro-4-methylphenyl)-1-(1,2,4-thiadiazol-5-yl)ethan-1-ol (I-6b)25863

[0180] 3.4 M methylmagnesium bromide in THF (1.80 ml, 6.30 mmol) was added to a solution of (3-fluoro-4-methylphenyl)(1,2,4-thiadiazol-5-yl)methanone (I-6a, 700 mg, 3.15 mmol) in THF (20 ml) at 0 °C. The mixture was stirred under nitrogen atmosphere at 0 °C for 2 hours, quenched with aqueous saturated NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-60 % ethyl acetate / hexane) to give compound I-6b. LCMS m / z (M+H): calculated 239.3, observed 239.1. Step 3: 5-(1-(3-fluoro-4-methylphenyl)vinyl)-1,2,4-thiadiazole (I-6c)

[0181] Et3N (1.88 ml, 13.45 mmol) and MsCl (0.70 ml, 8.96 mmol) was added to a solution of 1-(3-fluoro-4-methylphenyl)-1-(1,2,4-thiadiazol-5-yl)ethan-1-ol (I-6b, 534 mg, 2.241 mmol) in CH2Cl2 (20 ml) at 0 °C. The mixture was stirred at 0 °C for 1hour,then warmed to rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound I-6c. LCMS m / z (M+H): calculated 221.3, observed 221.2. Step 4: 5-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I-6d)

[0182] TFA (0.091 ml, 1.180 mmol) was added to a solution of 5-(1-(3-fluoro-4- methylphenyl)vinyl)-1,2,4-thiadiazole (I-6c, 1.30 g, 5.90 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (4.54 ml, 17.71 mmol) in THF (30 ml). The mixture was stirred at rt for 6 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / hexane) to give compound I- 6d. LCMS m / z (M+H): calculated 354.5, observed 355.4. Step 5: 5-(3-(3-fluoro-4-methylphenyl)pyrrolidine-3-yl)-1,2,4-thiadiazole hydrochloride (I-6)

[0183] 5-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I-6d, 325 mg, 0.919 mmol) and chloromethyl chloroformate (0.33 ml, 3.68 mmol) were combined in DCE (6 ml) and sealed in a tube. The mixture was heated to 80 °C, stirred for 3 hours, followed by addition of MeOH (10 ml) and heated to100 °C and stirred for 1 hour. The reaction was concentrated in vacuo. The residue was washed with diethyl ether, filtered to give intermediate I- 6. LCMS m / z (M+H): calculated 264.3, observed 264.5. Intermediate I-7 (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7)25863 7 Step 1: (2,2,6,6-tetramethylpiperidin- (I-7a)

[0184] Butyllithium (2.5 M in -40 °C and under argon atmosphere was added to a solution of 2,2,6,6-tetramethylpiperidine (12.71 g, 90 mmol) in THF (200 mL). The reaction was slowly warmed to -10 °C and stirred at -10 °C for 0.5 hour. Then zinc(II) chloride (0.7 M in THF) (141 mL, 99 mmol) was added to the reaction at -10 °C. The reaction was slowly warmed to 25 °C and stirred for 1 h. The resulted solution was directly used for next step. Step 2: 1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (I-7b)

[0185] 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (includes I-7a, 200 mL, 90 mmol, freshly prepared), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.43 g, 3.00 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (3.11 g, 3.00 mmol) and 4-bromo-2-fluoro-1-methylbenzene (6.80 g, 36.0 mmol) at room temperature and under nitrogen atmosphere were added to a mixture of 1-benzylpyrrolidin-2-one (5.26 g, 30 mmol) in THF (50 mL). The resulting mixture was stirred at 70 °C for 3 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by RP-Combiflash to afford compound I-7b. LCMS m / z (M+H): calculated 284.1, observed 284.1. Step 3: 1-benzyl-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-2-one (I-7c)

[0186] Sodium hydride (60% wt) (2.117 g, 52.9 mmol) at ambient temperature, followed by 5- chloro-1,2,4-thiadiazole (2.55 g, 21.18 mmol) under nitrogen atmosphere were added to a stirred mixture of 1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (I-7b, 5 g, 17.65 mmol) in 2- methyltetrahydrofuran (130 mL). The resulting mixture was stirred at 80 °C for 8 hours. The reaction mixture was quenched by aqueous saturated NH4Cl (400 mL) and diluted with ethyl acetate (500 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 ~ 60% ethyl acetate in PE to give compound I-7c. LCMS m / z (M+H): calculated 368.1, observed 368.1. Step 4: 5-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I-7d)

[0187] Aluminum trichloride (3.63 g, 27.2 mmol) and LiAlH4(16.33 mL, 16.33 mmol) at -40 °C and under nitrogen atmosphere were added to a stirred mixture of 1-benzyl-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-2-one (I-7c, 5 g, 13.61 mmol) in THF (10025863 mL). The resulting mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was quenched by aqueous saturated NaHCO3(200 mL) and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound I-7d. LCMS m / z (M+H): calculated 354.1, observed 354.1. Step 5: (R or S)-5-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I- 7da)

[0188] The racemic 5-(1-benzyl-3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I-7d, 21 g, 59.4 mmol) was separated by SFC (Cellulose-4 column, 30% IPA with 0.5% 2 M NH3 in MeOH). Fast peak (first eluted fraction) gave the desired isomer I-7da. LCMS m / z (M+H): calculated 354.1, observed 354.1. Step 6: (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7)

[0189] To a solution of the above desired isomer (R or S)-5-(1-benzyl-3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole (I-7da, 7.4 g, 20.94 mmol) in DCM (100 mL) were added chloromethyl chloroformate (5.99 g, 41.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was treated with MeOH (100 mL) at room temperature. The solution was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by RP-combiflash with C18 column and eluted with (0-100% water / acetonitrile to afford the intermediate I-7. LCMS m / z (M+H): calculated 264.1, observed 264.0.

[0190] Intermediates I-8 through I-9 depicted in Table 2 were prepared in an analogous fashion to that described for intermediate I-6 but using the appropriate commercially available starting material and reagents. Table 2: Intermediate Com ound Name Calc’d Observed ]+25863 Intermediate Compound Name Calc’d Observed [M+H]+[M+H]+Interm5-(difluoromethyl)-2-methoxyaniline (I-10) I-10 Step 1: 4-(difluoromethyl)-1-methoxy-2-nitrobenzene (I-10a)

[0191] 25% Sodium methylate in MeOH (4.39 ml, 19.21 mmol) was dropwise at rt to a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (3.06 g, 16.01 mmol) in MeOH (20 ml). The resulting mixture was stirred under nitrogen atmosphere at rt for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound I-10a. LCMS m / z (M+H): calculated 204.1, observed 204.3. Step 2: 5-(difluoromethyl)-2-methoxyaniline (I-10b)

[0192] 10% Pd-C (400 mg, 3.76 mmol) in MeOH (10 ml) and EtOAc (10.00 ml) was added to a solution of 4-(difluoromethyl)-1-methoxy-2-nitrobenzene (I-10, 3.25g, 16.00 mmol). The mixture was hydrogenated under H2balloon overnight, filtered through a pad of the Celite™ and washed with MeOH. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / DCM) to give the intermediate I-10. LCMS m / z (M+H): calculated 174.2, observed 174.2. Intermediate 11 6-cyclopropyl-3-methoxypyridin-2-amine (I-11)25863 Cyclopropylboronic acid (0.70 Pd(dppf)Cl2 (0.30 g, 0.40 mmol), K2CO3 (1.40 g, 10.10 mmol) and water (0.5a solution of 6-bromo-3-methoxypyridin- 2-amine (0.82 g, 4.04 mmol) in 1,4-dioxane (10 ml). The mixture was heated to 85 °C under nitrogen atmosphere and stirred overnight. The mixture then was cooled to RT, filtered through a pad of Celite™ and then washed with extra ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 100% ethyl acetate / DCM) to give the intermediate 11 (I-11). LCMS m / z (M+H): calculated 165.2, observed 165.1. Intermediate 12 2-(difluoromethyl)-5-methoxypyridin-4-amine (I-12) Step 1: 5-methoxy-4-nitro-2-

[0193] Pd(dppf)Cl2(471 mg, 0.644 mmol), K2CO3(1483 mg, 10.73 mmol) and water (2 mL), purged with N2 for 5 minutes was added to a solution of 2-bromo-5-methoxy-4-nitropyridine (1000 mg, 4.29 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1322 mg, 8.58 mmol) in 1,4-dioxane (20 ml). The mixture was heated to 90 °C and stirred under nitrogen atmosphere for 20 hours, cooled to rt, quenched with H2O and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30 % ethyl acetate / hexane to give compound I-12a. LCMS m / z (M+H): calculated 181.1, observed 181.4. Step 2: 5-methoxy-4-nitropicolinaldehyde (I-12b)

[0194] Water (1.5 ml), 2.5% osmium tetroxide in t-butanol (0.82 ml, 0.065 mmol), 2,6- dimethylpyridine (0.608 ml, 5.22 mmol) and sodium periodate (2.23 g, 10.43 mmol) was added sequentially to a solution of 5-methoxy-4-nitro-2-vinylpyridine (I-12a, 0.47 g, 2.61 mmol) in THF (25 ml). The resulting mixture was stirred at rt for 3 hours, diluted with diethyl ether andwater, filtered and washed with extra diethyl ether. The separated organic phase from the filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-8% CH3CN / DCM) to give compound I-12b. LCMS m / z (M+H): calculated 183.1, observed 183.1. Step 3: 2-(difluoromethyl)-5-methoxy-4-nitropyridine (I-12c)

[0195] DAST (2.14 ml, 2.14 mmol) and MeOH (2.166 µl, 0.054 mmol) was added to a solution of 5-methoxy-4-nitropicolinaldehyde (I-12b, 195 mg, 1.071 mmol) in DCM (6 ml). The mixture was heated to 40 °C and stirred under nitrogen atmosphere overnight. The mixture was then cooled to rt and 1ml MeOH was added. The mixture was then concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound I-12c. LCMS m / z (M+H): calculated 205.1, observed 205.2. Step 4: 2-(difluoromethyl)-5-methoxypyridin-4-amine (I-12)

[0196] 2-(difluoromethyl)-5-methoxy-4-nitropyridine (I-12c, 187 mg, 0.916 mmol) and 10% Pd-C (100 mg, 0.094 mmol) were combined in MeOH (10 ml). The mixture was hydrogenated under a H2 balloon at rt for 1h, filtered through a pad of the Celite™ and washed with extra MeOH. The combined filtrate was concentrated in vacuo to give the intermediate I-12. LCMS m / z (M+H): calculated 175.1, observed 175.1. Intermediate 13 (S)-N-((R or S)-1-(3-amino-4-methoxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (I-13) Step 1: (S)-N-(4-methoxy-3-2-sulfinamide (I-13a)

[0197] Cesium carbonate (13.49 g, 41.4 mmol) was added to a solution of 4-methoxy-3- nitrobenzaldehyde (5.0g, 27.6 mmol) and (S)-2-methylpropane-2-sulfinamide (4.01 g, 33.1 mmol) in DCM (50 ml). The mixture was heated to 40 °C and stirred for 2 hours. The mixture was then partitioned between DCM and H2O, and the separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give compound I-13a. LCMS m / z (M+H): calculated 285.3, observed 285.1.Step 2: (S)-2-methyl-N-((R or S)-2,2,2-trifluoro-1-(4-methoxy-3-nitrophenyl)ethyl)propane-2- sulfinamide

[0198] Tetrabutylammonium difluorotriphenylsilicate(IV) (5.01 g, 9.28 mmol) was added to a cold solution (-30 °C) of (S)-N-(4-methoxy-3-nitrobenzylidene)-2-methylpropane-2-sulfinamide (2.2g, 7.74 mmol) and trimethyl(trifluoromethyl)silane (1.60 ml, 10.83 mmol) in THF (50 ml). The mixture was stirred at -20 °C ~ -30 °C for 1 hour, then warmed to rt and stirred for 30 minutes. The mixture was then concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give a mixture of isomers, which was further separated by SFC (AD column, 60% EtOH co-solvent) to give compound I-13b (second eluted fraction, slow peak). LCMS m / z (M+H): calculated 354.3, observed 354.2. Step 3: (S)-N-((R or S)-1-(3-amino-4-methoxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (I-13)

[0199] 10% Pd-C (0.556 g, 0.522 mmol) was added to a solution of (S)-2-methyl-N-((R or S)- 2,2,2-trifluoro-1-(4-methoxy-3-nitrophenyl)ethyl)propane-2-sulfinamide (I-13b, 1.85 g, 5.22 mmol) in THF (30 ml). The mixture was hydrogenated under a H2 balloon overnight, filtered through a pad of Celite™, washed with extra THF. The combined filtrate was concentrated in vacuo to give the intermediate I-13. LCMS m / z (M+H): calculated 325.4, observed 325.6. Intermediate 14 2-(3-(p-tolyl)piperidin-3-yl)pyridine (I-14)Step 1: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile (I-14a)

[0200] A solution of 2-(p-tolyl)acetonitrile (1.0 g, 7.62 mmol) in THF (3.05 mL) under a nitrogen atmosphere was cooled to -78 °C. nBuLi (2.5M in hexanes, 3.65 mL) was added dropwise to the solution. Next, 2-bromopyridine (1.20 g, 7.62 mmol) was added dropwise. The mixture was allowed to warm slowly to room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate 3 times. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica25863 gel and eluted with 0-100% ethyl acetate / hexanes to provide compound I-14a. LCMS m / z (M+H): calculated 209.1, observed 209.1. Step 2: ethyl 4-cyano-4-(pyridin-2-yl)-4-(p-tolyl)butanoate (I-14b)

[0201] A solution of 2-(pyridin-2-yl)-(p-tolyl)acetonitrile (I-14a, 0.25 g, 1.20 mmol) in THF (4.8 mL) under a nitrogen atmosphere was cooled to -78 °C. nBuLi (2.5M in hexanes, 0.72 mL) was added to the solution dropwise, and the resultant solution was stirred for 30 minutes at -78 °C. Ethyl 3-bromopropanoate (0.27 g, 1.50 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate 3 times. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with 0-50% ethyl acetate / hexanes to provide compound I-14b. LCMS m / z (M+H): calculated 309.2, observed 309.1. Step 3: 5-(pyridin-2-yl)-5-(p-tolyl)piperidin-2-one (I-14c)

[0202] A solution of ethyl 4-cyano-4-(pyridin-2-yl)-4-(p-tolyl)butanoate (I-14b, 0.20 g, 0.65 mmol) dissolved in methanol / water (1:1, 0.8 mL) was cooled to 0 °C. To the solution was added cobalt(II) chloride hexahydrate (0.62 g, 2.59 mmol) followed by sodium borohydride (0.10 g, 2.59 mmol). The reaction mixture was heated to 50 °C overnight, then cooled to room temperature, filtered through a bed of Celite™ and concentrated. The residue was partitioned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with 0-100% (3:1 ethyl acetate / EtOH) / hexanes to provide compound I-14c. LCMS m / z (M+H): calculated 267.1, observed 267.2. Step 4: 2-(3-(p-tolyl)piperidin-3-yl)pyridine (I-14)

[0203] A solution of 5-(pyridin-2-yl)-5-(p-tolyl)piperidin-2-one (I-14c, 0.11 g, 0.41 mmol) in THF (2.1 mL) was cooled to 0 °C under an atmosphere of nitrogen. Lithium aluminum hydride (0.078 g, 2.07 mmol) was added to the solution and the reaction mixture was heated to 80 °C for 1.5 hours. The reaction mixture was then cooled to 0 °C and quenched slowly with ethyl acetate. Saturated aqueous Rochelle’s salt (sodium potassium tartrate) was added and the mixture was stirred at room temperature for 4 hours. The organic layer was separated and the aqueous layer was extracted ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo to give intermediate I-14. LCMS m / z (M+H): calculated 253.2, observed 253.2.

[0204] Intermediate I-15 depicted in Table 3 was prepared in an analogous fashion to that described for intermediate I-14 but using the appropriate commercially available starting material and intermediates.25863 Table 3: Intermediate Compound Name Calc’d Observed [M+H]+[M+H]+Intermmethyl 2-amino-4-cyclopropylbenzoate (I-16)

[0205] 1,1'-bis(diphenylphosphino) (II)dichloride dichloromethane complex(468.9 mg, 0.574 mmol) was added to a stirred solution of methyl 2-amino-4-bromobenzoate (1.2254 g, 5.33 mmol), cyclopropylboronic acid (1.8677 g, 21.74 mmol), and cesium carbonate (7.3634 g, 22.60 mmol) in dioxane (43.0 ml) and water (10.0 ml). The reaction mixture was degassed (3 x (times)) and placed under nitrogen before being heated to 100 °C. After 15.5 hours, the reaction mixture was cooled to room temperature before being partitioned between EtOAc (200 ml), water (150 ml), and 1.0 N HCl (50 ml). A scum layer formed between the two phases, so it was filtered through a pad of Celite™. The filtrate (mostly aqueous) was returned to the separation funnel along with the rest of the aqueous layer. The pad of Celite™ was washed with EtOAc (2 x 100 ml) and each wash was subsequently used to extract the aqueous layer. The organic layers were combined, washed with brine (1 x 40 ml), dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography and eluted with 0-20% EtOAc / hexanes to afford the intermediate I-16. LCMS m / z (M+H) calculated 191.1, observed 192.1. EXAMPLE 1 (R or S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine- 1-carboxamide (1)25863 1

[0206] 2-isocyanato-1,4- mmol) and Et3N (0.078 ml, 0.562mmol) were added to a solution pyrrolidin-3-yl)thiazole hydrochloride (I-1) (42mg, 0.141 mmol) in DCM (2 ml). The mixture was stirred under nitrogen atmosphere at rt for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give a mixture of isomers, which was further separated by SFC (AS column, 30% EtOH + 0.2% DIPEA co- solvent) to give compound 1 (second eluted fraction, slow peak). LCMS m / z (M+H): calculated 442.5, observed 442.4.

[0207] Examples 2-13 depicting Compounds 2-13 found in Table 4, were prepared in an analogous fashion to that described for Example 1 but using the appropriate intermediates and commercially available reagents. Table 4: Ex / cmpd Com ound Name Calc’d Observed Conditions H t: H H t: H H nt 2% astEx / cmpd No Compound Name Calc’d Observed [M+H]+[M+H]+Conditions H t: H H t: H k H nt % ast H t: ow H t: H H t: % astEx / cmpd No Compound Name Calc’d Observed [M+H]+[M+H]+Conditions H t: H H t: % ow H t: H k(R or S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (14)

[0208] Triphosgene (46.3 mg, 0.156 mmol) and triethylamine (149 mg, 1.468 mmol) were added to a solution of 2-methoxy-5-(trifluoromethyl)pyridin-3-amine (88 mg, 0.459 mmol) in DCM (3 ml). The mixture was stirred under nitrogen atmosphere at rt for 10 minutes, followed by the addition of 5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-6) (55 mg, 0.183 mmol). The mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and25863 eluted with (0-5% CH3CN / DCM) to give a mixture of isomers, which was further separated by SFC (AD column, 40% MeOH co-solvent) to give compound 14 (first eluted fraction, fast peak). LCMS m / z (M+H): calculated 482.5, observed 482.3.

[0209] Examples 15-20 depicting Compounds 15-20 found in Table 5, were prepared in an analogous fashion to that described for Example 14 but using the appropriate intermediates and commercially available reagents. Table 5: Ex / cmpd Name Calc’d Obse No Compound rved [M+H]+[M+H]+Conditions H t: H k H nt H k H nt H k H nt % ast25863 Ex / cmpd Comp Name Calc’d Observed No ound [M+H]+[M+H]+Conditions H nt 2% ast H nt .2 ) k(R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (21) 21 Step 1: methyl (R or S) 3-(3-(3-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoate (21-a)

[0210] Triphosgene (33.7 mg, 0.113 mmol) and triethylamine (0.15 ml, 1.067 mmol) were added to a solution of methyl 3-amino-4-methoxybenzoate (60.4 mg, 0.334 mmol) in DCM (3 ml). The mixture was stirred at rt for 10 minutes and then followed by addition of 5-(3-(3-fluoro- 4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-6) (40 mg, 0.133 mmol). The resulting mixture was stirred under nitrogen atmosphere at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to give a mixture of isomers, which was further separated by SFC (OD column, 55% EtOH co-solvent) to give compound 21-a (first eluted fraction, fast peak). LCMS m / z (M+H): calculated 471.5, observed 471.3. Step 2: (R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (21)25863

[0211] 3.4 M methylmagnesium bromide in THF (0.100 ml, 0.340 mmol) was added to a solution of methyl (R or S) 3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamido)-4-methoxybenzoate (21-a) (20 mg, 0.043 mmol) in THF (3 ml). The mixture was stirred under nitrogen atmosphere at rt for 30 minutes, quenched with aqueous saturated NH4Cl and extracted with ethyl actate. The separarted organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-40% ethyl acetate / DCM) to give compound 21. LCMS m / z (M+H): calculated 471.6, observed 471.4. EXAMPLE 22 (R or S)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (22) O2S Step 1: (4-(difluoromethyl)-2-a)

[0212] To a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (530 mg, 2.77 mmol) in CH3CN (15 ml) was addded sodium methanethiolate (250 mg, 3.57 mmol). The mixture was stirred at rt for 2 hours and partitoned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound 22-a. LCMS m / z (M+H): calculated 220.2, observed 220.1. Step 2: 5-(difluoromethyl)-2-(methylthio)aniline (22-b)

[0213] 10% Pd-C (300 mg, 2.82 mmol) was added to a solution of (4-(difluoromethyl)-2- nitrophenyl)(methyl)sulfane (22-a, 600 mg, 2.74 mmol) in ethyl acetate (2 ml) and MeOH (2 ml). The mixture was hydrogenated under H2 ballon for 4 hours, filtered through a pad of Celite™ and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. to give compound 22-b. LCMS m / z (M+H): calculated 190.2, observed 190.2. Step 3: (R or S)-N-(5-(difluoromethyl)-2-(methylthio)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (22-c)

[0214] To a solution of 5-(difluoromethyl)-2-(methylthio)aniline (31.6 mg, 0.167 mmol) in DCM (1.5 ml) was added triphosgene (17.22 mg, 0.058 mmol) and triethylamine (33.8 mg, 0.334 mmol). The mixture was stirred at rt for 5 minutes, added (R or S)-5-(3-(3-fluoro-4-25863 methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (intermediate 7)(20 mg, 0.067 mmol), stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to give compound 22-c. LCMS m / z (M+H): calculated 479.6, observed 479.4. Step 4: (R or S)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (22)

[0215] m-CPBA (34.0 mg, 0.138 mmol) was added to a solution of (R or S)-N-(5- (difluoromethyl)-2-(methylthio)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide (22-c, 22 mg, 0.046 mmol) in DCM(1.5 ml) was added. The mixture was stirred at rt for 4 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to give compound 22. LCMS m / z (M+H): calculated 511.6, observed 511.4. EXAMPLE 23 (R or S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (23) O F 23 Step 1: (R or S)-N-(5-((R or-2,2,2-trifluoroethyl)-2- methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (23-a)

[0216] (S)-N-((R or S)-1-(3-amino-4-methoxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (I-13, 1623 mg, 5.00 mmol) was dissolved in DCM (40 ml) and cooled to 0 °C. Triphosgene (520 mg, 1.751 mmol) was then added to the mixture followed by the addition of Et3N (2.79 ml, 20.01 mmol). The mixture was stirred at 0 ° C for 5 minutes, and then (R or S)-5- (3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 1000 mg, 3.34 mmol) was added. The mixture was warmed to rt, stirred for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-40% ethyl acetate / DCM) to give compound 23-a. LCMS m / z (M+H): calculated 614.7, observed 614.8. Step 2: (R or S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (23)25863

[0217] 4 M HCl in 1,4-dioxane (4 ml, 16.00 mmol) was added to a solution of (R or S)-N-(5- ((R or S)-1-(((S)-tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (23-a, 1.95 g, 3.18 mmol) in DCM (1.0 ml) and MeOH (1.0 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residual solid was partitioned between aqueous saturated NaHCO3 and ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH with 2N NH3 / DCM) to give compound 23. LCMS m / z (M+H): calculated 510.5, observed 510.4. EXAMPLE 24 (R or S)-N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (24)

[0218] Et3N (0.033 ml, 0.236µl, 0.118 mmol) were added to a solution of (R or S)-N-(5-(1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (23, 15 mg, 0.029 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 4 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give compound 24. LCMS m / z (M+H): calculated 552.6, observed 552.3. EXAMPLE 25 (R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (25) Step 1: 5-(((tert-(25-a)

[0219] Imidazole (9.33 g, 137 mmol) and tert-butyldimethylchlorosilane (10.33 g, 68.5 mmol), at room temperature, were added to a stirred mixture of (3-amino-4-methoxyphenyl)methanol (725863 g, 45.7 mmol) in DCM (100 mL). The resulting mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1~3% methanol in dichloromethane to afford compound 25-a. LCMS m / z (M+H): calculated 268.2, observed 268.2. Step 2: (R or S)-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (25-b)

[0220] DIEA (4.64 mL, 26.6 mmol) and triphosgene (0.883 g, 2.98 mmol), at room temperature under nitrogen atmosphere, were added to a mixture of 5-(((tert-butyldimethylsilyl)oxy)methyl)- 2-methoxyaniline (25-a, 2.56 g, 9.57 mmol) in DCM (30 mL). The resulting mixture was stirred at 25 °C for 30 minutes. Then (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4- thiadiazole hydrochloride (I-7, 1.4 g, 5.32 mmol) was added to the reaction mixture at 25 °C and stirred for 1 hour. The mixture was concentrated under reduced pressure. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1~60% ethyl acetate in petroleum ether to afford compound 25-b. LCMS m / z (M+H): calculated 557.2, observed 557.3. Step 3: (R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (25)

[0221] Ammonium fluoride (0.665 g, 17.96 mmol) at room temperature was added to a stirred mixture of (R or S)-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxyphenyl)-3-(3-fluoro- 4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (25-b, 2 g, 3.59 mmol) in MeOH (20 mL). The resulting mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The mixture was quenched by aqueous saturated NH4Cl (20 mL) and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0~100% ethyl acetate in petroleum ether to afford compound 25. LCMS m / z (M+H): calculated 443.1, observed 443.1.25863 EXAMPLE 26 (R or S)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (26) Step 1: 1-(3,3- (26-a)

[0222] 3,3- mg, NaH (126 mg, 3.14 mmol) at 0 °C under nitrogen atmosphere were added to a solution of 4-(difluoromethyl)-1-fluoro-2- nitrobenzene (400 mg, 2.093 mmol) in THF (10 mL). The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched by aquesous saturated NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 ~ 26% ethyl acetate in petroleum ether to afford compound 26-a. Step 2: 2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)aniline (26-b)

[0223] NH4Cl (86 mg, 1.612 mmol) and iron (180 mg, 3.22 mmol) were added at room temperature to a solution of 1-(3,3-difluorocyclobutoxy)-4-(difluoromethyl)-2-nitrobenzene (300 mg, 1.075 mmol) in EtOH (8.00 mL) and water (8 mL). The mixture was stirred at 60 °C for 4 hours. The reaction mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1~10% ethyl acetate in petroleum ether to afford compound 26-b. LCMS m / z (M+H): calculated 250.1, observed 250.1. Step 3: (R or S)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (26)

[0224] DIEA (0.126 mL, 0.722 mmol) and CDI (46.8 mg, 0.289 mmol) at rt and under nitrogen were added to a mixture of 2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)aniline (60 mg, 0.241 mmol) in DCM (1 mL). The mixture was stirred at rt for 30 minutes, and then (R or S)-5-(3-(3- fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 50.7 mg, 0.19325863 mmol) at 25 °C under nitrogen was added. The resulting mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by RP-combiflash C18 column, eluted with 0- 100%water with 0.05% TFA / CH3CN with 0.05% TFA to afford example 26. LCMS m / z (M+H): calculated 539.1, observed 539.1. EXAMPLE 27 (R or S)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (27) Step 1: 1-(difluoromethoxy)-4-

[0225] KOH (1121 mg, 19.98 mmol) at 0 °C and under argon atmosphere, was added to a stirred mixture of 4-methoxy-2-nitrophenol (169 mg, 0.999 mmol) in MeCN (5 mL) and water (5 mL). Then diethyl (bromodifluoromethyl) phosphonate (614 mg, 2.298 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give compound 27-a. Step 2: 2-(difluoromethoxy)-5-methoxyaniline (27-b)

[0226] To a solution of 1-(difluoromethoxy)-4-methoxy-2-nitrobenzene (90 mg, 0.411 mmol) in THF (5 mL) was added Pd / C (10%, 30 mg) at room temperature under H2atmosphere and stirred for 2 hours. The reaction was filtered. The filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to afford compound 27-b. LCMS m / z (M+H): calculated 190.1, observed 190.1. Step 3: (R or S)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (27)

[0227] Triethylamine (25.3 mg, 0.250 mmol) and triphosgene (8.89 mg, 0.030 mmol) at 0 °C and under argon atmosphere were added to a stirred mixture of 2-(difluoromethoxy)-5- methoxyaniline (30 mg, 0.159 mmol) in DCM (1 mL). The resulting mixture was stirred for an additional 5 minutes. Then (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4- thiadiazole hydrochloride (I-7, 26.3 mg, 0.100 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue25863 was purified by prep-HPLC Column, eluted with 0-100%water with 10% NaHCO3 / CH3CN to afford compound 27. LCMS m / z (M+H): calculated 479.1, observed 479.1. EXAMPLE 28 (R or S)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (28) Step 1: 2-amino-4-bromo-N-

[0228] At room temperature, N-ethyl-N-isopropylpropan-2-amine (897 mg, 6.94 mmol), methanamine (144 mg, 4.63 mmol) and HATU (1320 mg, 3.47 mmol) were added to a solution of 2-amino-4-bromobenzoic acid (500 mg, 2.314 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 1 hour and quenched with saturated aqueous NH4Cl (10 mL). The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using 10% - 60% gradient of ethyl acetate in petroleum ether as eluent. The fractions containing desired product were combined and concentrated under reduced pressure to give compound 28-a. Step 2: 2-amino-4-cyclopropyl-N-methylbenzamide (28-b)

[0229] At room temperature and under argon, Pd(dppf)Cl2(144 mg, 0.196 mmol), Cs2CO3(1920 mg, 5.89 mmol) and cyclopropylboronic acid (675 mg, 7.86 mmol) to a solution of 2- amino-4-bromo-N-methylbenzamide (28-a, 450 mg, 1.964 mmol) in 1,4-dioxane (20 mL) and water. The resulting mixture was stirred at 100 °C for 16 hours. Then the mixture was quenched with saturated aqueous and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using 10% - 60% gradient of ethyl acetate in petroleum ether as eluent. The fractions containing desired product were combined and concentrated under reduced pressure to afford compound 28-b. LCMS m / z (M+H): calculated 191.1, observed 191.1. Step 3: (R or S)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (28)25863

[0230] Bis(trichloromethyl) carbonate (46.3 mg, 0.156 mmol) at rt was added to a solution of 2-amino-4-cyclopropyl-N-methylbenzamide (90 mg, 0.473 mmol), N-ethyl-N-isopropylpropan- 2-amine (183 mg, 1.419 mmol) and (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)- 1,2,4-thiadiazole hydrochloride (I-7, 142 mg, 0.473 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 1h and concentrated in vacuo. The residue was purified by silica gel column chromatography using 10% - 60% gradient of ethyl acetate in petroleum ether as eluent. The fractions containing desired product were combined and concentrated under reduced pressure to afford compound 28. LCMS m / z (M+H): calculated 480.2, observed 480.1. EXAMPLE 29 tert-butyl (R or S)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate (29) Step 1: tert-butyl 6-(4-[3.3]heptane-2-carboxylate (29-a)

[0231] NaH (1.046 g, 26.2 mmol), at room temperature and under nitrogen atmosphere, was added to a stirred mixture of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.68 g, 12.56 mmol) in DMA (10 mL). The resulting mixture was stirred at room temperature for 0.5 hour. Then 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (2 g, 10.47 mmol) in DMA (1 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by aqueous saturated NH4Cl and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 ~ 40% ethyl acetate in petroleum ether afford compound 29-a. Step 2: tert-butyl 6-(2-amino-4-(difluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate (29-b)25863

[0232] At room temperature, iron (0.872 g, 15.61 mmol) and NH4Cl (0.417 g, 7.80 mmol) were added to a stirred mixture of tert-butyl 6-(4-(difluoromethyl)-2-nitrophenoxy)-2- azaspiro[3.3]heptane-2-carboxylate (29-a, 2 g, 5.20 mmol) in EtOH (5.00 mL) and water (5 mL). The resulting mixture was stirred at 40 °C for 3 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 ~ 40% ethyl acetate in petroleum ether to afford compound 29-b. Step 3: tert-butyl (R or S)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2- carboxylate (29)

[0233] DIEA (0.049 mL, 0.282 mmol) and bis(trichloromethyl) carbonate (84 mg, 0.282 mmol) at 0 °C were added to a mixture of tert-butyl 6-(2-amino-4-(difluoromethyl)phenoxy)-2- azaspiro[3.3]heptane-2-carboxylate (29-b, 100 mg, 0.282 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 25 minutes. (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 67.7 mg, 0.226 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC, eluted with petroleum ether / ethyl acetate (2:1) to afford compound 29. LCMS m / z (M+H): calculated 644.2, observed 644.2. EXAMPLE 30 (R or S)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (30) Step 1: (R or S)-N-(2-((6-phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (30-a)

[0234] HCl (4 M in 1,4-dioxane) (0.5 mL, 2.00 mmol) at room temperature, was added to a stirred mixture of compound 29 (50 mg, 0.076 mmol) in DCM (0.5 mL). The resulting mixture25863 was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by reversal phase chromatography (C18), eluted with 0-100% water / CH3CN to afford compound 30-a. LCMS m / z (M+H): calculated 558.2, observed 558.2. Step 2: (R or S)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (30)

[0235] Acetyl chloride (0.009 ml, 0.129 mmol) and DIEA (0.039 mL, 0.221 mmol), at room temperature, were added to a stirred mixture of (R or S)-N-(2-((2-azaspiro[3.3]heptan-6-yl)oxy)- 5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (30-a, 40 mg, 0.074 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure and the residue was purified by Prep-HPLC, eluted with 0-60% water / CH3CN to afford compound 30. LCMS m / z (M+H): calculated 586.2, observed 586.2. EXAMPLE 31 (R or S)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (31) Step 1: methyl trans-3-(4-1-carboxylate (31-a)

[0236] Methyl trans-3-hydroxycyclobutane-1-carboxylate (7800 mg, 59.9 mmol) was added dropwise to a solution of sodium hydride (488 mg, 20.34 mmol) in DMA (5 mL) at rt under nitrogen atmosphere. The resulting solution was stirred at rt for 30 minutes, followed by the addition of a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (1375 mg, 7.19 mmol) in DMA (1 mL). The mixture was stirred at rt under nitrogen atmosphere for 1 hour, quenched with saturated aqueous NH4Cl. and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 ~ 50%) to afford compound 31-a.25863 Step 2: methyl trans-3-(2-amino-4-(difluoromethyl)phenoxy)cyclobutane-1-carboxylate (31-b)

[0237] To a mixture of methyl trans-3-(4-(difluoromethyl)-2-nitrophenoxy)cyclobutane-1- carboxylate (20 mg, 0.066 mmol) in EtOH: water = 1: 1 (3 mL) was added ammonium chloride (5.33 mg, 0.100 mmol) and iron (11.12 mg, 0.199 mmol). The resulting mixture was stirred for 40 °C at 2 hours and partitioned between ethyl acetate and water. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 ~ 50%) to afford compound 31-b. LCMS m / z (M+H): calculated 272.1, observed 272.1. Step 3: methyl trans-3-(4-(difluoromethyl)-2-((R or S)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylate (31-c)

[0238] N,N-diisopropylethylamine (38.8 mg, 0.300 mmol) and triphosgene (9.98 mg, 0.034 mmol) at 0 °C were added to a stirred mixture of methyl trans-3-(2-amino-4- (difluoromethyl)phenoxy)cyclobutane-1-carboxylate (24.43 mg, 0.090 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 15 minutes, followed by addition of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 18 mg, 0.060 mmol). The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC, developed using ethyl acetate / petroleum ether (1 / 1) to afford compound 31-c. LCMS m / z (M+H): calculated 561.2, observed 561.2. Step 4: (R or S)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (31)

[0239] A solution of methyl trans-3-(4-(difluoromethyl)-2-((R or S)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)cyclobutane-1- carboxylate (31-c, 30 mg, 0.054 mmol) in methylamine in EtOH (1 mL, 0.054 mmol) was stirred at 80 °C for 2 hours and concentrated under reduced pressure. The residue was purified by prep- TLC, developed using ethyl acetate / petroleum ether (1 / 2) to afford compound 31. LCMS m / z (M+H): calculated 560.2, observed 560.2. EXAMPLE 32 (R or S)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (32)25863 Step 1: tert-butyl 3-(4- 1-carboxylate (32-a)

[0240] 60% NaH in mineral mg, was to a solution of 4- (difluoromethyl)-1-fluoro-2-nitrobenzene (200 mg, 1.047 mmol) and tert-butyl 3- hydroxyazetidine-1-carboxylate (272 mg, 1.570 mmol) in THF (10 ml). The mixture was stirred at rt overnight. The reaction was quenched with H2O and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford compound 32-a. LCMS m / z (M+H): calculated 345.3, observed 345.2. Step 2: tert-butyl 3-(2-amino-4-(difluoromethyl)phenoxy)azetidine-1-carboxylate (32-b)

[0241] 10% Pd-C (200 mg, 1.879 mmol) was added to a solution of tert-butyl 3-(4- (difluoromethyl)-2-nitrophenoxy)azetidine-1-carboxylate (32-a, 360 mg, 1.046 mmol) in MeOH (1 ml) and THF (1 ml). The mixture was hydrogenated under H2balloon for 3 hours, filered through a pad of the celite, washed with ethyl acetate and the combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 30% ethyl acetate / DCM) to give compound 32-b. LCMS m / z (M+H): calculated 315.3, observed 315.2. Step 3: tert-butyl (R or S)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate (32-c)

[0242] Triphosgene (13.86 mg, 0.047 mmol) and triethylamine (0.046 ml, 0.334 mmol) were added to a cold (0 °C) solution of tert-butyl 3-(2-amino-4-(difluoromethyl)phenoxy)azetidine-1- carboxylate (32-b, 41.9 mg, 0.133 mmol) in DCM (1 ml). The mixture was stirred at 0 ° C for 10 minutes, followed by the addition of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)- 1,2,4-thiadiazole hydrochloride (I-7, 20 mg, 0.067 mmol). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% ethyl acetate / DCM) to give compound 32-c. LCMS m / z (M+H): calculated 604.7, observed 604.5. Step 4: (R or S)-N-(2-(azetidin-3-yloxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide hydrochloride (32-d)25863

[0243] To a solution of tert-butyl (R or S)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1- carboxylate (30 mg, 0.050 mmol) in MeOH (0.25 ml) was added 4 M HCl in 1,4-dioxane (0.25 ml, 1.000 mmol). The mixture was stirred at rt for 4 hours and concentrated in vacuo to give compound 32-d. LCMS m / z (M+H): calculated 504.5, observed 504.4. Step 5: (R or S)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (32)

[0244] Et3N (0.025 ml, 0.176 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (40.8 mg, 0.176 mmol) were added to a solution of (R or S)-N-(2-(azetidin-3-yloxy)-5- (difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide hydrochloride (32-d, 19 mg, 0.035 mmol) in DCM (1 ml). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to give compound 32. LCMS m / z (M+H): calculated 586.6, observed 586.5. EXAMPLE 33 Cyclopropyl (R or S)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate (33)

[0245] Cyclopropyland Et3N (0.013 ml, 0.093 mmol) were added to a solution of (R or S)-N-(2-(azetidin-3-yloxy)-5-(difluoromethyl)phenyl)- 3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide hydrochloride (32-d, 10 mg, 0.019 mmol) in DCM (1 ml). The mixture was stirred at rt for 3 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-6% CH3CN / DCM) to give Compound 33. LCMS m / z (M+H): calculated 588.6, observed 588.5.25863 EXAMPLE 34 (R or S)-N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3- yl)oxy)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (34)

[0246] 4,4-difluoropiperidine- 0.050 mmol) and Et3N (0.012 ml,0.083 mmol)To a solution of (R or S)-N-(2-(azetidin-3-yloxy)-5-(difluoromethyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide hydrochloride (32-d, 9.5 mg, 0.015 mmol, 88 % yield) in DCM (0.25 ml) was added. The mixture was stirred at rt for 3 hours and concentrated in vacuo.The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give example 34. LCMS m / z (M+H): calculated 651.7, observed 651.5. EXAMPLE 35 (R or S)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (35) Step 1: 2-bromo-5-

[0247] Ammonium chloride (212 mg, 3.97 mmol) and zinc powder (259 mg, 3.97 mmol) were added to a solution of 1-bromo-4-(difluoromethyl)-2-nitrobenzene (100 mg, 0.397 mmol) in MeOH (10 ml). The mixture was heated to 35 °C and stirred for 3 hours. The reaction was cooled to rt, then ethyl acetate was added. The resulting mixture was stirred for 10 minutes, filtered and25863 washed with DCM / MeOH (1 / 1). The combined filtrate was concentrated in vacuo to afford compound 35-a. LCMS m / z (M+H): calculated 221.9, observed 222.1. Step 2: (R or S)-N-(2-bromo-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (35-b)

[0248] Triphosgene (35.4 mg, 0.119 mmol) and Et3N (0.151 ml, 1.084 mmol) were added to a solution of 2-bromo-5-(difluoromethyl)aniline (75 mg, 0.338 mmol) in DCM (3 ml) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, then (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 65 mg, 0.217 mmol) was added. The resulting mixture was warmed to rt and stirred for 1 hour. The reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to give compound 35-b. LCMS m / z (M+H): calculated 512.4, observed 512.2. Step 3: (R or S)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (35)

[0249] Cyclopropylboronic acid (13.44 mg, 0.156 mmol), cesium carbonate (63.7 mg, 0.196 mmol), Pd(dppf)Cl2 (8.59 mg, 0.012 mmol) and water (0.1 ml) were added to a solution of (R or S)-N-(2-bromo-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide (35-b, 20 mg, 0.039 mmol) in 1,4-dioxane (1 ml). The mixture was heated to 80 °C and stirred overnight. The reaction was cooled to rt, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to give compound 35. LCMS m / z (M+H): calculated 473.5, observed 473.4. EXAMPLE 36 (R or S)-N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (36)

[0250] Dicyanozinc (68.9(30.5 mg, 0.039 mmol) were added to a solution of (R or S)-N-(2-bromo-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (35-b, 100 mg, 0.196 mmol)25863 in DMF (2 ml). The mixture was heated to 90 °C and stirred for 6 hours. The reaction was cooled to rt and partitioned between ethyl acetate and H2O. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-3% MeOH / DCM) to give example 36. LCMS m / z (M+H): calculated 458.5, observed 458.2. Example 37 (R or S)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (37) Step 1: (R or S)-N-(5-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (37-a)

[0251] Pd(dppf)Cl2 (51.5 mg, 0.070 mmol), Cs2CO3 (344 mg, 1.056 mmol), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.178 ml, 1.056 mmol) and water (0.2 ml) were added to a solution of (R or S)-N-(2-bromo-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (35-b, 180 mg, 0.352 mmol) in 1,4-dioxane (2 ml). The mixture was heated to 85 °C and stirred overnight. The mixture was cooled to rt, filtered, washed with ethyl acetate and the combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / DCM) to afford compound 37-a. LCMS m / z (M+H): calculated 459.5, observed 459.2. Step 2: (R or S)-N-(5-(difluoromethyl)-2-formylphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (37-b)

[0252] Water (0.100 ml), 2.5% osmium tetroxide in t-butanol (0.027 ml, 2.181 µmol), 2,6- dimethylpyridine (0.020 ml, 0.174 mmol) and sodium periodate (74.6 mg, 0.349 mmol) werre added sequentially to a solution of (R or S)-N-(5-(difluoromethyl)-2-vinylphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (37-a, 40 mg, 0.087 mmol) in THF (1.5 ml). The resulting mixture was stirred at rt for 3 hours, diluted with 20 ml diethyl ether and filtered. The filtrate was partitioned between diethyl ether and water. The separated organic25863 phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, and eluted with (0-8% CH3CN / DCM) to give compound 37-b. LCMS m / z (M+H): calculated 461.5, observed 461.2. Step 3: (R or S)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (37)

[0253] Azetidin-3-ol hydrochloride (28.5 mg, 0.261 mmol) was added to a solution of (R or S)- N-(5-(difluoromethyl)-2-formylphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide (37-b, 30 mg, 0.065 mmol) in DMF (0.5 ml). The mixture was stirred at rt for 1 hour, cooled to 0 °C, and then followed by the addition of sodium cyanoborohydride (40.9 mg, 0.652 mmol). The mixture was stirred at 0 °C for 4 hours, warmed to rt and stirred overnight. The reaction was quenched with aqueous saturated NaHCO3 and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, and eluted with (0-5% MeOH / DCM) to give compound 37. LCMS m / z (M+H): calculated 518.6, observed 518.3. EXAMPLE 38 (R or S)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (38) Step 1: (R or S)-N-(5-bromo-2--3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide (38-a)

[0254] Triphosgene (148 mg, 0.500 mmol) and triethylamine (0.930 ml, 6.67 mmol) were added to a solution of 2-amino-4-bromobenzaldehyde (250 mg, 1.251 mmol) in DCM (10 ml). The mixture was stirred at rt for 5 minutes, and followed by addition of (R or S)-5-(3-(3-fluoro- 4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (intermediate 7) (250 mg, 0.834 mmol). The reaction mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue25863 was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / DCM) to afford compound 38-a. LCMS m / z (M+H): calculated 490.4, observed 491.2. Step 2: (R or S)-N-(5-cyclopropyl-2-formylphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (38-b)

[0255] Cyclopropylboronic acid (169 mg, 1.962 mmol), Pd(dppf)Cl2 (96 mg, 0.131 mmol), Cs2CO3(533 mg, 1.635 mmol) and water (0.20 ml) were added to a solution of (R or S)-N-(5- bromo-2-formylphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (38-a, 320 mg, 0.654 mmol) in 1,4-dioxane (15 ml). The mixture was heated to 80 °C and stirred overnight. The reaction was cooled to rt, fitltered, and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, and eluted with (0-5% CH3CN / DCM) to give compound 38-b. LCMS m / z (M+H): calculated 451.5, observed 451.2. Step 3: (R or S)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (38)

[0256] 3,3-difluoropyrrolidine hydrochloride (31.9 mg, 0.222 mmol) and sodium cyanoborohydride (27.9 mg, 0.444 mmol) were added to a solution of (R or S)-N-(5-cyclopropyl- 2-formylphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (38-b, 20 mg, 0.044 mmol) in DMA (0.5 ml). The mixture was stirred at rt overnight. The reaction was quenched with aqueous saturated NaHCO3, filtered through a pad of the Celite™ and washed with ethyl acetate. The organic phase was separated from the filtrate, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, and eluted with (0-5% MeOH / DCM) to give compound 38. LCMS m / z (M+H): calculated 542.6, observed 542.4. EXAMPLE 39 (R or S)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (39) Step 1: 3-(4-(difluoromethyl)-a)25863

[0257] 60% NaH in mineral oil (46.0 mg, 1.15 mmol) was added to a solution of oxazolidin-2- one (75 mg, 0.863 mmol), 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (110 mg, 0.576 mmol) in THF (5ml). The mixture was heated to 40 °C and stirred for 1 hour. The mixture was then cooled to rt, quenched with water, and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and the combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (40g ISCO) and eluted with (0-5% MeOH / DCM) to give compound 39-a. LCMS m / z (M+H): calculated 259.2, observed 259.1. Step 2: 3-(2-amino-4-(difluoromethyl)phenyl)oxazolidin-2-one (39-b)

[0258] 10% Pd-C (173 mg, 0.163 mmol) was added to a sloution of 3-(4-(difluoromethyl)-2- nitrophenyl)oxazolidin-2-one (140 mg, 0.542 mmol) in THF (2 ml). The mixture was hydrogenated under H2 balloon for 4 hours, filtered through a pad of Celite™ and washed with extra THF. The combined filtrate was concentrated in vacuo to give compound 39-b. LCMS m / z (M+H): calculated 229.2, observed 229.4. Step 3: (R or S)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (39)

[0259] Triphosgene (34.6 mg, 0.117 mmol) and then Et3N (0.023 ml, 0.167 mmol) were added to a solution of 3-(2-amino-4-(difluoromethyl)phenyl)oxazolidin-2-one (39-b, 76 mg, 0.334 mmol) in DCM (4 ml). The mixture was stirred at rt for 2 minutes and followed by the addition of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 50 mg, 0.167 mmol). The mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40g ISCO) and eluted with (0-4% MeOH / DCM) to give compound 39. LCMS m / z (M+H): calculated 518.5, observed 518.2. EXAMPLE 40 (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamido)-N-methylpicolinamide (40) Step 1: methyl 3-amino-5-

[0260] Cyclopropylboronic acid (744 mg, 8.66 mmol), Cs2CO3 (2820 mg, 8.66 mmol), Pd(dppf)Cl2 (253 mg, 0.346 mmol) and water (0.5 ml) were added to a solution of methyl 3-amino-5-bromopicolinate (800 mg, 3.46 mmol) in 1,4-dioxane (15 ml). The mixture was heated to 95 °C and stirred overnight. The reaction was cooled to rt and then partitoned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 50% ethyl acetate / DCM) to afford compound 40-a. LCMS m / z (M+H): calculated 193.2, observed 193.4. Step 2: methyl (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)picolinate (40-b)

[0261] Triphosgene (15.59 mg, 0.053 mmol) and then Et3N (0.058 ml, 0.417 mmol) were added to a solution of methyl 3-amino-5-cyclopropylpicolinate (28.9 mg, 0.150 mmol) in DCM (1.5 ml). The mixture was stirred at rt for 5 minutes followed by the addition of (R or S)-5-(3-(3- fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 25 mg, 0.083 mmol). The mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-6% CH3CN / DCM) to give compound 40-b. LCMS m / z (M+H): calculated 482.5, observed 482.3. Step 3: (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)picolinic acid (40-c)

[0262] 5M NaOH in H2O (18 µL, 0.090 mmol) was added to a solution of methyl (R or S)-5- cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)picolinate (40-b, 28 mg, 0.058 mmol) in MeOH (0.25 ml) and THF (0.25 ml). The mixture was stirred at rt overnight then added 4 M HCl in 1,4-dioxane (58.1 µL, 0.233 mmol) was added to the mixture. The reaction mixture was then concentrated in vacuo. The residue was treated with MeOH / DCM (1 / 1), filtered and washed with extra MeOH / DCM (1 / 1). The combined filtrate was concentrated in vacuo to give compound 40-c. LCMS m / z (M+H): calculated 468.5, observed 468.6. Step 4: (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)-N-methylpicolinamide (40)

[0263] HATU (19.52 mg, 0.051 mmol) and DIPEA (5.98 µl, 0.034 mmol) were added to a solution of (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)picolinic acid (40-c, 8 mg, 0.017 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 20 minutes followed by the addition of 2 M methanamine in THF (0.043 ml, 0.086 mmol). The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to give example 40. LCMS m / z (M+H): calculated 481.6, observed 481.3.

[0264] Examples 41 and 42 depicting Compounds 41 and 42 found in Table 6, were prepared in an analogous fashion to that described for Example 40 but using the appropriate intermediates and commercially available reagents. Table 6: Ex / cmpd Compound Name Calc’d Observed No [M+H]+[M+H]+EXAMPLE 43 (R or S)-6-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamido)-N-methylnicotinamide (43) Step 1: (R or S)-3-(3-fluoro-4-5-yl)pyrrolidine-1-carbonyl chloride (43-a)

[0265] Triphosgene (71.3 mg, 0.240 mmol) was addded to a suspension of (R or S)-5-(3-(3- fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 90 mg, 0.30025863 mmol) in DCM (4ml). The mixture was sealed to a microwave tube and heated to 40 °C and stirred overnight. The reaction was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / DCM) to afford compound 43-a. LCMS m / z (M+H): calculated 326.8, observed 326.1. Step 2: methyl (R or S)-6-chloro-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)nicotinate (43-b)

[0266] 60% NaH in mineral oil (34.4 mg, 0.859 mmol) was added to a cold solution (0 °C) of (R or S)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbonyl chloride (43-a,70 mg, 0.215 mmol) and methyl 2-amino-6-chloronicotinate (72.2 mg, 0.387 mmol) in THF (1.5 ml). The mixture wa stirred at 0 °C for 30 minutes and warmed to rt. The reaction was quenched with H2O and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / DCM) to give compound 43-b. LCMS m / z (M+H): calculated 476.9, observed 476.5. Step 3: methyl (R or S)-6-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)nicotinate (43-c)

[0267] Cyclopropylboronic acid (28.2 mg, 0.328 mmol), Cs2CO3 (89 mg, 0.273 mmol), Pd(dppf)Cl2 (15.99 mg, 0.022 mmol) and water (50 µL) were added to a solution of methyl (R or S)-6-chloro-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)nicotinate (43-b, 52 mg, 0.109 mmol) in 1,4-dioxane (1.5 ml). The mixture was heated to 100 °C and stirred for 3 hours, cooled to rt, filtered and then washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-6% CH3CN / DCM) to give compound 43-c. LCMS m / z (M+H): calculated 482.5, observed 482.3. Step 4: (R or S)-6-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)nicotinic acid (43-d)

[0268] 5M NaOH in H2O (4.98 µl, 0.025 mmol) was added to a solution of methyl (R or S)-6- cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)nicotinate (4 mg, 8.31 µmol) in MeOH (0.25 ml). The mixture was stirred at rt overnight and concentrated in vacuo to give compound 43-d. LCMS m / z (M+H): calculated 468.5, observed 468.3. Step 5: (R or S)-6-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)-N-methylnicotinamide (43)25863

[0269] HATU (25.2 mg, 0.066 mmol) and DIPEA (0.014 ml, 0.083 mmol) were added to a solution of (R or S)-6-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)nicotinic acid (3.88 mg, 8.30 µmol) in DCM (0.5 ml). The mixture was stirred at rt for 30 minutes. Then 2 N methanamine in THF (0.083 ml, 0.166 mmol) was added and the reaction mixture was stirred at rt for 2 hours. The resulting mixture was then concentrated in vacuo. The residue was purified by preparative TLC and eluted with (4% MeOH / DCM) to give compound 43. LCMS m / z (M+H): calculated 481.6, observed 481.3.

[0270] Examples 44 and 45 depicting Compounds 44 and 45 found in Table 7, were prepared in an analogous fashion to that described for Example 40 but using the appropriate intermediates and commercially available reagents. Table 7: Ex / Cmpd No Compound Name Calc’d Observed [M+H]+[M+H]+EXAMPLE 46 (R or S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N,6-dimethylnicotinamide (46)25863 Step 1: methyl (R or S)-4-(3-(3- thiadiazol-5-yl)pyrrolidine-1-carboxamido)-6-

[0271] Triphosgene (35.6 mg, 0.120 mmol) and Et3N (0.223 ml, 1.601 mmol were added to a solution of methyl 4-amino-6-methylnicotinate (49.9 mg, 0.300 mmol) in DCM (2 ml). The mixture was stirred at rt for 5 minutes and then (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 60 mg, 0.200 mmol) was added. The resulting mixture was stirred at rt for 1hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to afford compound 46-a. LCMS m / z (M+H): calculated 456.5, observed 456.6. Step 2: (R or S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-6-methylnicotinic acid (46-b)

[0272] 10M NaOH in H2O (0.058 ml, 0.580 mmol) was added to a solution of methyl (R or S)- 4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-6- methylnicotinate (46-a, 88 mg, 0.193 mmol) in MeOH (1 ml). The mixture was stirred at rt overnight, then 1ml 4M HCl in 1,4-dioxane was added. The resulting mixture was concentrated in vacuo. The residue was washed with MeOH / DCM (1 / 1), filtered and concentrated in vacuo to give compound 46-b. LCMS m / z (M+H): calculated 442.5, observed 442.3. Step 3: (R or S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N,6-dimethylnicotinamide (46)

[0273] HATU (64.6 mg, 0.170 mmol) and Et3N (0.047 ml, 0.340 mmol) were added to a solution of (R or S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-6-methylnicotinic acid (46-b, 30 mg, 0.068 mmol) in DCM (1.5 ml ). The mixture was stirred at rt for 20 minutes and then 2M methanamine in THF (0.340 ml, 0.680 mmol) was added. The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give compound 46. LCMS m / z (M+H): calculated 455.5, observed 455.6.

[0274] Examples 47, 48, and 49 depicting Compounds 47, 48, and 49 found in Table 8, were prepared in an analogous fashion to that described for Example 46 but using the appropriate intermediates and commercially available reagents.25863 Table 8: Ex / compd Compo Name Calc’d Observed No und [M+H]+[M+H]+EXAMPLE 50 (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamido)-N-methylpyrazine-2-carboxamide (50) Step 1: methyl 3-amino-5-a)25863

[0275] 0.5 M cyclopropylzinc(II) bromide (6.40 ml, 3.20 mmol) and sphos Pd G3 (83 mg, 0.107 mmol) were added to a solution of methyl 3-amino-5-chloropyrazine-2-carboxylate (200 mg, 1.066 mmol) in THF (2ml). The mixture was heated to 65 °C and stirred overnight. The reaction was cooled and quenched with aqueous saturated NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and washed. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to afford compound 50-a. LCMS m / z (M+H): calculated 194.2, observed 194.1. Step 2: methyl (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrazine-2-carboxylate (50-b)

[0276] Triphosgene (35.6 mg, 0.120 mmol) and Et3N (0.209 ml, 1.501 mmol) were added to a solution of methyl 3-amino-5-cyclopropylpyrazine-2-carboxylate (67 mg, 0.347 mmol) in THF (2 ml). The mixture was stirred at rt for 10 minutes and (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 90 mg, 0.300 mmol) was added. The resulting mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-3% MeOH / DCM) to give compound 50-b. LCMS m / z (M+H): calculated 483.5, observed 483.2. Step 3: (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrazine-2-carboxylic acid (50-c)

[0277] 10 M NaOH in H2O (0.022 ml, 0.218 mmol) were added to a solution of methyl (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)pyrazine-2-carboxylate (50-b, 35 mg, 0.073 mmol) in MeOH (0.5 ml). The mixture was stirred at rt overnight, then 4 M HCl in 1,4-dioxane (0.181 ml, 0.725 mmol) was added. The resulting mixture was concentrated in vacuo. The residue was treated with MeOH / DCM (1 / 1), filtered and washed. The combined filtrate was concentrated in vacuo to give compound 50-c. LCMS m / z (M+H): calculated 469.5, observed 469.5. Step 4: (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)-N-methylpyrazine-2-carboxamide (50)

[0278] HATU (20.29 mg, 0.053 mmol) and Et3N (0.015 ml, 0.107 mmol) were added to a solution of (R or S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrazine-2-carboxylic acid (50-c, 10 mg, 0.021 mmol) in DCM (1.5 ml ). The mixture was stirred at rt for 20 minutes, then 2 M methanamine in THF (0.107 ml, 0.213 mmol) was added. The mixture was stirred at rt overnight and concentrated in vacuo. The25863 residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give compound 50. LCMS m / z (M+H): calculated 482.6, observed 482.3. EXAMPLE 51 (R or S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamido)-N-methylpyrimidine-5-carboxamide (51) Step 1: methyl 4-amino-2- (51-a)

[0279] SPhos Pd G3 (133 mg, 0.171 mmol) and 0.5M cyclopropylzinc(II) bromide in THF (12.79 ml, 6.40 mmol) were added to a solution of methyl 4-amino-2-chloropyrimidine-5- carboxylate (400 mg, 2.132 mmol) in THF (15 ml). The mixture was stirred at rt overnight. The reaction was qenuched with aqueous saturated NH4Cl and extrated with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / DCM) to give compound 51-a. LCMS m / z (M+H): calculated 194.2, observed 194.1. Step 2: methyl (R or S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrimidine-5-carboxylate (51-b)

[0280] Methyl 4-amino-2-cyclopropyl pyrimidine-5-carboxylate (83 mg, 0.430 mmol) and (R or S)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbonyl chloride (51-a, 100 mg, 0.307 mmol) were dissolved in THF (4 ml) and cooled to 0 °C, followed by addition of NaH (36.8 mg, 0.921 mmol). The mixture was stirred at 0 °C for 3 hours, then warmed to rt and stirred for another 30 minutes. The reaction was quenched with aqueous saturated NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-3% MeOH / DCM) to give compound 51-b. LCMS m / z (M+H): calculated 483.5, observed 483.4. Step 3: (R or S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrimidine-5-carboxylic acid (51-c)

[0281] 10 M NaOH in H2O (0.044 ml, 0.435 mmol) was added to a solution of methyl (R or S)- 2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-25863 carboxamido)pyrimidine-5-carboxylate (51-b, 70 mg, 0.145 mmol) in MeOH (0.5 ml). The mixture was stirred at rt overnight, then added 4 M HCl in 1,4-dioxane (0.363 ml, 1.451 mmol) and concentrated in vacuo. The residue was treated with MeOH / DCM (1 / 1), filtered and washed. The combined filtrate was concentrated in vacuo to give compound 51-c. LCMS m / z (M+H): calculated 469.5, observed 469.3. Step 4: (R or S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)-N-methylpyrimidine-5-carboxamide (51)

[0282] HATU (20.29 mg, 0.053 mmol) and Et3N (0.015 ml, 0.107 mmol) were added to a solution of (R or S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)pyrimidine-5-carboxylic acid (51-c, 10 mg, 0.021 mmol) in DCM (0.8ml). The mixture was stirred at rt for 10 minutes, followed by addition of 2 M methanamine in THF (0.107 ml, 0.213 mmol). The resulting mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM to give compound 51. LCMS m / z (M+H): calculated 482.6, observed 482.3. EXAMPLE 52 (R or S)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (52) Step 1: 4-bromo-N-(2,4-(52-a)

[0283] 4-bromo-2-nitrobenzenesulfonyl chloride (250 mg, 0.832 mmol) was added to a solution of 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (181 mg, 0.998 mmol) and Et3N (0.174 ml, 1.248 mmol) in DCM (1 ml) and THF (1 ml). The mixture was stirred at rt for 4 hours. The reaction was partitioned between ethyl acetate and H2O. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound 52-a. Step 2: 4-cyclopropyl-N-(2,4-dimethoxybenzyl)-N-methyl-2-nitrobenzenesulfonamide (52-b)

[0284] Pd(dppf)Cl2 (91 mg, 0.125 mmol), cyclopropylboronic acid (214 mg, 2.493 mmol), Cs2CO3(541 mg, 1.662 mmol) and water (0.2 ml) were added to a solution of 4-bromo-N-(2,4- dimethoxybenzyl)-N-methyl-2-nitrobenzenesulfonamide (52-a, 370 mg, 0.831 mmol) in 1,4-25863 dioxane (10 ml). The mixture was heated to 90 °C and stirred for 2 days. The reaction was cooled to rt, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give compound 52-b. LCMS m / z (M+H): calculated 407.5, observed 407.2. Step 3: 2-amino-4-cyclopropyl-N-(2,4-dimethoxybenzyl)-N-methylbenzenesulfonamide (52-c)

[0285] 10% Pd-C (150 mg, 0.141 mmol) was added to a solution of 4-cyclopropyl-N-(2,4- dimethoxybenzyl)-N-methyl-2-nitrobenzenesulfonamide (52-b.115 mg, 0.283 mmol) in MeOH (8 ml). The mixture was hydrogenated under H2balloon and stirred at rt overnight. Filtered through a pad of Celite™, washed with extra MeOH. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / hexane) to to give compound 52-c. LCMS m / z (M+H): calculated 377.5, observed 377.2. Step 4: (R or S)-N-(5-cyclopropyl-2-(N-(2,4-dimethoxybenzyl)-N-methylsulfamoyl)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (52-d)

[0286] To a solution of 2-amino-4-cyclopropyl-N-(2,4-dimethoxybenzyl)-N- methylbenzenesulfonamide (52-c, 51.2 mg, 0.136 mmol) in DCM (5 ml) was added triphosgene (14.13 mg, 0.048 mmol) and triethylamine (0.126 ml, 0.907 mmol). The mixture was stirred at rt for 5 minutes, followed by addition of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)- 1,2,4-thiadiazole hydrochloride (intermediate 7) (34 mg, 0.113 mmol) and stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-3% MeOH / DCM) to give compound.52-c LCMS m / z (M+H): calculated 666.8, observed 666.3. Step 5: (R or S)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (52)

[0287] TFA (0.5 ml, 6.49 mmol) was added to a solution of (R or S)-N-(5-cyclopropyl-2-(N- (2,4-dimethoxybenzyl)-N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (52-d, 70 mg, 0.105 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 30 minutes and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give compound 52. LCMS m / z (M+H): calculated 516.2, observed 516.2. EXAMPLE 53 (R or S)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (53)25863 Step 1: (R or S)-4- -3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-

[0288] A vial was charged with (R or S)-N-(2-bromo-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (35-b, 100 mg, 0.196 mmol), xantphos palladacycle gen 2 (34.8 mg, 0.039 mmol), MeOH (0.158 ml, 3.91 mmol) and Et3N (1.5ml, 10.76 mmol). The mixture was sealed in CO (50 psi), heated to 90 °C and stirred for 18 hours. The reaction mixture was then cooled to rt, filtered, washed with MeOH and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 10% MeOH / DCM) to give compound 53-a. LCMS m / z (M+H): calculated 477.5, observed 477.2. Step 2: (R or S)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (53)

[0289] HATU (25.5 mg, 0.067 mmol), (R or S)-4-(difluoromethyl)-2-(3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)benzoic acid (53-b, 8 mg, 0.017 mmol), Et3N (0.023 ml, 0.168 mmol) and 2M methanamine in THF (0.050 ml, 0.101 mmol) was added to a solution of in DCM (1 ml). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH / DCM) to give compound 53. LCMS m / z (M+H): calculated 490.5, observed 490.2.

[0290] Examples 54 through 56 depicting Compounds 54 through 56 found in Table 9, were prepared in an analogous fashion to that described for Example 53 but using the appropriate intermediates and commercially available reagents. Table 9:25863 Example Compound Name Calc’d Observed [M+H]+[M+H]+EXAMPLE 57 (R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (57) Step 1: N-(2,4-(57-a)

[0291] 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (60.5 mg, 0.334 mmol) and Et3N (0.058 ml, 0.417 mmol) were added to a solution of 4-methoxy-2-nitrobenzenesulfonyl chloride25863 (70 mg, 0.278 mmol) in THF (2 ml). The mxiture was stirred at rt for 6 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give compound 57-a. Step 2: 2-amino-N-(2,4-dimethoxybenzyl)-4-methoxy-N-methylbenzenesulfonamide (57-b)

[0292] 10% Pd-C (100 mg, 0.094 mmol) to a solution of N-(2,4-dimethoxybenzyl)-4-methoxy- N-methyl-2-nitrobenzenesulfonamide (57-a, 105 mg, 0.265 mmol) in THF (1 ml). The mixture was hydrogenated under a H2 balloon for 3 hours, filtered through a pad of Celite™ and washed with extra THF. The combined filtrate was concentrated in vacuo to give compound 57-b. LCMS m / z (M+H): calculated 367.4, observed 367.2. Step 3: (R or S)-N-(2-(N-(2,4-dimethoxybenzyl)-N-methylsulfamoyl)-5-methoxyphenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (57-c)

[0293] Triphosgene (12.47 mg, 0.042 mmol) and triethylamine (0.112 ml, 0.801 mmol) were added to a solution of 2-amino-N-(2,4-dimethoxybenzyl)-4-methoxy-N- methylbenzenesulfonamide (57-b, 44.0 mg, 0.120 mmol) in DCM (5 ml). The mixture was stirred at rt for 5 minutes, followed by the addition of (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 30 mg, 0.100 mmol). The reaction mixture was then stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-3% MeOH / DCM) to give compound 57-c. LCMS m / z (M+H): calculated 656.8, observed 656.4. Step 4: (R or S)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (57)

[0294] TFA (0.5 ml, 6.49 mmol) was added to a solution of (R or S)-N-(2-(N-(2,4- dimethoxybenzyl)-N-methylsulfamoyl)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (57-c, 64 mg, 0.098 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% MeOH with 1.0 N NH3 / DCM) to give compound 57. LCMS m / z (M+H): calculated 506.6, observed 506.3. EXAMPLE 58 (R or S)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (58)25863 Step 1: 4,6-dichloro-N-(2,4- 3-sulfonamide (58-a)

[0295] 1-(2,4- - mg, 0.852 mmol) and 4,6- dichloropyridine-3-sulfonyl chloride (200 mg, 0.811 mmol) were added to a cold (0 °C) solution of 4,6-dichloropyridine-3-sulfonyl chloride (200 mg, 0.811 mmol) in DCM (8 ml). The mixture was stirred at 0 °C for 3 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound 58-a. Step 2: 4-chloro-6-cyclopropyl-N-(2,4-dimethoxybenzyl)-N-methylpyridine-3-sulfonamide (58- b)

[0296] Pd(Ph3P)4(180 mg, 0.156 mmol) and 0.5 M cyclopropylzinc(II) bromide in THF (1.871 ml, 0.935 mmol) were added to a solution of 4,6-dichloro-N-(2,4-dimethoxybenzyl)-N- methylpyridine-3-sulfonamide (305 mg, 0.780 mmol) in anhydrous THF (10 ml). The mixture was heated to 35 °C and stirred overnight. The reaction was cooled to rt, quenched with aqueous saturated NH4Cl, and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give compound 58-b. Step 3: (R or S)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (58-c)

[0297] Potassium cyanate (216 mg, 2.67 mmol) was added to a solution of (R or S)-5-(3-(3- fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 400 mg, 1.334 mmol) in water (8 ml). The mixture was heated to 60 °C, stirred for 2 hours, cooled to rt, and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound 58-c. LCMS m / z (M+H): calculated 307.3, observed 307.6. Step 4: (R or S)-N-(2-cyclopropyl-5-(N-(2,4-dimethoxybenzyl)-N-methylsulfamoyl)pyridin-4- yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (58- d)

[0298] (R or S)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide (58-c, 50.9 mg, 0.166 mmol), 4-chloro-6-cyclopropyl-N-(2,4-dimethoxybenzyl)-N-25863 methylpyridine-3-sulfonamide (55 mg, 0.139 mmol), Cs2CO3 (90 mg, 0.277 mmol), xantphos palladacycle gen 2 (24.63 mg, 0.028 mmol) and 1,4-dioxane (1.5 ml) were added to a microwave tube. The mixture was purged with N2 for 5 minutes, sealed and microwaved at 100 °C for 2.5 hours. The reaction was cooled to rt, filtered, washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / DCM) to give compound 58-d. LCMS m / z (M+H): calculated 667.8, observed 667.5. Step 5: (R or S)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (58)

[0299] TFA (0.5 ml, 6.49 mmol) was added to a solution of (R or S)-N-(2-cyclopropyl-5-(N- (2,4-dimethoxybenzyl)-N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide (58-d, 70 mg, 0.105 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was dissolved in 1 ml DCM, then Et3N (0.073 ml, 0.525 mmol) was added. The solution was stirred at rt for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH / DCM) to give compound 58. LCMS m / z (M+H): calculated 517.6, observed 517.7.

[0300] Example 59 depicting Compound 59 found in Table 10, was prepared in an analogous fashion to that described for Example 58 but using the appropriate intermediates and commercially available reagents. Table 10: Ex. / compd Compound Name Calc’d Observed + ]+EXAMPLE 60 (R or S)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (60)25863 Step 1: methyl (R or S)-2-(4- -3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-

[0301] Triphosgene (85 mg, 0.286 mmol) and triethylamine (0.407 ml, 2.92 mmol) were added to a solution of methyl 2-(2-amino-4-bromophenyl)acetate (199 mg, 0.817 mmol) in DCM (8 ml). The mixture was stirred at rt for 5 minutes, followed by addition of (R or S)-5-(3-(3-fluoro- 4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 175 mg, 0.584 mmol), then stirred at rt for 1 hour and conentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give the title compound. Step 2: (R or S)-2-(4-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenyl)acetic acid (60-b)

[0302] Cyclopropylboronic acid (49.1 mg, 0.572 mmol), Cs2CO3 (466 mg, 1.429 mmol), Pd(dppf)Cl2(84 mg, 0.114 mmol) and water (0.2 ml)To a solution of methyl (R or S)-2-(4- bromo-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)phenyl)acetate (60-a, 305 mg, 0.572 mmol) in 1,4-dioxane (8 ml) was added. The mixture was heated to 70 °C and stirred for 20 hours, cooled to rt, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH / DCM) to give compound 60-b. LCMS m / z (M+H): calculated 481.6, observed 481.3. Step 3: (R or S)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro- 4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (60)

[0303] Azetidin-3-ol (11.41 mg, 0.156 mmol), HATU (35.6 mg, 0.094 mmol) and Et3N (0.022 ml, 0.156 mmol) were added to a solution of (R or S)-2-(4-cyclopropyl-2-(3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)phenyl)acetic acid (60-b,25 mg, 0.052 mmol) in DCM(1 ml). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH / DCM) to give compound 60. LCMS m / z (M+H): calculated 536.6, observed 536.4.25863 EXAMPLE 61 (R or S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine- 1-carbothioamide (61)

[0304] Et3N (0.016 ml, 0.117 of 2-isothiocyanato-1,4-dimethoxybenzene (22.87 mg, 4-methylphenyl)pyrrolidin-3- yl)thiazole hydrochloride (I-1, 35 mg, 0.117 mmol) in DCM (2 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50% ethyl acetate / hexane) to give a mixture of isomers, which was further separated by SFC (OD column, 50% EtOH co-solvent) to give compound 61 (first eluted fraction, fast peak). LCMS m / z (M+H): calculated 458.6, observed 458.2.

[0305] Examples 62 and 63 depicting Compounds 62 and 63 found in Table 11, were prepared in an analogous fashion to that described for Example 61 but using the appropriate intermediates and commercially available reagents. Table 11: Ex. / compd Co Name Calc’d Observed N mpound [M+H]+[M+H]+C nditi ns -H nt H k -H nt: H k25863 EXAMPLE 64 (R or S)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carbothioamide (64)

[0306] Thiophosgene (5.11 (0.023 ml, 0.167 mmol) wereadded to a solution of 5- - 10, 11.55 mg, 0.067 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 5 minutes, then (R or S)-5-(3-(3-fluoro-4- methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 10 mg, 0.033 mmol) was added. The reaction was allow to continue at rt for 1 hour. The reaction mixture was then concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to to give compound 64. LCMS m / z (M+H): calculated 479.6, observed 479.4.

[0307] Example 65 depicting Compound 65 found in Table 12, was prepared in an analogous fashion to that described for Example 64 but using the appropriate intermediates and commercially available reagents. Table 12: Ex. / compd Compound Name Calc’d Observed + ]+EXAMPLE 66 (R or S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5- methoxyphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide (66)25863 Step 1: methyl (R or S)-2-(3-(3- thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4-

[0308] Thiophosgene (0.043 ml, 0.560 mmol) and Et3N (0.279 ml, 2.001 mmol) were added to a cold solution (0 °C) of methyl 2-amino-4-methoxybenzoate (102 mg, 0.560 mmol) in DCM (8 ml). The mixture was stirred at 0 °C for 5 minutes, followed by addition of (R or S)-5-(3-(3- fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 120 mg, 0.400 mmol). The mixture was warmed to rt, stirred for 1 hour, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-50 % ethyl acetate / hexane) to give compound 66-a. LCMS m / z (M+H): calculated 487.6, observed 487.3. Step 2: (R or S)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carbothioamido)-4-methoxybenzoic acid (66-b)

[0309] 2.0 M LiOH in H2O (1.11 ml, 2.220 mmol) was added to a solution of methyl (R or S)- 2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxybenzoate (66-a, 108 mg, 0.222 mmol) in THF (1 ml) and MeOH (1 ml). The mixture was stirred at rt overnight and 37% HCl in H2O (0.219 ml, 2.66 mmol) was aded to adjust to about pH = 1. The resulting mixture then was extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound 66-b. LCMS m / z (M+H): calculated 473.6, observed 473.3. Step 3: (R or S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5- methoxyphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide (66)

[0310] 2.0 M oxalyl dichloride in DCM (0.095 ml, 0.190 mmol) and one drop of DMF were added to a solution of (R or S)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamido)-4-methoxybenzoic acid (66-b, 60 mg, 0.127 mmol) in DCM (1 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was dissolved in DMF (0.8 ml) then azetidin-3-ol (37.1 mg, 0.508 mmol) and Et3N (0.088 ml, 0.635 mmol) were added. The resulting mixture was stirred at rt for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The separarted organic phase was dried over Na2SO4,25863 filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH / DCM) to give compound 66. LCMS m / z (M+H): calculated 528.6, observed 528.3. EXAMPLE 67 (R or S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide (67) Step 1: (R or S)-N-(5-((R or -2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carbothioamide (67-a)

[0311] Thiophosgene (0.012 ml, 0.150 mmol) and Et3N (0.058 ml, 0.417 mmol) were added to a cold solution (0 °C) of (S)-N-((R or S)-1-(3-amino-4-methoxyphenyl)-2,2,2-trifluoroethyl)-2- methylpropane-2-sulfinamide (I-13, 48.7 mg, 0.150 mmol) in DCM (11 ml) was added. The mixture was stirred at 0 °C for 2 minutes and (R or S)-5-(3-(3-fluoro-4-methylphenyl) pyrrolidin- 3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 25 mg, 0.083 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, warmed to rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% CH3CN / DCM) to give compound 67-a. LCMS m / z (M+H): calculated 630.8, observed 630.3. Step 2: (R or S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide (67)

[0312] 4.0 M HCl in 1,4-dioxane (0.5ml, 2.000 mmol) was added to a solution of (R or S)-N- (5-((R or S)-1-(((S)-tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide (67-a, 15 mg, 0.024 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was dissolved in 1 ml DCM and Et3N (0.033 ml, 0.238 mmol) was added. The mixture was purified by preparative TLC eluting with (30% CH3CN / DCM), to give compound 67. LCMS m / z (M+H): calculated 526.6, observed 526.2.25863 EXAMPLE 68 (R or S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H- indazol-3-yl)methanone (68)

[0313] HATU (140 mg, 0.367 0.734 mmol) was added to asolution of 5-(3-(3-fluoro-4- - thiadiazole hydrochloride (I-6, 55 mg, 0.183 mmol) and 5-methyl-1H-indazole-3-carboxylic acid (64.6 mg, 0.367 mmol) in DCM (3 ml). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by preparative TLC and eluted with (2% MeOH / DCM), to give a mixture of isomers, which was further separated by SFC (OJ column, 20% IPA with 0.2% DIPA co-solvent) to give compound 68 (first eluted fraction, fast peak). LCMS m / z (M+H): calculated 422.5, observed 422.3.

[0314] Example 69 depicting Compound 69 found in Table 13, was prepared in an analogous fashion to that described for Example 68 but using the appropriate intermediates and commercially available reagents. Table 12: Ex / compd Compo Name Calc’d Observed N und [M+H]+[M+H]+C diti ns H nt H kEXAMPLE 70 (R or S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2- hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)methanone (70)25863 Step 1: methyl 5-bromo-1-(2- 3-carboxylate (70-a)

[0315] 2,2-dimethyloxirane (325 mg, 2.352 mmol) werre added to a solution of methyl 5-bromo-1H-indazole-3-carboxylate (300 mg, 1.176 mmol) in DMF (5 ml). The mixture was heated to 80 °C and stirred overnight. The reaction was cooled to rt, partitioned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give compound 70-a. LCMS m / z (M+H): calculated 328.2, observed 329.3. Step 2: methyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylate (70-b)

[0316] methylboronic acid (282 mg, 4.71 mmol), Cs2CO3 (1150 mg, 3.53 mmol), Pd(dppf)Cl2 (172 mg, 0.235 mmol) and water (50 µL) were added to a solution of methyl 5-bromo-1-(2- hydroxy-2-methylpropyl)-1H-indazole-3-carboxylate (70-a, 385 mg, 1.177 mmol) in 1,4-dioxane (8 ml). The mixture was heated to 90 °C and stirred overnight. The reaction was cooled to rt, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to afford compound 70-b. LCMS m / z (M+H): calculated 263.3, observed 263.3. Step 3: 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylic acid (70-c)

[0317] NaOH (102 mg, 2.56 mmol) and water (0.50 ml) were added to a solution of methyl 1- (2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylate (168 mg, 0.640 mmol) in MeOH (0.50 ml) and THF (0.50 ml). The mixture was heated to 50 °C, stirred for 3 hours, cooled to rt and then concentrated HCl (37%) (0.117 ml, 3.84 mmol) was added. The volatiles were removed under reduced pressure. The residue was washed with DCM / MeOH (1 / 1) and filtered. The filtrate was concentrated in vacuo to give compound 70-c. LCMS m / z (M+H): calculated 249.3, observed 249.4. Step 4: (R or S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2- hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)methanone (70)

[0318] 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylic acid (18.63 mg, 0.075 mmol), HATU (38.0 mg, 0.100 mmol) and Et3N (0.035 ml, 0.250 mmol) were added to a solution of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 15 mg, 0.050 mmol) in DCM (1 ml). The mixture was stirred at rt overnight25863 and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-10% CH3CN / DCM) to afford compound 70. LCMS m / z (M+H): calculated 494.6, observed 494.5. EXAMPLE 71 (R or S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2- methoxyethyl)-5-methyl-1H-indazol-3-yl)methanone (71) Step 1: methyl 1-(2- (71-a)

[0319] 2-methoxyethan-1-ol (600 mg, 7.89 mmol), triphenylphosphane (2069 mg, 7.89 mmol) and diisopropyl (E)-diazene-1,2-dicarboxylate (1.548 ml, 7.89 mmol) were added to a solution of methyl 5-methyl-1H-indazole-3-carboxylate (500 mg, 2.63 mmol) in DCM (15 ml). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-40% ethyl acetate / hexane) to give compound 71-a. LCMS m / z (M+H): calculated 249.3, observed 249.3. Step 2: 1-(2-methoxyethyl)-5-methyl-1H-indazole-3-carboxylic acid (71-b)

[0320] NaOH (155 mg, 3.87 mmol) and water (0.25 ml) were added to a solution of methyl 1- (2-methoxyethyl)-5-methyl-1H-indazole-3-carboxylate (70-a, 240 mg, 0.967 mmol) in MeOH (0.5 ml) and THF (0.5 ml). The mixture was heated to 40 °C and stirred for 3 hours, then cooled to rt, followed by the addition of concentrated HCL (37% aqueous) until the solution obtain approximately a pH = 2. The solution then was concentrated under reduced pressure. The residue was washed with MeOH / DCM (1 / 1), filtered and the filtrate was concentrated to afford compound 71-b. LCMS m / z (M+H): calculated 235.3, observed 235.4. Step 3: (R or S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2- methoxyethyl)-5-methyl-1H-indazol-3-yl)methanone (71)

[0321] 1-(2-methoxyethyl)-5-methyl-1H-indazole-3-carboxylic acid (14.07 mg, 0.060 mmol), HATU (30.4 mg, 0.080 mmol) and Et3N (0.028 ml, 0.200 mmol) were added to a solution of (R or S)-5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)-1,2,4-thiadiazole hydrochloride (I-7, 12 mg, 0.040 mmol) in DCM (0.5 ml). The mixture was stirred at rt for 2 hours and concentrated in25863 vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-6% CH3CN / DCM) to give compound 71. LCMS m / z (M+H): calculated 480.6, observed 480.5. EXAMPLE 72 (2R or 2S, 4R or 4S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4- (thiazol-2-yl)pyrrolidine-1-carboxamide (72) Step 1: 1-benzyl-3-(3-fluoro-4- 2-one (72-a)

[0322] 1.0 M LiHDMS in was to a solution of 1-benzyl-5- methylpyrrolidin-2-one (620 mg, 3.28 mmol) in anhyrous THF (6 ml) at -20 °C. The mixture was stirred at -20 °C for 30 minutes, then warmed to 0 °C.1.9 M zinc(II) chloride in THF (2.59 ml, 4.91 mmol) was added to the solution. The resulting solution was stirred at rt for 30 minutes and then Pd2(dba)3 (150 mg, 0.164 mmol), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (233 mg, 0.328 mmol)and 2-fluoro-4-iodo-1-methylbenzene (1083 mg, 4.59 mmol) were added. The resulting mixture was sealed in a tube. The mixture was heated to 60 °C and stirred for 3 days. The reaction was quenched with aqueous saturated NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5 % CH3CN / DCM) to give compound 72-a. LCMS m / z (M+H): calculated 298.4, observed 298.3. Step 2: 1-benzyl-3-(3-fluoro-4-methylphenyl)-5-methyl-3-(thiazol-2-yl)pyrrolidin-2-one (72-b)

[0323] 60% NaH in mineral oil (202 mg, 5.04 mmol) and 2-chlorothiazole (0.346 ml, 4.04 mmol) wre added to a solution of 1-benzyl-3-(3-fluoro-4-methylphenyl)-5-methylpyrrolidin-2- one (72-a, 300 mg, 1.009 mmol) in THF (8 ml). The mixture was heated to 50 °C and stirred overnight. The reaction was cooled to rt and quenched with water and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-4% CH3CN / DCM) to afford two fractions with the desired LCMS and fast fraction (72-b) was sbmitted for next step. LCMS m / z (M+H): calculated 381.5, observed 381.4. Step 3: 2-(1-benzyl-3-(3-fluoro-4-methylphenyl)-5-methylpyrrolidin-3-yl)thiazole (72-c)25863

[0324] 1-benzyl-3-(3-fluoro-4-methylphenyl)-5-methyl-3-(thiazol-2-yl)pyrrolidin-2-one (72-b, fast fraction from step 2, 300 mg, 0.788 mmol) was dissolved in THF (8 ml) and cooled to -20 °C. Aluminum trichloride (158 mg, 1.183 mmol) was then added to the mixture. The mixture was stirred at -20 °C for 10 minutes, then added 1.0 M LAH in THF (0.788 ml, 0.788 mmol). The mixture was stirred at -20 °C for 20 minutes, then warmed to rt and stirred for 1 hour. The reaction was quenched with aqueous saturated NaHCO3, filtered through a pad of Celite™ and washed with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated to give compound 72-c. LCMS m / z (M+H): calculated 367.5, observed 367.5. Step 4: 2-(3-(3-fluoro-4-methylphenyl)-5-methylpyrrolidin-3-yl)thiazole hydrochloride (72-d)

[0325] Chloromethyl carbonochloridate (0.226 ml, 2.210 mmol) and 2-(1-benzyl-3-(3-fluoro-4- methylphenyl)-5-methylpyrrolidin-3-yl)thiazole (270 mg, 0.737 mmol) were combined in DCE (1 ml) and sealed in a microwave tube. The mxiture was heated to 80 °C and stirred for 2 hours and MeOH (6ml) was added using a syringe. The mixture was microwaved at 100 °C for 1 hour and concentrated in vacuo to give compound 72-d. LCMS m / z (M+H): calculated 277.4, observed 277.3. Step 5: (2R or 2S, 4R or 4S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4- (thiazol-2-yl)pyrrolidine-1-carboxamide (72)

[0326] 2-isocyanato-1,4-dimethoxybenzene (34.4 mg, 0.192 mmol) and Et3N (0.089 ml, 0.639 mmol) were added to a solution of 2-(3-(3-fluoro-4-methylphenyl)-5-methylpyrrolidin-3- yl)thiazole hydrochloride (72-d, 40 mg, 0.128 mmol) in DCM (2ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-40% ethyl acetate / hexane) to give a mixture of isomers, which was further separated by SFC (AD column, 45% MeOH co-solvent) to give compound 72 as the second eluted fraction, slow peak. LCMS m / z (M+H): calculated 456.5, observed 456.4. EXAMPLE 73 (2R or 2S, 4R or 4S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4- (thiazol-2-yl)pyrrolidine-1-carbothioamide (73)25863

[0327] 2-isothiocyanato-1,4-dimethoxybenzene (287 mg, 1.470 mmol) and Et3N (0.089 ml, 0.639 mmol) were added to a solution of 2-(3-(3-fluoro-4-methylphenyl)-5-methylpyrrolidin-3- yl)thiazole hydrochloride (72-d, 40 mg, 0.128 mmol) in DCM (2 ml). The mixture was stirred at rt for 1 hour and concentrtaed in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-30% ethyl acetate / hexane) to give a mixture of isomers, which was further separated by SFC (AD column, 45% MeOH co-solvent) to give compound 73 (second eluted fraction, slow peak). LCMS m / z (M+H): calculated 472.6, observed 472.4. EXAMPLE 74 (3R or 3S, 4R or 4S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p- tolyl)pyrrolidine-1-carboxamide (74) Step 1: morpholino(thiazol-2-yl)

[0328] A solution of morpholine (1.778 ml, 20.33 mmol) and Et3N (4.25 ml, 30.5 mmol) in DCM (5 ml) was slowly added to a solution of thiazole-2-carbonyl chloride (3.0 g, 20.33 mmol) in DCM (30 ml) at 0 °C. After addition, the mixture was stirred at 0 °C for 1 hour and then warmed to rt for 1 hour. The mixture was then partitoned between ethyl acetate and saturated aqueous NaHCO3. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 70% ethyl acetate / hexane) to give compound 74-a. LCMS m / z (M+H): calculated 199.2, observed 199.1. Step 2: thiazol-2-yl(p-tolyl)methanone (74-b)

[0329] A cold (0 °C) solution of morpholino(thiazol-2-yl)methanone (1000 mg, 5.04 mmol) in THF (20 ml) was added 1.0 M p-tolylmagnesium bromide in THF (6.56 ml, 6.56 mmol). The mixture was stirred at 0 °C for 2 hours, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0- 50% ethyl acetate / hexane) to give compound 74-b. LCMS m / z (M+H): calculated 204.3, observed 204.1. Step 3: 2-(1-(p-tolyl)prop-1-en-1-yl)thiazole (74-c)25863

[0330] 1.0 M potassium bis(trimethylsilyl)amide in THF (1.279 ml, 1.279 mmol) was added to a solution of ethyltriphenylphosphonium bromide (475 mg, 1.279 mmol) in THF (10 ml) at 0 °C. The mixture was stirred rt 0 °C for 1 hour, followed by the addition of thiazol-2-yl(p- tolyl)methanone (200 mg, 0.984 mmol). The solution was then warmed to rt and stirred for 3 hours. The reaction was quenched with aqueous saturated NH4Cl and extracted with diethyl ether. The separated organic solvent was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-20% ethyl acetate / hexane) to give compound 74-c. LCMS m / z (M+H): calculated 216.3, observed 216.3. Step 4: 2-(1,4-dimethyl-3-(p-tolyl)pyrrolidin-3-yl)thiazole (74-d)

[0331] Trimethylamine n-oxide (105 mg, 1.393 mmol), followed by 2 M LDA in THF (1.219 ml, 2.438 mmol) over 5 minutes were added to a cold (0 °C) solution of 2-(1-(p-tolyl)prop-1-en- 1-yl)thiazole (74-c, 150 mg, 0.697 mmol) in anhydrous THF (5 ml). The mixture was stirred at 0 °C for 1 hour and quenched with aqueous saturated NaHCO3, then extracted with diethyl ether. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with (0-5% MeOH with 2N NH3 / DCM) to give compound 74-d. LCMS m / z (M+H): calculated 273.4, observed 273.5. Step 5: 2-(4-methyl-3-(p-tolyl)pyrrolidin-3-yl)thiazole hydrochloride (74-e)

[0332] 1-chloroethyl carbonochloridate (0.166 ml, 1.542 mmol) was added to a solution of 2- (1,4-dimethyl-3-(p-tolyl)pyrrolidin-3-yl)thiazole (140 mg, 0.514 mmol) in THF (8 ml). The mixture was heated to 70 °C and stirred for 7 hours. Then MeOH (4 ml) was added to the solution and it was stirred at reflux for 2 hours. Subsequently, the solution was concentrated in vacuo to give compound 74-e. LCMS m / z (M+H): calculated 259.4, observed 259.2. Step 6: (3R or 3S, 4R or 4S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p- tolyl)pyrrolidine-1-carboxamide (74)

[0333] Et3N (0.026 ml, 0.190 mmol) and 2-isocyanato-1,4-dimethoxybenzene (11.06 mg, 0.062 mmol) were added to a solution of 2-(4-methyl-3-(p-tolyl)pyrrolidin-3-yl)thiazole hydrochloride (70 mg, 0.047 mmol) in DCM (5 ml). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was purified by preparative TLC and eluted with 25% ethyl acetate in hexane to give two fractions, a slow and a fast fraction, each as a mixture of two isomers. The fast fraction (mixture of two isomers) was further separated by SFC (AS column, 30% EtOH co- solvent) to give compound 74 (second eluted fraction, slow peak). LCMS m / z (M+H): calculated 438.6, observed 438.4.25863 EXAMPLE 75 (2R or 2S, 3R or 3S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p- tolyl)pyrrolidine-1-carboxamide (75) Step 1: 1-benzyl-3-(p-tolyl)

[0334] (2,2,6,6- (60 mL, 90 mmol) at room temperature was added to a solution of 1-benzylpyrrolidin-2-one (5257 mg, 30 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1430 mg, 3.00 mmol) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (3105 mg, 3.00 mmol) in THF (300 mL). Then, 1-bromo-4-methylbenzene (5131 mg, 30.0 mmol) was added to the reaction mixture. The reaction mixture was stirred at 70 °C for 5 hours. The solvent was removed and the residue was purified by RP-combiflash and eluted with 0-60% CH3CN / water with 0.1% NH3H2O to give compound 75-a. LCMS m / z (M+H): calculated 267.1, observed 267.1. Step 2: 1-benzyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidin-2-one (75-b)

[0335] Sodium hydride (60%) (0.663 g, 16.58 mmol) at 0 °C and under argon atmosphere was added to a solution of 1-benzyl-3-(p-tolyl)pyrrolidin-2-one (2.2g, 8.29 mmol) in THF (50 mL). The reaction was stirred at 0 °C for 30 minutes, then 2-chlorothiazole (1.983 g, 16.58 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 2 hours, cooled to rt, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed by brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column, eluted by 30% ethyl acetate in Pet. ether to give compound 75-b. LCMS m / z (M+H): calculated 350.1, observed 350.1. Step 3: 1-benzyl-5-methyl-4-(thiazol-2-yl)-4-(p-tolyl)-3,4-dihydro-2H-pyrrol-1-ium chloride (75- c)

[0336] Chromium (IV) chloride (779 mg, 4.02 mmol) and methylmagnesium bromide (1 M in THF) (6.03 mL, 6.03 mmol), at rt and under argon atmosphere, were added to a solution of 1- benzyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidin-2-one (1400 mg, 4.02 mmol) in THF (40 mL). The reaction was stirred at rt for 2 hours. The reaction mixture was used for next step directly. Step 4: 2-(2-methyl-3-(p-tolyl)pyrrolidin-3-yl)thiazole (75-d)

[0337] Pd / C (10% Pd on C) (3.33 g, 3.13 mmol) under argon atmosphere was added to a solution of 1-benzyl-5-methyl-4-(thiazol-2-yl)-4-(p-tolyl)-3,4-dihydro-2H-pyrrol-1-ium chloride25863 (1.2 g, 3.13 mmol) in THF (5 mL). The reaction was charged with H2 (1.5 atm). The reaction mixture was stirred at room temperature for 36 hours, filtered via a diatomite and washed with MeOH. The filtrate was conentrated in vacuo and the residue was purified by RP-combiflash and eluted with 0-60% CH3CN / water with 0.1% NH3H2O to give compound 75-d. LCMS m / z (M+H): calculated 260.1, observed 260.1. Step 5: (2R or 2S, 3R or 3S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p- tolyl)pyrrolidine-1-carboxamide (75)

[0338] N-isopropyl-N-methylpropan-2-amine (66.9 mg, 0.581 mmol) and 2-isocyanato-1,4- dimethoxybenzene (41.6 mg, 0.232 mmol) were added to a solution of 2-(2-methyl-3-(p- tolyl)pyrrolidin-3-yl)thiazole (75-d, 50 mg, 0.194 mmol) in DCM (3 mL), The solution was stirred at rt for 1 hour. The reaction solvent was removed under reduced pressure and the residue was purified by RP-combiflash and eluted with 0-60% CH3CN / water with 0.1% NH3H2O to give a mixture of isomers which was further separated by chiral-HPLC (Column: CHIRAL ART Cellulose-SC) and eluted with 0-50% EtOH / hexane with 0.5% 2M NH3-MeOH to give compound 75. LCMS m / z (M+H): calculated 438.6, observed 438.4. EXAMPLE 76 (R or S)-(5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone (76)

[0339] HATU (157 mg, 0.412of 2-(3-(p-tolyl)piperidin-3- yl)pyridine (I-14, 52 mg, 0.206 mmol) and 5-methyl-1H-indazole-3-carboxylic acid (45.4 mg, 0.258 mmol) in DMF (2.1 mL) and then followed by the addition of DIEA (108 µl, 0.618 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified on a (C-18) Waters™ SunFire 30x150 mm column (Waters Corporation, Milford, MA) and eluted with Acetonitrile / Water + 0.05% TFA at 20 mL / min using a 10 minute 20-90% Acetonitrile / Water gradient. The product containing fractions were frozen and lyophilized. The mixture of isomers was separated by chiral-SFC (column OJ, co-solvent 15% MeOH) to obtain compound 76 (second eluted fraction, slow peak). LCMS m / z (M+H): calculated 411.2, observed 411.2.25863 EXAMPLE 77 (R or S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1- yl)methanone (77) Step 1: 3-bromo-1,5-dimethyl-

[0340] Iodomethane (1.009 g, g, 9.48 mmol) at 25 °C and under argon were added to a stirred mixture of 3-bromo-5-methyl-1H-indazole (1 g, 4.74 mmol) in DMF (10 mL). The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched by NH4Cl and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography, eluted with 1~10% ethyl acetate in PE to afford compound 77-a. LCMS m / z (M+H): calculated 224.99,observed 225.00. Step 2: methyl 1,5-dimethyl-1H-indazole-3-carboxylate (77-b)

[0341] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (195 mg, 0.267 mmol) and TEA (1.115 mL, 8.00 mmol) at 25 °C, under CO (50 atm) atmosphere, were added to a stirred mixture of 3-bromo-1,5-dimethyl-1H-indazole (77-a, 600 mg, 2.67 mmol) in MeOH (10 mL). The resulting mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue and the residue was purified by silica gel column chromatography, eluted with 1~14% EA in PE to afford compound 77-b. LCMS m / z (M+H): calculated 205.09, observed 205.15. Step 3: 1,5-dimethyl-1H-indazole-3-carboxylic acid (77-c)

[0342] LiOH (1 M in water, 7.83 mL, 7.83 mmol), at 25 °C under argon atmosphere, was added to a stirred mixture of methyl 1,5-dimethyl-1H-indazole-3-carboxylate (400 mg, 1.959 mmol) in THF (8 mL). The pH value of the solution was adjusted to 5~6 with HCl (1M in water). The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by RP-Flash (Column: C1840g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 60% B in 30 min, Detector: UV 210 nm; RT = 28 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford compound 77-c. LCMS m / z (M+H): calculated 191.1, observed 191.2.25863 Step 4: (1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone (77- d)

[0343] HATU (270 mg, 0.710 mmol), DIEA (0.248 mL, 1.420 mmol) and 2-(3-(p- tolyl)piperidin-3-yl)pyridine (I-14,101 mg, 0.426 mmol), at 25 °C nitrogen atmosphere, were added to a stirred mixture of 1,5-dimethyl-1H-indazole-3-carboxylic acid (77-c, 90 mg, 0.473 mmol) in DMF (2 mL). The reaction was stirred at 25 °C for 2 hours. The reaction mixture was purified directly by RP-combiflash with following conditions: C18, 40 g, Mobile Phase A: water, Mobile Phase B: acetonitrile, gradient: 0 ~ 50% B in 30min, Flow rate: 40 mL / min, detector: 254 nm. At 21 min to afford compound 77-d. LCMS m / z (M+H): calculated 425.23, observed 425.30. Step 5: (R or S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1- yl)methanone (77)

[0344] The racemic (1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1- yl)methanone (77-d, 70 mg, 0.165 mmol) was separated by prep-chiral-HPLC with following conditions Column: CHIRALPAK i.e., 2 x 25 cm, 5 µm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH Flow rate: 15 mL / min; Gradient: 10% B to 10% B in 20 min; Wave Length: 220 / 254 nm; At RT19.335 min to give compound 77 (first eluted fraction, fast peak). LCMS m / z (M+H): calculated 425.23, observed 425.20. EXAMPLE 78 (R or S)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone (78) Step 1: ethyl 2-(3-bromo-5-a)

[0345] Ethyl 2-bromoacetate (1.424 g, 8.53 mmol) and Cs2CO3 (3.70 g, 11.37 mmol), at room temperature under nitrogen atmosphere, were added to a mixture of 3-bromo-5-methyl-1H- indazole (1.2 g, 5.69 mmol) in DMF (10 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched by aqueous saturated NH4Cl and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by25863 silica gel column chromatography, eluted with 1~18% EtOAc in PE to afford compound 78-a. LCMS m / z (M+H): calculated 297.02, observed 299.05 (297.02). Step 2: 1-(3-bromo-5-methyl-1H-indazol-1-yl)-2-methylpropan-2-ol (78-b)

[0346] Methylmagnesium bromide (4.04 mL, 4.04 mmol), at 0 °C under nitrogen atmosphere, was added to a mixture of ethyl 2-(3-bromo-5-methyl-1H-indazol-1-yl)acetate (78-a, 400 mg, 1.346 mmol) in THF (8 mL). The resulting mixture was warmed to 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give compound 78-b. LCMS m / z (M+H): calculated 283.04, observed 283.10. Step 3: 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylic acid (78-c)

[0347] PdCl2(dppf) (59.4 mg, 0.081 mmol) and TEA (0.340 mL, 2.437 mmol), at room temperature under CO (30 atm) atmosphere, were added to a stirred mixture of 1-(3-bromo-5- methyl-1H-indazol-1-yl)-2-methylpropan-2-ol (78-b, 230 mg, 0.812 mmol) in MeOH (8 mL). The resulting mixture was stirred at 100°C for 16 h. The mixture was concentrated under reduced pressure to give methyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylate. The above methyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazole-3-carboxylate (430 mg, 0.738 mmol) in THF (5 mL) was added LiOH (5 mL, 5.00 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 2 hours. The mixture was diluted with water, and adjusted pH to 4.8 by adding 1 M HCl, then extracted with DCM. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced to afford compound 78-c. LCMS m / z (M+H): calculated 249.12, observed 249.10. Step 4: (1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone (78-d)

[0348] HATU (203 mg, 0.535 mmol), DIEA (0.187 mL, 1.070 mmol) and 1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazole-3-carboxylic acid (78-c, 80 mg, 0.321 mmol) at 25 °C nitrogen atmosphere were added to a stirred mixture of 2-(3-(p-tolyl)piperidin-3-yl)pyridine (I- 14, 90 mg, 0.357 mmol) in DMF (3 mL). The reaction was stirred at 25 °C for 2 hours. The reaction was purified by RP-combiflash with following conditions: C18, 40 g, Mobile Phase A: water, Mobile Phase B: acetonitrile, gradient: 0 ~ 50% B in 40 min, Flow rate: 40 mL / min, detector: 254 nm. At 23 min to give compound 78-d. LCMS m / z (M+H): calculated 483.27, observed 483.40. Step 5: (R or S)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3- (p-tolyl)piperidin-1-yl)methanone (78)25863

[0349] The racemic (1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2- yl)-3-(p-tolyl)piperidin-1-yl)methanone (78-d, 60 mg, 0.124 mmol) was separated by chiral- prep-HPLC with following conditions: Column: CHIRALPAK i.e., 2 x 25 cm, 5 µm; Mobile Phase A: Hex: DCM = 3: 1(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 15 mL / min; Wave Length: 220 / 254 nm. At RT124.086 min to give compound 78. LCMS m / z (M+H): calculated 483.27, observed 483.25. EXAMPLE 79 (R or S)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (79) Step 1: methyl (R or S)-4--3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)benzoate (79-a)

[0350] Triphosgene (321.2 mg, 1.082 mmol) and triethylamine (1.9 ml, 13.63 mmol) were added to a stirred solution of methyl 2-amino-4-cyclopropylbenzoate (I-16, 498.7 mg, 2.61 mmol) in DCM (33.0 ml). After 5 minutes, (R or S)5-(3-(3-fluoro-4-methylphenyl)pyrrolidin-3- yl)-1,2,4-thiadiazole hydrochloride (I-7, 519.6 mg, 1.733 mmol) was added to the reaction mixture. After 4 hours, the reaction mixture was evaporated under reduced pressure. The resulting solid was purified by silica gel column chromatography and eluted with 0-30% EtOAc / hexanes to afford compound 79-a. LCMS m / z (M+H) calculated 481.2, observed 481.2. Step 2: (R or S)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (79)

[0351] 2-methoxyethylamine (0.15 ml, 1.717 mmol) was added to a stirred suspension of methyl (R or S)-4-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)benzoate (79-a, 40.8 mg, 0.085 mmol) in EtOH (0.7 ml). The reaction mixture was heated to 80 °C. After 3 hours, additional 2-methoxyethylamine (0.15 ml, 1.717 mmol) was added to the reaction mixture. After an additional 3 days, more 2- methoxyethylamine (0.15 ml, 1.717 mmol) was added to the reaction mixture. After one more25863 day, the reaction mixture was evaporated under reduced pressure and the resulting residue was purified on a HPLC Reverse phase (C-18) Waters™ SunFire 30x150 mm column (Waters Corporation, Milford, MA) and eluted with Acetonitrile / Water + 0.05% TFA at 30 ml / min using a 14 minute 30-100% Acetonitrile / Water gradient. The product fractions were combined and concentrated under reduced pressure until most of the ACN had evaporated. The remaining solvent was transferred to a separation funnel and extracted with DCM (7 ml). The organic layer was washed with 4:1 water / saturated aqueous NaHCO3 (10 ml). The organic layer was dried over Na2SO4and filtered. The aqueous layer was extracted with DCM (2 x 7 ml). Both extracts were sequentially used to extract the bicarb layer and wash the Na2SO4 and funnel. The combined filtrates were evaporated under reduced pressure and the resulting residue was dissolved in ACN (~10 ml), filtered, diluted with water (~6 ml), frozen, and lyophilized to afford compound 79. LCMS m / z (M+H) calculated 524.2, observed 524.3. EXAMPLE 80 (R or S)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (80) Step 1: 4-cyclopropyl-2-(3-(3-thiadiazol-5-yl)pyrrolidine-1- carboxamido)benzoic acid (80-a)

[0352] LiOH 1.0 M aqueous (16.0 ml, 16.00 mmol) was added to a stirred solution of methyl (R or S)-4-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)benzoate (79-a, 768.4 mg, 1.599 mmol) in THF (16.0 ml). After 22.5 hours, the reaction mixture was concentrated under reduced pressure until most of the THF had been removed. The mixture was diluted with water (100 ml) and EtOAc (50 ml). The biphasic solution was cooled to 0 °C in an ice bath prior to being acidified to pH 0 through the dropwise addition of 1 N HCl. The biphasic mixture was removed from the ice bath and partitioned with additional EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to afford compound 80-a. LCMS m / z (M+H) calculated 467.2, observed 467.1.25863 Step 2: (R or S)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide (80)

[0353] (R or S)-4-cyclopropyl-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)benzoic acid (80-a, 20.6 mg, 0.044 mmol), HATU (36.2 mg, 0.095 mmol), 3-hydroxyazetidine hydrochloride (18.5 mg, 0.169 mmol), diisopropylethylamine (70 µl, 0.401 mmol), and DMF (0.45 ml) were combined to give a solution that was stirred at room temperature. After 5 hours, the reaction mixture was directly purified on a (C-18) Waters™ SunFire 30x150 mm column (Waters Corporation, Milford, MA) and eluted with Acetonitrile / Water + 0.05% TFA at 30 ml / min using a 14 minute 20-100% Acetonitrile / Water gradient. Product fractions were combined and concentrated under reduced pressure until most of the ACN had evaporated. The remaining solvent was transferred to a separation funnel and extracted with DCM (7 ml). The organic layer was washed with 4:1 water / saturated aqueous NaHCO3 (10 ml). The organic layer was dried over Na2SO4 and filtered. The aqueous layer was extracted with DCM (2 x 7 ml). Both extracts were sequentially used to extract the bicarb layer and wash the Na2SO4 and funnel. The combined filtrates were evaporated under reduced pressure and the resulting residue was dissolved in ACN (~12 ml), filtered, diluted with water (~6 ml), frozen, and lyophilized to afford compound 80. LCMS m / z (M+H) calculated 522.2, observed 522.2. BIOLOGICAL ASSAYS Qube®Ion Channel Automated Patch-Clamp Electrophysiology Experimental Procedure

[0354] 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. 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.

[0355] 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%.25863

[0356] 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. 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. IC50values 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); where IC50 = half maximal inhibitory concentration; Imin = minimal current; Imax = maximal current; h = Hill coefficient.

[0357] Table 13 depicts the activity levels of the compounds of Examples 1 through -80 with respect to their inhibition of the HCN1, HCN2, HCN3 and HCN4 isoforms. Table 13 Biological Activities of Example Compounds 1–80 Example # HCN1_ EC50 HCN2_ EC50 HCN4_ EC50 HCN3_ EC50 (nM) (nM) (nM) (nM)25863 Example # HCN1_ EC50 HCN2_ EC50 HCN4_ EC50 HCN3_ EC50 (nM) (nM) (nM) (nM) 18402 171 1710 26025863 Example # HCN1_ EC50 HCN2_ EC50 HCN4_ EC50 HCN3_ EC50 (nM) (nM) (nM) (nM) 64659 126 3167 359

Claims

25863 WHAT IS CLAIMED IS:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein (I) wherein: 1each R R2is hydrogen or C1-6alkyl; R3is hydrogen or C1-6alkyl; each Rbindependently is hydrogen or C1-4alkyl; R4is selected from phenyl, 2,3-dihydro-1H-indenyl, pyridyl, quinolinyl, isoquinolinyl, naphthalenyl, indazolyl, pyrimidyl, benzo[d]imidazolyl, pyrazinyl, and pyridazinyl; wherein R4is substituted by 0, 1, or 2 R5substituents;each R5independently is selected from (1) halogen, (2) cyano (3) -SO2(C1-4alkyl), (4) -SO2NH2, (5) SO2NH(C1-4alkyl), (6) –(C1-6alkyl)OH (7) C1-6alkyl, (8) C1-6fluoroalkyl, (9) (C1-6alkyloxy(C0-4alkyl), (10) (C1-6fluoroalkyloxy(C0-4alkyl), (11) (C3-12cycloalkyl)oxy(C0-4alkyl), (12) (heterocycloalkyl)oxy(C0-4alkyl), (13) (C3-12cycloalkyl)carbonyl(C0-4alkyl), (14) (heterocycloalkyl)carbonyl(C0-4alkyl),25863 (15) (C1-6alkyl) carbonylamino(C0-4alkyl), (16) (C0-6alkyl)0-2aminocarbonyl(C0-4alkyl), (17) (C3-12cycloalkyl)(C0-4alkyl) and (18) (heterocycloalkyl)(C0-4alkyl), wherein each R5is independently substituted by 0, 1, 2, 3 or 4 R5a; R5aindependently is (1) halogen, (2) hydroxy, (3) C1-6alkyl (4) C1-6fluoroalkyl (5) amino, (6) cyano, (7) =O, (8) C1-6alkoxy, (9) (C3-6cycloalkyl)carbonyl, (10) (heterocycloalkyl)carbonyl, (11) (C1-6alkyl)oxycarbonyl, (12) (C1-6alkyl)carbonyl, (13) (C0-6alkyl)aminocarbonyl, (14) (C0-6alkyl)carbonylamino, (15) (C0-6alkyl)oxycarbonylamino, (16) –(O-C1-6alkyl)m, (17) (C3-6cycloalkyl)-O-(C=O)-, (18) (heterocycloalkyl)-O-(C=O)-, (19) (C3-6cycloalkyl)-O-(C=O)-, and (20) –(C1-6alkyl)OH, wherein R5ais substituted by 0, 1, 2, or 3 R5b; R5bis hydroxy, (C1-4alkoxy), or halogen; W is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, thiadiazolyl, and isothiazolyl; B is O or S n is 0 or 1; z is 0, 1, 2, or 3; and m is 1, 2, or 3.25863 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, 2,2-dimethylbutyl, pent-3yl, (2-ethyl)butyl, fluoro, chloro, bromo, methoxy, ethoxy, or propoxy.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, pentyl, neopentyl, 2,2- dimethylbutyl, pent-3yl, or (2-ethyl)butyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R3ishydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, pentyl, neopentyl, 2,2- dimethylbutyl, pent-3yl, or (2-ethyl)butyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl, 2,3-dihydro-1H-indenyl, pyridyl, quinolinyl, isoquinolinyl, naphthalenyl, indazolyl, pyrimidyl, benzo[d]imidazolyl, pyrazinyl, or pyridazinyl; wherein R4 is substituted by 0, 1, or 2 R5 substituents.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein each R5 substituent independently is selected from halogen, cyano -SO2(C1-4alkyl), -SO2NH2, SO2NH(C1-4alkyl), –(C1-6alkyl)OH, C1-6alkyl, C1-4fluoroalkyl, (C1-4alkyloxy(C0-4alkyl), (C1-4fluoroalkyloxy(C0-4alkyl), (C3-6cycloalkyl)oxy(C0-4alkyl), (heterocycloalkyl)oxy(C0-4alkyl), (C3-6cycloalkyl)carbonyl(C0-4alkyl), (heterocycloalkyl)carbonyl(C0-4alkyl), (C1-6alkyl) carbonylamino(C0-4alkyl), (C0-6alkyl)0-2aminocarbonyl(C0-4alkyl), (C3-6cycloalkyl)(C0-4alkyl) and(heterocycloalkyl)(C0-4alkyl), wherein each R5independently is substituted by 0, 1, 2, 3 or 4R5a.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein eachR5asubstituent independently is selected from chloro, fluoro, hydroxy, methyl, ethyl, propyl,isopropyl, butyl, trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, amino, =O, methoxy, ethoxy, propoxy, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, piperidinycarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, oxazolidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, (tert- butyl)oxycarbonyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,25863 butylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, (C0-6alkyl)carbonylamino, –(O-C1-6alkyl)m, cyclopropyl-O-(C=O)-, cyclobutyl-O-(C=O)-,cyclopentyl-O-(C=O)-, hydroxymethyl, and hydroxyethyl, wherein each R5aindependently issubstituted by 0, 1, 2, 3 or 4 R5b.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, whereineach R5bsubstituent independently is fluoro, chloro, hydoxy, methoxy, or ethoxy.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein W is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, and 1,2,3-thiadiazolyl.

10. The compound of claim 1 selected from the group consisting of N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (R)-N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (S)-N-phenyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(thiazol-2- yl)pyrrolidine-1-carboxamide; N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(5-chloro-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide;25863 N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(2-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; 3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (R)-3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (S)-3-(3-chloro-4-methylphenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carboxamide; (3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; (R)-(3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; (S)-(3-(4-chlorophenyl)-N-(2,5-dimethoxyphenyl)-3-(thiazol-2-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide;25863 N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carboxamide; (R)-N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-N-(2,3-dihydro-1H-inden-5-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-methoxy-5-(methylsulfonyl)phenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide;25863 (S)-3-(3-fluoro-4-methylphenyl)-N-(6-methoxyquinolin-8-yl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (S)-N-(6-cyclopropyl-3-methoxypyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(methylsulfonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 (R)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-((R or S)-1-acetamido-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-(hydroxymethyl)-2-methoxyphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-(3,3-difluorocyclobutoxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-(difluoromethoxy)-5-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 tert-butyl-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; tert-butyl (R)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; tert-butyl (S)-6-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate; N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5-(difluoromethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(trans-3-(methylcarbamoyl)cyclobutoxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; Cyclopropyl-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate; Cyclopropyl (R)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate; Cyclopropyl (S)-3-(4-(difluoromethyl)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamido)phenoxy)azetidine-1-carboxylate; N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 (S)-N-(5-(difluoromethyl)-2-((1-(4,4-difluoropiperidine-1-carbonyl)azetidin-3-yl)oxy)phenyl)-3- (3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyclopropyl-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyano-5-(difluoromethyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((3-hydroxyazetidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(2-oxooxazolidin-3-yl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide;25863 (R)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide; (S)-5-cyclopropyl-3-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpicolinamide; 6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; (R)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; (S)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylnicotinamide; 6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; (R)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; (S)-6-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-(2-hydroxyethyl)nicotinamide; 4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; (R)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; (S)-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamido)-N,6- dimethylnicotinamide; 2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide; (R)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide; (S)-2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamido)-4- methoxy-N-methylbenzamide; 3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 tert-butyl-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; tert-butyl (R)-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; tert-butyl (S)-(1-(2-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-4-methoxybenzoyl)azetidin-3-yl)carbamate; 2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; (R)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; (S)-2-cyclopropyl-4-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carboxamido)-N-methylpyrimidine-5-carboxamide; N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(N-methylsulfamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(methylcarbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3-fluoro- 4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 (S)-N-(5-(difluoromethyl)-2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-3-(3- fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-(difluoromethyl)-2-((2-hydroxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)- 3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; 3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4-thiadiazol- 5-yl)pyrrolidine-1-carboxamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(5-methoxy-2-(N-methylsulfamoyl)phenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(2-cyclopropyl-5-(N-methylsulfamoyl)pyridin-4-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(6-cyclopropyl-3-(N-methylsulfamoyl)pyridin-2-yl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide;25863 (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(thiazol-2-yl)pyrrolidine-1- carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyrazin-2-yl)pyrrolidine-1- carbothioamide; N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; (64) (R)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; (S)-N-(5-(difluoromethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidine-1-carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(pyridin-2-yl)pyrrolidine-1- carbothioamide; N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1- carbothioamide; (R)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carbothioamide; (S)-N-(2,5-dimethoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine- 1-carbothioamide; 3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (R)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (S)-3-(3-fluoro-4-methylphenyl)-N-(2-(3-hydroxyazetidine-1-carbonyl)-5-methoxyphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide;25863 N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (R)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (S)-N-(5-((R or S)-1-amino-2,2,2-trifluoroethyl)-2-methoxyphenyl)-3-(3-fluoro-4- methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidine-1-carbothioamide; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol-3- yl)methanone; (R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol- 3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(5-methyl-1H-indazol- 3-yl)methanone; (1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin- 1-yl)methanone; (R)-(1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidin-1-yl)methanone; (S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5- yl)pyrrolidin-1-yl)methanone; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-hydroxy-2- methylpropyl)-5-methyl-1H-indazol-3-yl)methanone; (3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone; (R)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone; (S)-(3-(3-fluoro-4-methylphenyl)-3-(1,2,4-thiadiazol-5-yl)pyrrolidin-1-yl)(1-(2-methoxyethyl)-5- methyl-1H-indazol-3-yl)methanone; N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2-yl)pyrrolidine-1- carboxamide; (2R)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide;25863 (2S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; (4R)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; (4S)-N-(2,5-dimethoxyphenyl)-4-(3-fluoro-4-methylphenyl)-2-methyl-4-(thiazol-2- yl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3R)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (4R)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (4S)-N-(2,5-dimethoxyphenyl)-4-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (2R)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (2S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3R)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (3S)-N-(2,5-dimethoxyphenyl)-2-methyl-3-(thiazol-2-yl)-3-(p-tolyl)pyrrolidine-1-carboxamide; (5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (R)-(5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (S)-(5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (R)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (S)-(1,5-dimethyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin-1-yl)methanone; (1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p-tolyl)piperidin- 1-yl)methanone; (R)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone; (S)-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-indazol-3-yl)(3-(pyridin-2-yl)-3-(p- tolyl)piperidin-1-yl)methanone; N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3-(1,2,4- thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (S)-N-(5-cyclopropyl-2-((2-methoxyethyl)carbamoyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide;25863 N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; (R)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide; and (S)-N-(5-cyclopropyl-2-(3-hydroxyazetidine-1-carbonyl)phenyl)-3-(3-fluoro-4-methylphenyl)-3- (1,2,4-thiadiazol-5-yl)pyrrolidine-1-carboxamide, 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 HCN1 / 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 HCN1 / 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), idiopathic small fiber neuropathy, 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.25863 17. Use of a compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof for treating pain and other HCN1 / HCN2-driven is at least one are selected fromdisorders.

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), idiopathic small fiber neuropathy, 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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