Indazole derivatives useful as HCN1 / HCN 2 modulators

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, that 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

25958INDAZOLE DERIVATIVES USEFUL AS HCN1 / HCN 2 MODULATORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 693,788, filed September 12, 2024, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to certain indazole 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 (Ap, AS and C fibers) and central neurons. The damage to the somatosensory system results in disorderly transmission of sensory signals to the brain and triggers the generation of pain. Symptoms of neuropathic pain include abnormal sensation of painful and other stimuli, known as dysesthesia (e.g., hyperesthesia, hyperalgesia, allodynia (pain due to a non-noxious stimulus), and hyperpathia) and / or ongoing pain, typically sensed as deep and aching pain. NP is often long-lasting and typically persists after apparent resolution of the primary cause.

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

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

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

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

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

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

[0013] The HCN isoforms perform an important pacemaker function in both cardiac and nervous tissue. HCN4 is considered the major regulator of cardiac rhythmicity. Inducible deletion of cardiac HCN4 causes a progressive decrease in heart rate which is fatal in mice after a few days (Baruscotti et al., "Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene HCN4"; Proc. Natl. Acad. Sci. USA 108, 2011, 1705- 1710). 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 findings suggest that peripherally restricted blockers of HCN ion channels would provide a new class of analgesics. (Young et al., "Inflammatory and neuropathic pain are rapidly suppressed by25958 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 -60m V. 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 Ihcurrent 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 associatedwith 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).There are no drug therapies currently approved by the FDA for the treatment of tinnitus and there is, therefore, an unmet medical need for an effective treatment of the condition. It has been found that HCN2 inhibitors can be effective in the treatment of tinnitus. McNaughton, P. et al., has shown that the peripherally restricted HCN blocker, ivabradine and peripherally restricted HCN2 inhibitors provide an effective treatment for tinnitus in an in-vivo model for the condition (See, WO 2022 / 185058).SUMMARY OF THE DISCLOSURE

[0025] 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.

[0026] 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), postoperative 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.

[0027] 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.

[0028] In one aspect, the present disclosure provides compounds of Formula (I)and their pharmaceutically acceptable salts.25958

[0029] 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 INVENTIONCompounds of the Disclosure

[0030] In one embodiment, the present disclosure provides a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof:wherein:Rhs hydrogen, Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci- 4fluoroalkyl, and hydroxy; orR2is Ci-ealkyl, Ci-ealkenyl, C4-6cycloalkyl, 5-10 membered heterocycloalkyl, aryl, or heteroaryl; provided that when R’is H, then R2is not substituted or unsubstitutedwherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; each R3, R4, R5, and R6independently is hydrogen, halo, methyl or CF3; each Ra, Rb, Rc, and Rdis H; orRaand Rctaken together with the atoms to which they are attached form a five membered ring and each Rband Rdis H;n is 0 or 1; p is 0, 1, or 2; and r is 0, 1, or 2 z is 0 or 1.

[0031] In a first embodiment of the invention, RHs Cs-ecycloalkyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci-4fhioroalkyl, and hydroxy, and the other groups are as provided in the general Formula (I) above.

[0032] In a second embodiment of the invention, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l. l.l]pentanyl, spiro[2.3]hexyl, or spiro[2.2]pentyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci-4fhioroalkyl, and hydroxy, and the other groups are as provided in the general Formula (I) above.

[0033] In a third embodiment of the invention Rhs Cs-ecycloalkyl, aryl, or heterocycloalkyl having 5 to 10 ring atoms, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of fluoro, -CH2F, -CHF2, -CFsand hydroxy, and the other groups are as provided in the general Formula (I) above or as in the first through second embodiments.above.

[0035] In a fifth embodiment of the invention, R1isthe other groups are as provided in the generalFormula (I) above.

[0036] In a sixth embodiment of the invention, R2is phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, thiophenyl, pyrimidinyl, tetrahydroquinolinyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3, and the other groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0037] In a seventh embodiment of the invention, R2is / / -propyl, phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, or thiophenyl, and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3, and the other groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0038] In an eighth embodiment, R2is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl and wherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3, and the other groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0039] In a ninth embodiment, R2is substituted by 1, 2, or 3 substituents selected from the group consisting of halo, methyl, and cyano, and the other groups are as provided in the general Formula (I) above or as in the first through eighth embodiments.

[0040] In a tenth embodiment of the invention, R2is -CH2CH2CF3, -CHCH2,groups are as provided in the general Formula (I) above or as in the first through fifth embodiments.

[0041] In an eleventh embodiment of the invention, each R3, R4, R5, and R6independently is hydrogen, methyl or fluoro, and the other groups are as provided in the general Formula (I) above or as in the first through ninth embodiments.

[0042] In a twelfth embodiment of the invention, n is i and Raand Rctaken together with the atoms to which they are attached form a five membered ring and Rband Rdare each H, and the other groups are as provided in the general Formula (I) above, or as in the first through tenth embodiments.

[0043] In a thirteenth embodiment of the invention, Raand Rbare each H, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0044] In a fourteenth 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 twelfth embodiments.

[0045] In a fifteenth embodiment of the invention, n is i and Rcand Rdare each H, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0046] In a sixteenth embodiment of the invention, if Rfis H, then R2is not substituted or unsubstituted pyridyl, and the other groups are as provided in the general Formula (I) above, or as in the first through eleventh embodiments.

[0047] In a seventeenth embodiment of the invention, if R’is H, then R2is not substituted or unsubstituted aryl and R2is not substituted or unsubstituted heteroaryl, and the other groups are as provided in the general Formula (I) above, or as in the first through eleventh embodiments.

[0048] In an eighteenth embodiment of the invention, the present disclosure provides a compound having structural formula II:25958wherein:RHs hydrogen, Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci- 4fluoroalkyl, and hydroxy; orRHsR2is Ci-ealkyl, Ci-ealkenyl, C4-6cycloalkyl, 5 to 10 membered heterocycloalkyl, aryl, or heteroaryl, provided that when R’is H, then R2is not substituted or unsubstitutedwherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; each R3, R4, R5, and R6independently is hydrogen or halo;p is 0, 1, or 2; r is 0, 1, or 2; and z is 0 or 1.

[0049] In a nineteenth embodiment of the invention, the present disclosure provides a compound having structural formula III:25958wherein:Rhs hydrogen, Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen or Ci- 4fluoroalkyl, and hydroxy; orRHsR2is Ci-6 alkyl, Ci-ealkenyl, C4-6 cycloalkyl, 5 to 10 membered heterocycloalkyl, aryl, or heteroaryl, provided that when R1is H, then R2is not substituted or unsubstitutedwherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; each R3, R4, R5, and R6independently is hydrogen or halo; and p is 0 or 1.

[0050] In a twentieth embodiment of the invention, R1is C3-6 cycloalkyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci-4fluoroalkyl, and hydroxy, and the other groups are as provided in either the general Formula (II) above or the general Formula (III) above (that is, as in the eighteenth, or nineteenth embodiment).

[0051] In a twentieth-first embodiment of the invention, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l. l]pentanyl, spiro[2.3]hexyl, or spiro[2.2]pentyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci- 4fluoroalkyl, and hydroxy, and the other groups are as provided in the eighteenth, or nineteenth embodiment.

[0052] In a twentieth-second embodiment of the invention R1is Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, and R1is substituted by 0, 1 or 2 substituents selected from the25958 group consisting of fluoro, -CF, -CF2, -CF3 and hydroxy, and the other groups are as provided in the eighteenth through twentieth-first embodiment., , and the other groups are as provided in the eighteenth, or nineteenth embodiment.

[0054] In a twenty -fourth embodiment of the invention, R1is, and the other groups are as provided in the eighteenth, or nineteenth embodiment.

[0055] In a twenty -fifth embodiment of the invention, R2is phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, thiophenyl, pyrimidinyl, tetrahydroquinolinyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl, and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3, and the other groups are as provided in the eighteenth through twentieth-third embodiment.

[0056] In a twenty-sixth embodiment of the invention, R2is phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, or thiophenyl, and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3, and the other groups are as provided in the eighteenth through twentieth-third embodiment.

[0057] In a twenty-seventh embodiment, R2is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl and wherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -25958OCF3, and the other groups are as provided in the eighteenth through twentieth-third embodiment.

[0058] In a twenty-eighth embodiment, wherein R2is substituted by 1 or 2 substituents selected from the group consisting of halo, methyl, and cyano, and the other groups are as provided in provided in the eighteenth through twentieth-seventh embodiment.

[0059] In a twenty -ninth embodiment of the invention, R2is -CH2CH2CF3,groups are as provided in the eighteenth through twentieth-fourth embodiment.

[0060] In a thirtieth embodiment of the invention, each R3, R4, R5, and R6independently is hydrogen, methyl or fluoro, and the other groups are as provided in the eighteenth through twenty-ninth embodiment.

[0061] In a thirtieth-first embodiment of the invention, if R1is H, then R2is not substituted or unsubstituted pyridyl, and the other groups are as provided in the eighteenth through thirtieth embodiment.

[0062] In a thirtieth-second embodiment of the invention, if RHs H, then R2is not substituted or unsubstituted aryl and R2is not substituted or unsubstituted heteroaryl, and the other groups are as provided in eighteenth through thirtieth-first embodiment.

[0063] In a thirtieth-third embodiment of the invention, the compound is selected from the group consisting of:25958 l-(3-(lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine;1 -(2-(3 -phenylpyrrolidin-2-yl)pyri din-3 -yl)- IH-indazole;3-cyclopropyl-l-(2-(3-(5-fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin-3-yl)-lH-indazole; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan-l -amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(thi ophen-2 -yl)ethan-l -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(4-fluorophenyl)ethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-3 -(benzyloxy)propan- 1 -amine;3-(2-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-aminoethyl)benzonitrile; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lH-pyrazol-l-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(oxazol-2-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylisoxazol-3-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylisothiazol-3-yl)ethanamine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-phenylethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-cyclobutylethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-cyclohexylethan- 1 -amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethan-l-amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-3 -((2,3 -dihydrobenzofb] [ 1 ,4]dioxin-5-yl)oxy)propan- 1 - amine; l-(3-(lH-indazol-l-yl) pyridin-2-yl)-2-(2,4-difluorophenyl) ethanamine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3 -methylpiperidin- 1 -yl)ethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-4,4-difluoro-2-methylpiperidin- 1 -yl)ethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)ethan- 1 -amine;1 -(3 -( 1 H-indazol- 1 -yl)pyridin-2-yl)-2-(3 -fluorophenoxy)ethan- 1 -amine; l-(3-(lJH-indazol-l-yl)pyridin-2-yl)-7V2-methyl-7V2-(3,3,3-trifluoropropyl)ethane-l,2-diamine;1 -(3 -(3 -(2,3 -dihydrobenzofb] [ 1 , 4] di oxin-5 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;1 -(3 -(3 -phenyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3 -(3 -cyclobutyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine; l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethanamine; l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;259581 -(3 -(3 -cyclopentyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;1 -(3 -(3 -cyclohexyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3 -(3 -(bicyclof 1.1.1 ]pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(l-(2-((S)-l-amino-2-(pyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)-2,2,2-tri fluoroethanol; l-(3-(3-(2,2-difluorocyclopropyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(3,5-difluoropyridin-2- yl)ethanamine; l-(3-(3-(3-fluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3-(3 -cyclopropyl- lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine;( 1 S)- 1 -(3 -(3 -(3,3 -difluorocy cl opentyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)-2-(5 -fluoropyridin-2-yl)ethanamine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)ethanamine;6-(2-amino-2-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)ethyl)picolinonitrile; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine; l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine; l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol; l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;1 -( 1 -(2-( 1 -amino-2-(5 -fluoropyridin-2-yl)ethyl)pyri din-3 -yl)- 1 H-indazol -3 -yl)cy clobutan- 1 -ol ; l-(3-(3-cyclobutyl-4-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lH-indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol;1 -(1 -(2-( 1 -amino-2-cy cl obutylethyl)pyri din-3 -yl)- lH-indazol-3 -yl)-2,2,2-trifluoroethan- 1 -ol;1 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl)cy cl opropyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethan- 1 -amine;259581 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl) cyclobutyl)- IH-indazol- 1 -yl) pyridin-2-yl)-2-(5- fluoropyridin-2-yl) ethan-1 -amine;1-(3-(4-fluoro-3-(spiro[2.3]hexan-5-yl)-lH-indazol-l-ylpyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;1 -(3 -(4-fluoro-3 -(spiro [2.2] pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;2-(5-fluoropyridin-2-yl)-l-(3-(3-(3-(trifluoromethyl) cyclobutyl)-lH-indazol-l-yl) pyridin-2-yl) ethan-1 -amine; l-(3-(3-(3-(difluoromethyl)cyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethan-l- amine;1-(3-(3-cyclobutyl-4,7-difluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine 2,2,2-trifluoroacetate;2-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lH-indazol-3-yl)-l,l,l- trifluoropropan-2-ol; l-(3-(3-(3,3-difluorocyclobutyl)-4-methyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine; l-(3-(3-cyclobutyl-4-methyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-4-fluoro-lH-indazol-3-yl)-2,2- difluoroethan-l-ol; and1 -(3 -(3 -cyclobutyl- IH-indazol- 1 -yl)-5-methylpyri din-2-yl)-2-(pyri din-2 -yl)ethan- 1 -amine.

[0064] In a thirtieth-fourth embodiment of the invention, the compound is selected from the group consisting of:(lS)-(3-(lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine;(5)- 1 -(3 -(3 -(2,3 -dihydrobenzo[b] [ 1 , 4] di oxin-5 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;(S)-l-(3-(3-phenyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)- 1 -(3 -(3 -cyclopropyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8- yl)methanamine;(S)-l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-l-(3-(3-cyclopentyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-l-(3-(3-cyclohexyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;25958(S)- 1 -(3 -(3 -(bicyclof 1.1.1 ]pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyri din-2 - yl)ethanamine;(S)-l-(3-(3-(3-fluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;( 1 S)- 1 -(3 -(3 -(3,3 -difluorocyclopentyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;(S)-l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; and(S)-l-(3-(3-(3-(difluoromethyl)cyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethan- 1 -amine.

[0065] In a thirtieth-fifth embodiment of the invention, the compound is selected from the group consisting of:(R)- 1 -(3 -( IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan- 1 -amine;(5)- 1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan- 1 -amine;(R)- 1 -(3 -( I / / -i ndazol - 1 -y l)pyridin-2-yl)-2-(thiazol -2-yl)ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-(oxazol-2-yl)ethanamine;(R)- 1 -(3 -( I / / -i ndazol - 1 -y l)pyridin-2-yl)-2-(oxazol -2-yl)ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-(4-methylisoxazol-3 -yl)ethanamine;(R)- 1 -(3 -( 1 / 7-indazol - 1 -y l)pyridin-2-yl)-2-(4-methyli soxazol -3 -yl)ethanamine;(R)- 1 -(3 -( 1 / 7-indazol - 1 -y l)pyridin-2-yl)-2-(4-methyli sothiazol-3 -yl)ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-(4-methylisothiazol-3 -yl)ethanamine;(7?)-l-(3-(lH-indazol-l-yl) pyridin-2-yl)-2-(2,4-difluorophenyl) ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl) pyridin-2-yl)-2-(2,4-difluorophenyl) ethanamine;(5)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3 -methylpiperidin- 1 -yl)ethan- 1 - amine hydrochloride;(R)- 1 -(3 -( I / / -i ndazol - 1 -y l)pyridin-2-yl)-2-((S)-4,4-difluoro-3 -methylpiperi din- 1 -yl)ethan- 1 - amine hydrochloride;(5)- 1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(5)-(4,4-difluoro-2-methylpiperidin- 1 -yl)ethan- 1 - amine hydrochloride;(7?)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2- R)-(4,4-difhroro-2-methylpiperidin-l-yl)ethan-l- amine hydrochloride;(5)- 1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(7?)-(4,4-difluoro-2-methylpiperidin- 1 -yl)ethan- 1 - amine hydrochloride;(7?)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5)-(4,4-difluoro-2-methylpiperidin-l-yl)ethan-l- amine hydrochloride;25958(S)- 1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(S)-(3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 - amine hydrochloride;(R)- 1 -(3 -( IH-indazol- 1 -yl)pyridin-2-yl)-2-(7?)-(3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 - amine hydrochloride;(S)- 1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-2-(7?)-(3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 - amine hydrochloride;(R)- 1 -(3 -( IH-indazol- 1 -yl)pyridin-2-yl)-2-(S)-(3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 - amine hydrochloride;($)- 1 -(3 -(1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-((5)-3 -(trifluoromethoxy)pyrrolidin- 1 -yl)ethan- 1 - amine;(R)- 1 -(3 -( 17 / -i ndazol - 1 -y l)pyridin-2-yl)-2-((7?)-3 -(trifluoromethoxy)pyrrolidin- 1 -yl)ethan- 1 - amine;($)- 1 -(3 -( 1 / 7-indazol- 1 -yl)pyridin-2-yl)-2-((7?)-3 -(trifluorom ethoxy )pyrroli din- 1 -yl)ethan- 1 - amine;(R)- 1 -(3 -( 17 / -i ndazol - 1 -y l)pyridin-2-yl)-2-((5)-3 -(trifluorom ethoxy )pyrrolidin- 1 -yl)ethan- 1 - amine;(S)- 1 -(3 -( 1 / 7-indazol- 1 -yl)pyri din-2 -yl)-2-(3 -fluorophenoxy)ethan- 1 -amine, 2,2,2- trifluoroacetate;(S)- 1 -(3 -( 1 / 7-indazol- 1 -yl)pyri din-2 -yl)-2-(3 -fluorophenoxy)ethan- 1 -amine, 2,2,2- trifluoroacetate;(5)-l-(3-(lJH-indazol-l-yl)pyridin-2-yl)-7V2-methyl-7V2-(3,3,3-trifluoropropyl)ethane-l,2-diamine 2,2,2-trifluoroacetate;(R)- 1 -(3 -( 1 / 7-indazol - 1 -y l)pyridin-2-yl)-7V2-methyl -Rp-(3,3, 3 -trifluoropropyl)ethane- 1 ,2-di amine 2,2,2-trifluoroacetate;(5)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)((5)-5,6,7,8-tetrahydroquinolin-8- yl)methanamine;(5)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)((7?)-5,6,7,8-tetrahydroquinolin-8- yl)methanamine;(5)-l-(3-(3-cyclobutyl-U / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;(7?)-l-(3-(3-cyclobutyl-U / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;(5)- 1 -(3 -(3 -cyclopropyl- 17 / -i ndazol - 1 -yl)pyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine;(7?)-l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine;(5)- 1 -(3 -(3 -cyclopropyl- 17 / -i ndazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine;(R)- 1 -(3 -(3 -cyclopropyl - 17 / -i ndazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine;25958(7?)-l-(3-(3-cyclopropyl-l#-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine2,2,2-trifluoroacetate;(5)-l-(3-(3-cyclopropyl-l#-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine2,2,2-trifluoroacetate;(5)- 1 -(3 -(3 -cyclopropyl- 1 / / -i ndazol - 1 -yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine;( / ?)-! -(3-(3-cyclopropyl- l / / -indazol- l-yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine;(7?)-l-(3-(3-(3,3-difluorocyclobutyl)-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;(5)- 1 -(3 -(3 -(3 ,3 -difluorocyclobutyl)- lJ7-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan- 1 -amine;(5)-l-(3-(3-cyclobutyl-5-fluoro-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethanamine;(R)- 1 -(3 -(3 -cyclobutyl -5 -fluoro- I / / -i ndazol - 1 -yl)pyridin-2-yl)-2-(5 -fluoropyridin-2- yl)ethanamine;(S)- 1 -(1 -(2-( 1 -amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3 -yl)- lJ7-indazol-3 -yl)cyclobutan- 1 - ol;(R)- 1 -( 1 -(2-( 1 -amino-2-(5 -fluoropyridin-2-yl)ethyl)pyri din-3 -yl)- lJ7-indazol -3 -yl)cy clobutan- 1 - ol;(5)- 1 -(3 -(3 -cyclobutyl-4-fluoro- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan- 1 - amine;(7?)-l-(3-(3-cyclobutyl-4-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine;(R)- 1 -(3 -(4-fluoro-3 -( 1 -(trifluoromethyl)cy clopropyl)- lJ7-indazol - 1 -yl)pyridin-2-yl)-2-(5 - fluoropyridin-2-yl)ethan- 1 -amine;(5)- 1 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl)cy clopropyl)- I / / -i ndazol - 1 -yl)pyri din-2-yl)-2-(5 - fluoropyridin-2-yl)ethan- 1 -amine;(R)- 1 -(3 -(4-fluoro-3 -( 1 -(trifluoromethyl) cyclobutyl)- lJ7-indazol - 1 -yl) pyri din-2-yl)-2-(5 - fluoropyridin-2-yl) ethan-1 -amine;(5)- 1 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl) cyclobutyl)- 1 / / -i ndazol - 1 -yl) pyridin-2-yl)-2-(5- fluoropyridin-2-yl) ethan-1 -amine;(R)- 1 -(3 -(4-fluoro-3 -(spiro[2.3 ]hexan-5-yl)- lJ7-indazol- 1 -ylpyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;(5)-l-(3-(4-fluoro-3-(spiro[2.3]hexan-5-yl)-lJH-indazol-l-ylpyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;25958(S)-l-(3-(3-cyclobutyl-lH-indazol-l-yl)-5-methylpyridin-2-yl)-2-(pyridin-2-yl)ethan-l -amine2.2.2-trifluoroacetate and(R)- 1 -(3 -(3 -cyclobutyl- IH-indazol- 1 -yl)-5-methylpyridin-2-yl)-2-(pyridin-2-yl)ethan- 1 -amine2.2.2-trifluoroacetate.

[0066] In a thirtieth-sixth embodiment of the invention, the salt is a 2,2,2-trifluoroacetate salt and the other groups are as provided in the second through thirtieth-fifth embodiments.

[0067] Further provided is a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0068] Further provided is a method of treating pain and other HCNl / HCN2-driven diseases comprising administering a therapeutically effective amount a compound of the disclosure or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said pain and other HCNl / HCN2-driven diseases is at least one are selected from inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) and psychiatric disorders.

[0069] In an embodiment, 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.

[0070] In an embodiment, 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.

[0071] In an embodiment, the effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0072] Further provided is the use of a compound of the disclosure or a pharmaceutically acceptable salt thereof in therapy.

[0073] Further provided is the use of a compound of the disclosure or a pharmaceutically acceptable salt thereof for treating pain and other HCNl / HCN2-driven disease selected from at least one of inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) and psychiatric disorders.

[0074] In an embodiment, said inflammatory pain and neuropathic pain is selected from at least one of infection pain, osteoarthritis, rheumatoid arthritis, post-operative pain, dental pain, and25958 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.

[0075] In an embodiment, 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.

[0076] Non-limiting examples of the Compounds of Formula I include compounds 1 through 75 or pharmaceutically acceptable salts thereof, as set forth in the Examples.Definitions

[0077] 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.

[0078] 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). In embodiments, the disclosed compounds of Formula (II) and Formula (III) are included in any reference to 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.25958

[0079] The term “Co” or “CO” or “Co” as employed in expressions such as “Co-6 alkyl” and “Co-6 alkyl” means a direct covalent bond; or when the term appears at the terminus of a substituent, Co-6 alkyl means hydrogen or Ci-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 adjacent thereto are connected directly by a bond. For example, in the structurewherein s is an integer equal to zero, 1 or 2, the structure iswhen s is zero.

[0080] The term “alkyl”, as well as other groups having the prefix “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 group contains from 1 to 6 carbon atoms (Ci-6 alkyl) or from about 1 to about 4 carbon atoms (C1-C4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, w-propyl, isopropyl, / / -butyl, ec-butyl, isobutyl, tert-butyl, w-pentyl, neopentyl, isopentyl, w-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 (and any other group recited herein) is unsubstituted.

[0081] "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined.Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2- butenyl, 2-methyl-2-butenyl, and the like.

[0082] “Amino” means a -NH2 group.

[0083] “Aminocarbonyl” means -C(=O)NH2.

[0084] “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-).

[0085] “ Celite®” (Honeywell Fluka™) diatomite is diatomaceous earth and can be referred to as "celite".

[0086] “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.

[0087] “Carbonyl” means a functional group composed of a carbon atom double-bonded to an oxygen atom (C=O).25958

[0088] “Carbonylamino” means -NHC(=O)H.

[0089] “Cycloalkyl” or “C3.12 cycloalkyl” means any univalent non-aromatic radical derived from a monocyclic, bicyclic, tricyclic or tetracyclic ring system having 3 to 12 ring carbons atoms. These non-aromatic radicals, which have 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms may be fully saturated, or partially unsaturated. Unless stated specifically in the specification, the cycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Here, the point of attachment for a “cycloalkyl” to the 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., norbomyl).

[0090] 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[l. l.l]pentanyl, bicyclo[2.2.1]heptanyl, [l.l.l]-bicyclo pentane, bicyclo[3.1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.3]hexyl, spiro[2.2]pentyl, and norbomyl.

[0091] The term “C3-8 cycloalkyl” (or “C3-C8 cycloalkyl” or “C3.8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C3-7 cycloalkyl”, “C3-6 cycloalkyl”, “C5-7 cycloalkyl” and the like have analogous meanings.

[0092] “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.

[0093] “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).

[0094] 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 to10 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, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, 5-oxide (S=O) or 5-dioxide (SO2). One or more nitrogen atoms, if present, are optionally quatemized. 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).

[0095] 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.

[0096] 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, Z>eta-lactam, gamma-lactam, t / c7 / a-lactam, Ac / a-lactone, gamma-lactone, t / c7 / a-lactone, piperidinyl, 3-azabixyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 2,3-dihydro-U / -indenyl, dihydro- 177-indenyl, 3H- spiro[benzofuran-2’, 4’ -piperidinyl, 2,3-dihydro-17 / -pyrrolo[3,2,l-z / ][l,6]naphthyridinyl, 3, 4,6,7- tetrahydro-5J / -imidazo[4,5-c]pyridyl, 3a,5,6,6a-tetrahydro-4J / -pyrrolo[3,4-J]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridyl, hexahydro-27 / - pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, bicyclo[2,2,l]heptenyl, 2',3'-dihydro- 17 / -spiro[piperidine-4,4'-quinazolin], octahydropyrrolo[3,4-Z>][l,4]oxazinyl, (diazabicyclo[2.2. l]heptanyl), 2,5-diazabicyclo[2.2. l]heptanyl, tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, dihydro- 5J / -pyrrolo[3,4-J]thiazolyl, 4,6-dihydro-5J / -pyrrolo[3,4-J]thiazolyl, dihydro-5J / -pyrrolo[3,4- d]oxazolyl, 4,6-dihydro-5J / -pyrrolo[3,4-J]oxazolyl, dihydrothiazolo[5,4-c]pyridin-5(4J7)-yl, 6,7- dihydrothiazolo[5,4-c]pyridin-5(4J7)-yl, benzo[J]imidazolyl, U / -enzo[d]imidazolyl, diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and pyrrolidinone, and oxides thereofand all isomers thereof. In one embodiment of the invention, heterocycloalkyl rings include: piperidinyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, dihydrobenzyl, dioxinyl, and tetrahydroquinolinyl,

[0097] "Aryl" refers to an aromatic monocyclic or multicyclic ring moiety comprising 6 to 14 ring carbon atoms, or more specifically, 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl and naphthyl. Bonding can be through any of the carbon atoms of any ring.

[0098] “Heteroaryl” refers to an aromatic monocyclic or multicyclic ring moiety comprising ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from S, N, or O. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0099] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl group is a 5-14 membered heteroaryl.

[0100] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms25958 include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothi azolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroarylgroups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0101] The term “hydroxy” means -OH.

[0102] The term “oxo” means (=0).

[0103] The term “oxy” means an oxygen (O) atom.

[0104] The term “thio” means a sulfur (S) atom.

[0105] 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.

[0106] When any variable (e.g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, Formula II or Formula III, 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.

[0107] 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 Woxide.

[0108] 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.

[0109] 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.25958

[0110] 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.[OHl] 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.

[0112] 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.

[0113] 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 (2006), Wiley, New York.

[0114] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is preceded by the adjacent functionality toward the point of attachment. For example, a “(C1.5 alkyl)carbonylamino(Ci-6 alkyl)” substituent is equivalent to o-C^e alkyl-HN-''^C1.5alkyl .

[0115] Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “Me”, “-Me”, “CH3”, fl (1“-CH3” or using a straight line representing the presence of the methyl group, e.g., - ,•’ II III - CH3and | - i.e., « « have equivalent meanings.

[0116] For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where r is the integer 2, Rj is a defined variable, and Rj is a defined variable, the value of Rj may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it25958 occurs. For example, if Rj and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CRjRj)2 can

[0117] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For 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, Ci-6 or Ci-6 or Ci-Ce when used with a chain, for example an alkyl chains 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, Cs-Ce, and all other possible combinations.

[0118] 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.

[0119] 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.

[0120] When any variable (e.g., Rla) occurs more than one time in any constituent or in Formula (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., Rla, are to be chosen in conformity with well-known principles of chemical structure connectivity 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).25958

[0121] 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.

[0122] The wavy line -n-rLP5as used herein, indicates a point of attachment to the rest of the compound.

[0123] 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.

[0124] In the compounds of the disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well-known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0125] 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+, and Mg2+, and other cations such as A13+ 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,25958 diethylamine, triethylamine and ethylenediamine. When a compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable nontoxic 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.

[0126] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as, but not limited to, acetic acid or acetonitrile. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0127] 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.

[0128] 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.

[0129] “ 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.

[0130] “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.

[0131] 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 doctor25958 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

[0132] The dosage regimen utilizing a compound of the present disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an immunological condition, and a prophylactically effective amount, e.g., for prevention of an immunological condition.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, 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 most25958 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

[0133] 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.

[0134] Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of or desire treatment for an existing disease or medical condition or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of the disease or medical condition. As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0135] 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.

[0136] 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.

[0137] 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,25958 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.

[0138] 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). Non-limiting examples of NP include painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), pain associated with cancer, chemotherapy induced pain (chemotherapy -induced peripheral neuropathy), post-operative pain, trigeminal neuralgia, complex regional pain syndrome (CRPS), opioid resistant pain, pudendal neuralgia, neuropathic pain associated with lower back pain, sciatica, nerve damage following traumatic injury and carpal tunnel syndrome.

[0139] 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.

[0140] 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.

[0141] 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.25958

[0142] 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.

[0143] 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.

[0144] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0145] 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.

[0146] 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),25958 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.

[0147] Carriers are compounds and substances that improve and / or prolong the delivery of an active ingredient to a subject in the context of a pharmaceutical composition. Carriers may serve to prolong the in vivo activity of a drug or slow the release of the drug in a subject, using controlled-release technologies. Carriers may also decrease drug metabolism in a subject and / or reduce the toxicity of the drug. Carriers can also be used to target the delivery of the drug to particular cells or tissues in a subject. Common carriers (both hydrophilic and hydrophobic carriers) include fat emulsions, lipids, PEGylated phospholipids, PEGylated liposomes, PEGylated liposomes coated via a PEG spacer with a cyclic RGD peptide, liposomes and lipospheres, microspheres (including those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, protein-DNA complexes, protein conjugates, erythrocytes, vesicles, nanoparticles, and side chains for hydrocarbon stapling. The aforementioned carriers can also be used to increase cell membrane permeability of the compounds of Formula (I). In addition to their use in the pharmaceutical compositions of the present disclosure, carriers may also be used in compositions for other uses, such as research uses in vitro (e.g., for delivery to cultured cells) and / or in vivo.

[0148] 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 enzymes25958 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.

[0149] 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).

[0150] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

[0151] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0152] 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.

[0153] 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.

[0154] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0155] 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 include25958 water-for-inj ection, 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 Disclosure

[0156] 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.

[0157] In some embodiments, the present disclosure provides a method of treating pain and other HCNl / 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 HCNl / HCN2-driven pain is inflammatory pain. In some embodiments, the HCNl / HCN2-driven pain is neuropathic pain. In some embodiments, the HCNl / 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 HCNl / HCN2-driven disease is tinnitus. In some embodiments, the HCNl / HCN2-driven inflammatory pain disease is rheumatoid arthritis. In some embodiments, the HCNl / HCN2-driven pain disease is migraine. In some embodiments of the invention, the HCNl / 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.

[0158] In some embodiments, the present disclosure provides a method of treating an inflammatory pain, the method comprising administering a therapeutically effective amount a25958 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.

[0159] 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.

[0160] In some embodiments, the present disclosure provides a method of treating a chronic inflammatory pain, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a therapeutically effective amount a compound of the25958 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.

[0166] 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.

[0167] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.

[0168] 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 HCNl / HCN2-driven diseases selected from inflammatory pain, neuropathic pain, tinnitus, and migraine.

[0169] 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 HCNl / HCN2-driven CNS and psychiatric disorders selected from (CIAS), (EIEE), schizophrenia, autism (sensory sensitivity), and depression.

[0170] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCNl / HCN2-driven diseases selected from inflammatory pain.

[0171] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCNl / HCN2-driven diseases selected from neuropathic pain.

[0172] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCNl / HCN2-driven diseases that is tinnitus.

[0173] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating pain and other HCNl / HCN2-driven diseases that is migraine.Combination Therapies

[0174] 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.25958

[0175] 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 antiinflammatory 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

[0176] 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 mediumpressure 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, Nalorac 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).

[0177] Reverse phase chromatography was generally 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 lOmM 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.25958

[0178] SFC chiral resolution was carried out on a Sepiate Prep SFC 100 (Sepiatec GmBH, Berlin, Germany), Multi gram® 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).

[0179] 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) 2.7pm 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 Cl 8, (1.0 x 50 mm) 1.7 pm 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) 5pm, (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) 5pm 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.

[0180] Proton or 1H NMR was generally 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 (5) values are reported in delta (5) units, parts per million (ppm). Chemical shifts for 'H NMR spectra are given relative to signals for residual non-deuterated solvent (CDCh referenced at 5 7.26 ppm; DMSO d-6 referenced at 5259582.50 ppm and CD3OD referenced at 5 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).

[0181] 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.

[0182] 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.

[0183] 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 intended product. In the examples, chemical synthesis schemes are provided for reagents and intermediates which were not commercially available.AbbreviationsAbbreviations and acronyms employed herein include the following:25958Preparation of IntermediatesIntermediate- 1(AE)-N-((3-(lH-indazol-l-yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfmamide

[0184] Step 1 : To a solution of IJT-indazole (1 g, 8.46 mmol) in DMF (25 mL) was added sodium hydride (0.508 g, 12.70 mmol, 60% in mineral oil) at 0 °C under argon. After stirring for 30 min at 0 °C, ethyl 3 -fluoropicolinate (1.718 g, 10.16 mmol) was added into the mixture under argon. The resulting mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (2 x 80mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column, eluted with 0 ~ 20% ethyl acetate in petroleum ether to afford ethyl 3-(17 / -indazol-l-yl)picolinate. MS ESI calculated for C15H14N3O2 [M + H]+, 268.29, found 268.00.

[0185] Step 2: To a solution of ethyl 3-(17 / -indazol-l-yl)picolinate (1 g, 3.74 mmol) in DCM (15 mL) was added DIBAL-H (4.49 mL, 4.49 mmol, 1 M in DCM) at -65 °C under argon. The resulting mixture was stirred at -65 °C for 1 h and quenched with saturated aqueous NH4CI (40 mL). The mixture was extracted with DCM (3 x 120 mL), and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-(U / -indazol-l-yl)picolinaldehyde. MS ESI calculated for C13H10N3O [M + H]+, 224.24, found 224.10.

[0186] Step 3: To a mixture of 3-(17 / -indazol-l-yl)picolinaldehyde (800 mg, 3.58 mmol) in DCM (15 mL) were added cesium carbonate (1460 mg, 4.48 mmol) and (5)-2-methylpropane-2- sulfinamide (543 mg, 4.48 mmol) at ambient temperature under nitrogen. The reaction solution was stirred at 40 °C for 1 h and quenched with water (80 mL). The mixture was extracted with ethyl acetate (3 x 150 mL), and the combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under25958 reduced pressure, and the residue was purified by reverse column chromatography with the following conditions: Column, C18, 40 g, 19 x 150 mm; mobile phase: acetonitrile in Water (20 mmol / L ammonium bicarbonate), 2% ~ 70% in 35 min; Detector, UV 254 nm; to give (S,E)-N- ((3-(lJ7-indazol-l-yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. MS ESI calculated for Ci7Hi9N4OS[M + H]+, 327.12, found 327.05.Intermediate-2(S)-N-((S)- 1 -(3 -(3 -bromo- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane- 2-sulfinamide

[0187] Step 1 : To a mixture of 3-bromo-lJ / -indazole (20 g, 169 mmol) in DMF (350 mL) was added sodium hydride (60% in mineral oil, 10.16 g, 254 mmol) at 0 °C under argon atmosphere. After stirring for 0.5 h at 0 °C, ethyl 3 -fluoropicolinate (25.8 g, 152 mmol) was added into this mixture. The resulting mixture was stirred at room temperature for 10 min and heated to 70 °C for 16 h. The reaction was quenched with water (150 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column using a gradient of 0% - 20% ethyl acetate in petroleum ether to afford ethyl 3-(U / -indazol-l-yl)picolinate. MS ESI calculated for Ci5Hi3BrN3O2 [M + H]+, 346.18, 348.18, found 346.05, 348.05.

[0188] Step 2: To a mixture of ethyl 3-(17 / -indazol-l-yl)picolinate (19 g, 71.1 mmol) in dichloromethane (500 mL) was added diisobutylaluminum hydride (1 M in DCM, 85 mL, 85 mmol) at -75 °C under argon atmosphere. The mixture was stirred at -75 °C for 1.5 h. The reaction was quenched by 10% NaOH (85 mL), and additional water (85 mL) was added. The mixture was stirred at room temperature for about 30 min and extracted with DCM (10 x 250 mL). The combined organic layers were dried over Na2SO4and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0 ~ 20% EtOAc in DCM to afford the desired product 3-(3-bromo- U / -indazol-l-yl)picolinaldehyde. MS ESI calculated for CnELBrNsO [M + H]+, 301.99, 303.99 found 302.00, 304.00.

[0189] Step 3: To a mixture of 3-(3-bromo-17 / -indazol-l-yl)picolinaldehyde (13 g, 43.0 mmol) in DCM (300 mL) were added cesium carbonate (17.52 g, 53.8 mmol) and (5)-2-methylpropane- 2-sulfinamide (6.52 g, 53.8 mmol) at room temperature under nitrogen. The reaction solution was refluxed at 40 °C for 1 h. The resulting solution was diluted with water (500 mL), and the mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate25958 was concentrated in vacuum, and the residue was purified by silica gel column chromatography, eluting with 0 ~ 10% DCM in MeOH to give ( ,£)-7V-((3-(3-bromo-l / / -indazol-l-yl)pyridin-2- yl)methylene)-2-methylpropane-2-sulfinamide. MS ESI calculated for CnHisBrlS OS [M + H]+, 405.31, found 405.05.

[0190] Step 4: To a mixture of 2-methylpyridine (5.05 g, 54.3 mmol) in THF (250 mL) were added / / -BuLi (2.5 M in Hexane, 22.80 mL, 57.0 mmol) at -65 °C. After stirring for 30 min at - 65 °C, a solution of (5',£)-A-((3-(3-bromo-U / -indazol-l-yl)pyridin-2-yl)methylene)-2- methylpropane-2-sulfmamide (11 g, 27.1 mmol) in THF (20 mL) was added. Then the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting solution was diluted with water (50 mL), and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel column chromatography, eluting with 0 ~ 10% DCM in MeOH to give (5)-A-((5)-l-(3- (3-bromo-lZ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C23H25BrN5OS [M + H]+, 500.07, found 500.10.Intermediate-3(SJI)-N-((3 -(3 -cyclopropyl- UT-indazol- 1 -yl)pyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide

[0191] Step 1 : To a mixture of ethyl 3 -fluoropicolinate (1.497 g, 8.85 mmol) in DMF (20 mL) was added 3 -cyclopropyl -UT-indazole (1.4 g, 8.85 mmol) and cesium carbonate (8.65 g, 26.5 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate (3 x 400 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel column using a gradient of 25% EtOAc in PE to afford ethyl 3-(3- cyclopropyl-U7-indazol-l-yl)picolinate. MS ESI calculated for CisHisNsCL [M + H]+, 308.13, found 308.10.

[0192] Step 2: To a mixture of ethyl 3-(3-cyclopropyl-U / -indazol-l-yl)picolinate (624 mg, 2.030 mmol) in DCM (15 ml) was added diisobutylaluminum hydride (1 M in DMC, 0.2 mL, 2.030 mmol) at -78 °C under N2. The reaction was stirred at -78 °C for 1 h. and quenched with NaOH (1 M in H2O, 10 mL, 10 mmol). The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-(3-25958 cycl opropyl -1 / / -i ndazol -1 -yl )pi col i nal dehyde. MS ESI calculated for C16H14N3O [M + H]+, 264.11, found 264.22.

[0193] Step 3 : To a mixture of 3 -(3 -cyclopropyl- l / Z-indazol-l-yl)picolinaldehyde (250 mg, 0.950 mmol) in DCM (5 ml) were added cesium carbonate (371 mg, 1.139 mmol) and (5)-2- methylpropane-2-sulfmamide (138 mg, 1.139 mmol) at room temperature. The reaction was stirred at 40 °C for 16 h. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate (3 x 400 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel column using 26 % EtOAc in PE to afford (5,£)-A-((3 -(3 -cyclopropyl- IT / -indazol- l -yl)pyridine-2-yl)methylene)-2-methylpropane-2- sulfmamide. MS ESI calculated for C20H23N4OS [M + H]+, 367.15, found 367.20.Intermediate-4(M-l-(3-bromopyridin-2-yl)-2-(pyridinyl-2-yl)ethanamine

[0194] Step 1 : A mixture of 3-bromopicolinaldehyde (5 g, 26.9 mmol), (5)-2-methylpropane-2- sulfinamide (3.91 g, 32.3 mmol) and CS2CO3 (10.51 g, 32.3 mmol) in DMF (50 mL) under N2 atmosphere was stirred at 40 °C for 16 h. LCMS showed major was product. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (6 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column with a gradient of ethyl acetate: PE (40%-50%) to afford (5, E)-N- ((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. MS ESI calculated for CioHi4BrN2OS [M + H]+288.99, found 288.95.

[0195] Step 2: To a mixture of 2-methylpyridine (3.19 g, 34.2 mmol) in THF (33 mL) was added w-BuLi (13.69 mL, 34.2 mmol, 2.5 M in hexane) at -78 °C. After stirring the mixture for 30 min at -78 °C, a solution of (5, £)-A-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide (6.6 g, 22.82 mmol) in THF (33 mL) was added. The resulting mixture was stirred for 1 h at -60 °C, then diluted with water (200 mL) and extracted with ethyl acetate (3 x 120 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (S)- A-((5)-(l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for Ci6H2iBrN3OS [M + H]+382.05, found 382.10.

[0196] Step 3: To a mixture of f5J-A-((5)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2- methylpropane-2-sulfmamide (200 mg, 0.523 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (1.3 mL, 5.23 mmol) at room temperature. After stirring for 30 min at room temperature,25958 the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (30 mL), washed with aqueous NaHCCL (3 x 10 mL). The organic layers were dried over anhydrous ISfeSCU and then concentrated under reduced pressure to afford (5)-l-(3- bromopyridin-2-yl)-2-(pyri din-2 -yl)ethanamine. MS ESI calculated for CnHisBrNs [M + H]+, 277.02 found 278.05.Intermediate-5 l-(3-bromopyridin-2-yl)-2-(5-fluoropyrimidin-2-yl) ethanamine

[0197] Step 1 : A mixture of (3-bromopyridin-2-yl) methanamine (5 g, 26.7 mmol) and diphenylmethanimine (5.33 g, 29.4 mmol) were stirred at 80 °C under nitrogen atmosphere for 2 h, and the solution was concentrated under reduced pressure. The reaction was quenched by water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic fractions were washed with brine (3 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1-10% methanol in di chloromethane to afford l-(3- bromopyridin-2-yl)-7V-(diphenylmethylene) methanamine. MS ESI calculated for CigHieBrN? [M + H]+, 351.04, found 353.10.

[0198] Step 2 : To a stirred mixture of l-(3-bromopyridin-2-yl)-7V-(diphenylmethylene) methanamine (700 mg, 1.993 mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (2.99 mL, 5.98 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h, then 2-(bromomethyl)-5-fluoropyrimidine (495 mg, 2.59 mmol) was added. The resulting mixture was stirred for 2 h. The reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane to afford l-(3-bromopyridin-2-yl)-7V-(diphenylmethylene)-2-(5- fluoropyrimidin-2-yl) ethanamine. MS ESI calculated for C24Hi9BrFN4 [M + H]+461.07, found 461.15.

[0199] Step 3 : To a stirred mixture of l-(3-bromopyridin-2-yl)-7V-(diphenylmethylene)-2-(5- fluoropyrimidin-2-yl) ethanamine (1.1 g, 2.384 mmol) in DCM (10 mL) was added hydrogen chloride (10 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 3 h and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1-30% ethyl acetate in petroleum ether to afford l-(3- bromopyridin-2-yl)-2-(5-fluoropyrimidin-2-yl) ethanamine. MS ESI calculated for CnHnBrFN [M + H]+297.01, found 297.00.25958Intermediate-6 l-(3-bromopyridin-2-yl)-2-(3,5-difluoropyridin-2-yl) ethanamine

[0200] Step 1: To a mixture of 3, 5-difluoropicolinic acid (2 g, 12.57 mmol) in EtOH (20 mL) was added H2SO4 (0.670 mL, 12.57 mmol) at room temperature. After stirring for 2 h at 80 °C, the reaction mixture was concentrated under reduced pressure. Then the mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to afford ethyl 3, 5-difluoropicolinate. MS ESI calculated for C8H8F2NO2[M + H]+, 188.04 found 188.05.

[0201] Step 2: To a mixture of ethyl 3, 5-difluoropicolinate (1.7g, 9.08 mmol) in MeOH (20 mL) was added LiBEL (0.594 g, 27.3 mmol) at 0 °C. The reaction mixture was stirred for 16 h at 40 °C then concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL). The organic layer was washed with brine (4 x 25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc = 1 : 1 to afford (3,5-difluoropyridin-2-yl) methanol. MS ESI calculated for C6H6F2NO [M + H]+146.03 found 146.15.

[0202] Step 3 : To a mixture of (3,5-difhioropyridin-2-yl) methanol (1.1 g, 7.58 mmol) in DCM (10 mL) was added TEA (2.113 mL, 15.16 mmol) at room temperature. Ms-Cl (0.886 mL, 11.37 mmol) in DCM (2 mL) was added at 0 °C and stirred for 2 h at 0 °C. The mixture was diluted with DCM (100 mL). The organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford (3, 5- difluoropyridin-2-yl) methyl methanesulfonate. MS ESI calculated for C7EEF2NO3S [M + H]+224.01 found 223.90.

[0203] Step 4 : To a mixture of (3,5-difluoropyridin-2-yl) methyl methanesulfonate (500 mg, 2.240 mmol) in DCM (10 mL) were added KOH (1257 mg, 22.40 mmol), K2CO3 (3096 mg, 22.40 mmol), TBAI (83 mg, 0.224 mmol) and l-(3-bromopyridin-2-yl)-A-(diphenylmethylene) methanamine (787 mg, 2.240 mmol) at room temperature. The reaction mixture was stirred for 16 h at 35 °C then filtered. The filtrate was concentrated under reduced pressure to afford l-(3- bromopyridin-2-yl)-2-(3,5-difluoropyridin-2-yl)-A-(diphenylmethylene) ethanamine. MS ESI calculated for C25Hi9BrF2N3 [M + H]+478.07 found 478.15.

[0204] Step 5 : To a mixture of l-(3-bromopyridin-2-yl)-2-(3,5-difluoropyridin-2-yl)-A- (diphenylmethylene) ethanamine (1 g, 2.091 mmol) in DCM (10 mL) was added 4 M HC1 in dioxane (1.042 g, 8.36 mmol) at room temperature. The resulting mixture was stirred for 30min at room temperature. The residue was purified by silica gel column chromatography, eluting with2595810% MeOH in DCM to afford l-(3-bromopyridin-2-yl)-2-(3,5-difluoropyridin-2-yl) ethanamine. MS ESI calculated for Ci2HnBrF2N3[M + H]+314.00 found 314.00.Intermediate-7(M-l-(3-(3-bromo-lJ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine

[0205] To a mixture of (S)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethanamine (900 mg, 3.24 mmol) in DMF (10 mL) were added copper (I) iodide (61.6 mg, 0.324 mmol), potassium carbonate (894 mg, 6.47 mmol), BPMPO (272 mg, 0.647 mmol) and 3-bromo-lH-indazole (956 mg, 4.85 mmol) at ambient temperature under argon. The reaction was stirred at 110 °C for 16 h and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of MeOH / DCM = 0 ~ 15% to afford (S)-l-(3-(3-bromo-lH-indazol-l- yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C^HnBrNs [M + H]+, 394.06, found 394.05.Intermediate-8(M-terLbutyl (1 -(3 -(3 -bromo- 1 JT-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)carbamate

[0206] To a mixture of (5)-l-(3-(3-bromo-lZ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine (200 mg, 0.507 mmol) in DCM (10 mL) were added TEA (0.106 mL, 0.761 mmol) and Boc2O (0.353 mL, 1.522 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 2 h and concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of MeOH / DCM -0 ~ 10% to afford CS')- / c / 7-butyl (l-(3- (3-bromo-l / / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)carbamate. MS ESI calculated for C24H25BrN5O2[M + H]+, 494.11, found 494.20.Intermediate-9(M-(l-(2-(l-amino-2-(pyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)methanol

[0207] To a mixture of (5)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethanamine (1 g, 3.60 mmol) in N,N-dimethylformamide (10 mL) were added (lH-indazol-3-yl)methanol (0.586 g, 3.95 mmol), potassium carbonate (0.994 g, 7.19 mmol), Nl,N2-bis(5-methyl-[l,l’-biphenyl]-2- yl)oxalamide (0.302 g, 0.719 mmol) and copper(I) iodide (0.068 g, 0.360 mmol) at rt under argon. The reaction was stirred at 110 °C for 16h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by reverse phase with the following conditions: Column, C18, 80 g, 19 xl50 mm; mobile phase: acetonitrile in Water (0.05% TFA), 2%-70% in 35 min; Detector, UV 254 nm. The collected fractions were combined and25958 concentrated under reduced pressure to give (5)-(l-(2-(l-amino-2-(pyridin-2-yl)ethyl)pyridin-3- yl)- 1 H-indazol -3 -yl)m ethanol .Intermediate -10(S)-tert-butyl (1 -(3 -(3 -(hydroxymethyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyri din-2 - yl)ethyl)carbamate

[0208] To a mixture of (5)-(l-(2-(l-amino-2-(pyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3- yl)methanol (600 mg, 1.737 mmol) in dichloromethane (10 mL) were added triethylamine (0.484 mL, 3.47 mmol) and di -tert-butyl dicarbonate (0.605 mL, 2.61 mmol) at rt. The reaction was stirred at rt for Ih. The resulting solution was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of methanol: dichloromethane — 0: 1 to 1 :5 to afford (^-tert-butyl (l-(3-(3- (hydroxymethyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)carbamate.Intermediate -11(S)-tert-butyl (l-(3-(3-formyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)carbamate

[0209] To a stirred mixture of CS')- / c / 7-butyl (l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethyl)carbamate (460 mg, 1.107 mmol) in DCM (5 mL) was added Dess-Martin (563 mg, 1.329 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h, then it was quenched by saturated solution of sodium thiosulfate (5 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic fractions were washed with brine (3 x 15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1-10% methanol in di chloromethane to afford CS')- / c77-butyl (l-(3-(3-formyl-U / -indazol-l-yl)pyridin-2-yl)-2- (pyridin-2-yl)ethyl)carbamate. MS ESI calculated for C25H26N5O3 [M + H]+, 444.20, found 444.20.Intermediate- 12 l-(3-(lH-indazol-l-yl)pyridin-2-yl)-N-(diphenylmethylene)methanamine

[0210] Step 1: To a mixture of (5',£)-7V-((3-(U / -indazol-l-yl)pyridin-2-yl)methylene)-2- methylpropane-2-sulfmamide (600 mg, 1.838 mmol) in MeOH (9 mL) was added NaBEL (139 mg, 3.68 mmol). The reaction mixture was stirred for 1 h at 28 °C and then 4 M HC1 in dioxane (10 mL) was added. The resulting mixture was stirred for another 20 min and then concentrated under reduced pressure. The residue was diluted with saturated aqueous of NaHCCL (80 mL). The mixture was extracted with DCM (3 x 60 mL). The combined organic layers were washed25958 with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with 10% MeOH in DCM to afford (3-(l / / -indazol-l-yl)pyridin-2-yl)methanamine.

[0211] Step 2 : A neat mixture of (3-(l / / -indazol-l-yl)pyridin-2-yl)methanamine (1.30 g, 5.80 mmol) and diphenylmethanimine (1.051 g, 5.80 mmol) was stirred for 16 h at 50 °C. The mixture was purified with silica gel chromatography, eluting with 30% EtOAc in PE to afford l-(3-(l / 7- indazol-l-yl)pyridin-2-yl)-A-(diphenylmethylene)methanamine. MS ESI calculated for C26H21N4 [M + H]+389.17, found 389.15.Intermediate- 12 l-(2-bromophenyl)-lH-indazole

[0212] To a solution of 177-indazole (1 g, 8.46 mmol) in-di methyl form am ide (15 mL) were added l-bromo-2-fluorobenzene (1.180 g, 6.74 mmol) and CS2CO3 (8.288 g, 25.4 mmol) at 25°C under nitrogen atmosphere. The reaction solution was stirred at 60 °C for 1.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (3 x 80mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction mixture was purified by column chromatography, eluting with 0% to 15% ethyl acetate in petroleum ether to afford l-(2- bromophenyl)-lJ7-indazole. MS ESI calculated for CisHioBrlS [M + H]+273.99 found 274.05.Preparation of ExamplesEXAMPLES 1 AND 2(lM-(3-(l -indazol-l-yl)pyridin-2-yl)(5 7,8-tetrahydroquinolin-8-yl)methanamine and (lM-(3- indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine

[0213] Step 1 : To a solution of 5,6,7,8-tetrahydroquinoline (204 mg, 1.532 mmol) in THF (10 mL) was added w-BuLi (0.643 mL, 1.608 mmol, 2.5M in Hexane) at -60 °C under argon. After stirring for 30 min at -60 °C, (5,£)-A-((3-(lZ / -indazol-l-yl)pyridin-2-yl)methylene)-2- methylpropane-2-sulfmamide (250 mg, 0.766 mmol) was added into this mixture. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The resulting solution was quenched with water (30 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by25958Prep-HPLC with the following conditions: Column: Xbridge C18 OBD Prep Column, 100A, 10 pm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 60% B in 4.8 min; 210 / 254 nm; to give (5)-7V-((15)- (3-(U / -indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methyl)-2-methylpropane-2- sulfinamide. MS ESI calculated for C26H30N5OS [M + H]+, 460.21, found 460.10.

[0214] Step 2: To a mixture of (5)-A-((15)-(3-(U / -indazol-l-yl)pyridin-2-yl)(5, 6,7,8- tetrahydroquinolin-8-yl)methyl)-2-methylpropane-2-sulfinamide (130 mg, 0.283 mmol) in DCM (5 mL) was added hydrogen chloride (8 mL, 32.0 mmol, 4 M in 1,4-dioxane) at room temperature. The reaction mixture was stirred for 1 h and concentrated in vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep C18 OBD Column, 19 x 150 mm 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 50% B to 80% B in 5 min; 254 nm; fast peak; to afford Example 1, (15)-(3-(17 / -indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine. MS ESI calculated for C22H22N5 [M + H]+356.45, found 356.15.

[0215] And slow peak to afford Example 2, (15)-(3-(17 / -indazol-l-yl)pyridin-2-yl)(5, 6,7,8- tetrahydroquinolin-8-yl)methanamine. MS ESI calculated for C22H22N5 [M + H]+356.18, found 356.15.EXAMPLE 31 -(2-(3 -phenylpyrrolidin-2-yl)pyri din-3 -yl)- IH-indazole

[0216] Step 1 : To a dried Schlenk flask were added, under argon, 4,4’-di-tert-butyl-2,2’- bipyridine (9.79 mg, 0.036 mmol) and nickel(II) bromide ethylene glycol dimethyl ether complex (11.26 mg, 0.036 mmol). The flask was evacuated and backfilled with argon 3 times, then DMF (0.1 mL) was added by syringe, and the mixture was allowed to stir for 10 minutes at room temperature. This Ni(DTBBPY)Br2 was used freshly.

[0217] To a mixture of 1 -(2 -brom opyri din-3 -yl)-17 / -indazole (200 mg, 0.730 mmol), l-(tert- butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid (213 mg, 0.730 mmol), 4CZIPN (28.8 mg, 0.036 mmol) and DBU (0.220 mL, 1.459 mmol) in acetonitrile (4 mL) was added the25958 solution of Ni(DTBBPY)Br2 under an atmosphere of argon. The resulting mixture was irradiated with blue LED (400 nm) for 3 h at ambient temperature under argon protection. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was applied onto a silica gel column chromatography with EtOAc / PE (0-40%). This resulted in / c77-butyl-2-(3-( l H-indazol- l - yl)pyridin-2-yl)-3-phenylpyrrolidine-l -carboxylate. MS ESI calculated for C27H29N4O2 [M + H]+441.22 found 441.

[0218] Step 2: To a mixture of / c / V-butyl 2-(3-(U7-indazol-l-yl)pyridin-2-yl)-3- phenylpyrrolidine-1 -carboxylate (300 mg, 0.647 mmol,) in DCM (2 mL) was added HC1 (4 M in dioxane, 109 mg, 0.878 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature and concentrated under reduced pressure. The residue was purified by Prep- HPLC under the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm 5 pm 10 nm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 15 B to 40 B in 4.3 min; 210 / 254 nm; to afford l-(2-(3-phenylpyrrolidin-2-yl)pyridin- 3-yl)-U7-indazole as the faster moving peak. MS ESI calculated for C22H21N4 [M + H]+, 341.13 found 341.20.

[0219] Step 3 : The mixture from step 2 was then separated by Chiral-HPLC under the following conditions: Column: Chiral pak AD-H, 2 x 25 cm (5 pm); Mobile Phase A: Hex (8 mmol / L NHs^MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30 B to 30 B in 17 min; 220 / 254 nm; (fast peak) to afford the title compound, Example 3, l-(2-(3- phenylpyrrolidin-2-yl)pyridin-3-yl)-U7-indazole. MS ESI calculated for C22H21N4 [M + H]+, 341.13 found 341.20.

[0220] And (slower moving peak), to afford isomeric l-(2-(3-phenylpyrrolidin-2-yl)pyri din-3 - yl)-U / -indazole. MS ESI calculated for C22H21N4 [M + H]+, 341.13 found 341.20.EXAMPLE 4259583-cyclopropyl-l-(2-(3-(5-fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin-3-yl)-U / -indazole 2,2,2- trifluoroacetate

[0221] Step 1 : To a solution of l-pivaloylpyrrolidine-2-carboxylic acid (7 g, 35.1 mmol) in DMF (80 mL) were added N, A-diethylpropan-2-amine (12.14 g, 105 mmol), 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouroniumhexafluorophosphate (V) (20.04 g, 52.7 mmol) and quinolin-8-amine (6.08 g, 42.2 mmol) at room temperature. After the resulting mixture was stirred at room temperature for 16 h, it was diluted with ethyl acetate (100 mL) and washed with brine (5 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography using a gradient of 0 ~ 80% ethyl acetate in petroleum ether to afford 1 -pivaloyl -7V-(quinolin-8- yl)pyrrolidine-2-carboxamide. MS ESI calculated for C19H24N3O2 [M + H]+, 326.18, found 326.25.

[0222] Step 2 : To a solution of 5-fluoro-2-iodopyridine (4.11 g, 18.44 mmol), diacetoxypalladium (0.083 g, 0.369 mmol), acetyl(oxo)silver (1.231 g, 7.38 mmol) and dibenzyl hydrogen phosphate (0.513 g, 1.844 mmol) in toluene (25 mL) was added 1 -pivaloyl -N- (quinolin-8-yl)pyrrolidine-2-carboxamide (1.2 g, 3.69 mmol) at room temperature. The reaction was stirred at 110 °C for 24 h. The solvent was removed and the residue was purified by silica gel column chromatography using a gradient of 0 ~ 100% ethyl acetate in petroleum ether to afford 3-(5-fluoropyridin-2-yl)-l-pivaloyl-7V-(quinolin-8-yl)pyrrolidine-2-carboxamide. MS ESI calculated for C24H26FN4O2 [M + H]+, 420.18, found 420.21.

[0223] Step 3 : To a solution of 3-(5-fluoropyridin-2-yl)-l-pivaloyl-A-(quinolin-8- yl)pyrrolidine-2-carboxamide (1 g, 2.378 mmol) in water (5 mL) was added HC1 (12 M) (5.00 mL) at room temperature, then the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was extracted with DCM (5 x 100 mL), the water layer was collected and adjusted pH = 8 (K2CO3 solid). Then the reaction mixture used for next step directly.

[0224] Step 4 : To a solution of crude 3-(5-fluoropyridin-2-yl)pyrrolidine-2-carboxylic acid (2.378 mmol) in water 10 mL and 1,4-dioxane (10 mL) was added (Boc)2O (1 mL) at room temperature. After stirring for 2 h, the mixture was extracted with DCM (5 x 100 mL). The aqueous layer was collected and adjusted pH = 5.8 with 1 M HC1, and then the mixture was extracted with DCM (5 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford l -( / c / 7-butoxycarbonyl)-3-(5-fluoropyridin-2-yl)pyrrolidine-2-carboxylic acid. MS ESI calculated for C15H20FN2O4 [M + H]+, 311.13, found 311.20.25958

[0225] Step 5 : Into a 40-mL vial were placed nickel (II) chlorideglyeme (16.09 mg, 0.124 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (33.3 mg, 0.124 mmol) in DMA (2 mL) which were stirred at room temperature for 30 min. Into an another 50 mL vial were placed l-(2- bromopyri din-3 -yl)-3 -cyclopropyl- UT-indazole (390 mg, 1.241 mmol), l-(tert-butoxycarbonyl)- 3-(5-fluoropyridin-2-yl)pyrrolidine-2-carboxylic acid (347 mg, 1.117 mmol), (Ir[dF(CF3)ppy]2(dtbbpy))PFe (13.93 mg, 0.012 mmol) and CS2CO3 (1213 mg, 3.72 mmol) in DMA (4 mL). The resulting mixture was stirred at room temperature for 5 min. The previous reaction mixture was transferred to this vial via syringe. The resulting mixture was irradiated with blue LED for 3 h at ambient temperature. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to dryness. The residue was purified by silica gel column chromatography, eluting with 0 ~ 40% ethyl acetate in petroleum ether to give a mixture of tert-butyl 2-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2- yl)-3-(5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate. The mixture was purified by / Vc -HPLC under the following conditions: Column: Xbridge Shield RP18 OBD Column, 5 pm, 19 x 150 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 27% B to 40% B in 4.5 min; 254 / 210 nm; to give the first peak, tert-butyl 2- (3 -(3 -cyclopropyl- 1 JT-indazol- 1 -yl)pyridin-2-yl)-3 -(5-fluoropyridin-2-yl)pyrrolidine- 1 - carboxylate. MS ESI calculated for C29H31FN5O2 [M + H]+, 500.24, found 500.40, and to give the second peak (single isomer) tert-butyl 2-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-3- (5-fluoropyridin-2-yl)pyrrolidine-l -carboxylate. MS ESI calculated for C29H31FN5O2 [M + H]+, 500.24, found 500.40, and to give the third peak (single isomer) tert-butyl 2-(3 -(3 -cyclopropyl - U / -indazol-l-yl)pyridin-2-yl)-3-(5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate. MS ESI calculated for C29H31FN5O2 [M + H]+, 500.24, found 500.40

[0226] Step 6 : The first peak from Step 5, / cr / -butyl 2-(3 -(3 -cyclopropyl- UT-indazol-1- yl)pyridin-2-yl)-3-(5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate (130 mg, 0.260 mmol) was further separated by Chiral -HPLC under the following conditions: Column: (R,R) WHELK-01, 4.6 x 50 mm, 3.5 pm; Mobile Phase A: Hex (0.1%DEA): EtOH = 90%: 10%, Flow rate: 1 mL / min; Gradient: 0% B to 0% B in 8 min. to give the fast peak, single isomer, tert-butyl 2-(3- (3 -cyclopropyl- UT-indazol- 1 -yl)pyridin-2-yl)-3 -(5-fluoropyridin-2-yl)pyrrolidine- 1 -carboxylate. MS ESI calculated for C29H31FN5O2 [M + H]+, 500.24, found 500.40; and to give the slow peak, single isomer, tert-butyl 2-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-3-(5-fluoropyridin-2- yl)pyrrolidine-l-carboxylate. MS ESI calculated for C29H31FN5O2 [M + H]+, 500.24, found 500.40

[0227] Step 7 : To a solution of tert-butyl 2-(3 -(3 -cyclopropyl- 177-indazol-l-yl)pyri din-2 -yl)-3- (5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate (fast peak, Step 6, 50 mg, 0.100 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The mixture was stirred for 2 h and concentrated under reduced pressure. The residue was lyophilized to give isomeric 3- cyclopropyl-l-(2-(3-(5-fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin-3-yl)-17 / -indazole 2,2,2- trifluoroacetate (single isomer). MS ESI calculated for C24H23FN5 [M + H]+, 400.19, found 400.10.

[0228] Step 8 : To a solution of tert-butyl 2-(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyri din-2 -yl)-3- (5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate (slow peak, Step 6, 50 mg, 0.100 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The solvent was removed, and the residue was lyophilized to give the title compound (single isomer), Example 4, 3-cyclopropyl-l-(2-(3-(5- fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin-3-yl)-17 / -indazole 2,2,2-trifluoroacetate. MS ESI calculated for C24H23FN5 [M + H]+, 400.19, found 400.10.

[0229] Step 9 : To a solution of tert-butyl 2-(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyri din-2 -yl)-3- (5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate (10 mg, 0.020 mmol, the second peak from step 5) in DCM (2 mL) was added TFA (2 mL) at room temperature. The solvent was removed, and the residue was lyophilized to give isomeric 3-cyclopropyl-l-(2-(3-(5-fluoropyridin-2- yl)pyrrolidin-2-yl)pyridin-3-yl)-U7-indazole 2,2,2-trifluoroacetate. MS ESI calculated for C24H23FN5 [M + H]+, 400.19, found 400.10.

[0230] Step 10: To a solution of tert-butyl 2-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)- 3-(5-fluoropyridin-2-yl)pyrrolidine-l-carboxylate (10 mg, 0.020 mmol, the third peak from step 5) in DCM (2 mL) was added TFA (2 mL) at rt. The solvent was removed and the residue was lyophilized to give isomeric 3-cyclopropyl-l-(2-(3-(5-fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin- 3-yl)-U7-indazole 2,2,2-trifluoroacetate. MS ESI calculated for C24H23FN5 [M + H]+, 400.19, found 400.10.EXAMPLE 5(R or M-l -(3-(lH-indazol-l -yDpyri din-2 -yl)-2-(5-fluoropyrimidin-2-yl)ethan-l -amine

[0231] Step 1 : To a stirred solution of l-(3-fluoropyridin-2-yl)ethanone (1 g, 7.19 mmol) in DMF (5 mL), were added CS2CO3 (8.5 g, 26.1 mmol), and UT-indazole (1.1741 g, 8.63 mmol). The reaction mixture was stirred for 2 h at room temperature. Water (40 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine (60 mL x 3), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, eluting with 0 to 42% ethyl acetate in petroleum ether to afford l-(3-(lH- indazol-l-yl)pyridin-2-yl)ethan-l-one. MS (ESI, m / z) calculated for C14H12N3O [M + H]+, 238.08, found 238.05 [M + H]+.

[0232] Step 2: To a stirred solution of l-(3-(17 / -indazol-l-yl)pyridin-2-yl)ethan-l-one (700 mg, 2.74 mmol) in THF (10 mL) were added 2-chloro-5-fluoropyrimidine (300 mg, 2.264 mmol) and NaH (180 mg, 4.50 mmol, 60% in mineral oil) at -30 °C. The reaction mixture was stirred for 16 h at 65 °C. Water (40 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine (60 mL x 3), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, eluting with 0% to 30% ethyl acetate in petroleum ether to afford l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan-l- one. MS (ESI, m / z): calculated for CI8HI3FN5O [M + H]+334.09 found 334.09.

[0233] Step 3: To a stirred solution of l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyrimidin-2-yl)ethan-l-one (110 mg, 0.313 mmol) in methanol (10 mL) was added hydroxylamine hydrochloride (110 mg, 1.583 mmol) at 25 °C under nitrogen atmosphere. The reaction mixture and stirred for 2 h at 25 °C. Water (50 mL) was added to quench the mixture. The mixture was extracted with dichloromethane (3 x 60 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (80 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford ((E)- 1 -(3- (l / 7-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan-l-one oxime, which was used in next step without further purification. MS (ESI, m / z): calculated for CisHuFNeO [M + H]+349.11, found 349.25.

[0234] Step 4: To a stirred solution of ((£)-l-(3-(l / 7-indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyrimidin-2-yl)ethan-l-one oxime (100 mg, 0.246 mmol) in ethanol (5 mL) were added zinc (80 mg, 1.224 mmol) and acetic acid (120 mg, 1.998 mmol) at 25 °C. The reaction mixture was stirred for 16 h at 40 °C. Water (40 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate (3x 40 mL). The combined organic layer was washed with brine (3 x 60 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm 5 pm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient: 15% B to 50% B in 4.3 min; 254 / 210 nm; to afford l-(3-(l / / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethan-l-amine. MS (ESI, m / z): calculated for CI8HI6FN6[M + H]+334.11, found 334.25.

[0235] Step 5: The racemic mixture was resolved by Chiral -Prep-HPLC Column: CHIRALPAK IC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM = 3: 1 (lOmM NH3-MEOH), Mobile Phase B: IP A; Flow rate: 20 mL / min; Gradient:40 B to 40 B in 30 min; 220 / 254 nm; (fast peak) to afford the title compound, Example 5, (5 or A)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyrimidin-2-yl)ethan-l -amine. MS (ESI, m / z) calculated for CisHieFNe [M + H]+334.11, found 334.25.

[0236] And (slow peak)to afford isomeric (R or 5)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyrimidin-2-yl)ethan-l -amine. MS (ESI, m / z): calculated for CisHieFNe [M + H]+334.11, 334.25.EXAMPLES 6-9

[0237] To the 4 mL scintillation vials containing the carboxylic acid monomers (1.5 equiv) was added 290 pl of l-(2-bromopyridin-3-yl)-lH-indazole (DMSO stock solution, 0.073 M), 22 pl of neat BTMG, 146 pl of NiBr2-glyme / dtbpy stock solution [prepared by mixing 125 mg ofNiBr2 glyme with 109 mg of 4,4’-Di-tert-butyl-2,2’-bipyridine and 8.12 mL of DMSO], 292 pl of photocatalyst stock solution [prepared by mixing 82.2 mg of [Ir(dF(Me)ppy)2(dtbbpy)]PFe with 16.2 mL of DMSO], The resulting mixture was shaken on the nano-photoreactor for 24 h using 100% light intensity and 20% on time. The reaction mixtures were concentrated. Then 365 pl of dichloromethane and 365 pl of TFA were added to each of the reaction vials, and the reaction was stirred at rt for about 1 hour. The reaction mixtures were concentrated. About 2 mL of DMSO was added and the reaction mixtures were filtered through a 96 well fritted plate. The filtrate was purified using reverse phase chromatography to afford the final products.

[0238] The following Examples in Table 1 were prepared using the above procedure.25958Table 1EXAMPLE 10(R or N)-l-(3- indazol-l-yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine

[0239] Step 1: To a stirred solution of l-(3-(U / -indazol-l-yl)pyridin-2-yl)ethanone (719 mg, 3.03 mmol) in THF (15 mL) were added 2 -chlorothiazole (362 mg, 3.03 mmol) and NaH (182 mg, 4.55 mmol, 60% in mineral oil) at -40 °C. The reaction mixture was stirred for 16 h at 65 °C. The reaction was quenched by water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over sodium sulfate and25958 filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0 to 30% ethyl acetate in petroleum ether to afford 1- (3-(l / / -indazol-l-yl)pyridin-2-yl)-2-(oxazol-2-yl)ethanone. MS ESI: calculated for C17H13N4SO [M + H]+321.07, found 321.10.

[0240] Step 2: To a stirred solution of l-(3-(l / / -indazol-l-yl)pyridin-2-yl)-2-(oxazol-2- yl)ethanone (200 mg, 0.657 mmol) in methanol (10 mL) was added hydroxylamine hydrochloride (228 mg, 3.29 mmol) at 25 °C under nitrogen atmosphere. The reaction mixture and stirred for 2 h at 25 °C. The reaction was quenched by water (50 mL) and extracted with dichloromethane (3 x 60 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford (£)-l-(3-(l / / -indazol-l-yl)pyridin-2- yl)-2-(thiazol-2-yl)ethanone oxime, which was used in next step without further purification. MS ESI: calculated for C17H14N5OS [M + H]+336.08, found 336.10.

[0241] Step 3: To a stirred solution of (£)-l-(3-(l / / -indazol-l-yl)pyridin-2-yl)-2-(thiazol-2- yl)ethanone oxime (173.8 mg, 0.518 mmol) in ethanol (5 mL) were added zinc (339 mg, 5.18 mmol) and ammonium acetate (399 mg, 5.18 mmol) at 25 °C. The reaction mixture was stirred for 16 h at 40 °C. The reaction was quenched by water (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm 5 pm 10 nm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient: 15% B to 50% B in 4.3 min; 254 / 210 nm; to afford l-(3-(177- indazol-l-yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine. MS ESI: calculated for C17H16N5S [M + H]+322.40, found 322.20.

[0242] Step 4 : The racemic mixture was separated by Chiral-HPLC under the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane: DCM = 3: 1(10 mM NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 20 min; 220 / 254 nm. to afford the title compound as fast peak, Example 10, (5 or 7?)-l-(3- (l / / -indazol-l-yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine. MS ESI calculated for C17H16N5S [M + H]+322.10, found 322.05.

[0243] And to afford the slow peak, isomeric compound, (R or 5)-l-(3-(l / / -indazol-l- yl)pyridin-2-yl)-2-(thiazol-2-yl)ethanamine. MS ESI calculated for C17H16N5S [M + H]+322.10, found 322.05.25958EXAMPLE 11l-(3-(l / / -indazol-l-yl)pyri din-2 -yl)-2-(5-methyl-U / -pyrazol-l-yl)ethanamine

[0244] Step 1 : To a mixture of l-(3-fluoropyridin-2-yl)ethanone (2 g, 14.38 mmol) in hydrogen bromide (48% in acetic acid, 20 mL, 177 mmol) was added bromine (1.481 mL, 28.8 mmol) at 0 °C. The reaction was warmed to ambient temperature and stirred for 16 h. The resulting solution was filtered, and the filter-cake was washed with ether (2 x 100 mL) to afford 2-bromo- l-(3-fluoropyridin-2-yl)ethanone hydrobromide. MS ESI calculated for CTELB^FNO [M + H]+, 217.95,219.95, found 215.90, 217.90.

[0245] Step 2: To a mixture of 2-bromo-l-(3-fluoropyridin-2-yl)ethanone hydrobromide (1 g, 3.35 mmol) in ethanol (15 mL) was added sodium tetrahydroborate (0.253 g, 6.69 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 2 h. The resulting solution was quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 500mL), dried over anhydrous sodium sulfate and filtered. The organic phase was evaporated in vacuum to afford 3-fluoro-2-(oxiran-2- yl)pyridine. MS ESI calculated for C7H7FNO [M + H]+, 140.13, found 140.10.

[0246] Step 3: To a mixture of 5-methyl-177-pyrazole (177 mg, 2.156 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 103 mg, 2.59 mmol) at 0 °C under argon. The mixture was stirred at 0 °C for 30 min, and then 3-fluoro-2-(oxiran-2-yl)pyridine (300 mg, 2.156 mmol) was added to the mixture at 0 °C. The reaction was warmed to ambient temperature and stirred for 2 h. The resulting solution was quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 500mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of 0 ~ 35% ethyl acetate in petroleum ether to afford l -(3-fluoropyridin-2-yl)-2-(5-methyl- IT / - pyrazol-l-yl)ethanol. MS ESI calculated for C11H13FN3O [M + H]+, 222.23, found 222.10.

[0247] Step 4: To a mixture of l-(3-fluoropyridin-2-yl)-2-(5-methyl-lJ7-pyrazol-l-yl)ethanol (300 mg, 1.356 mmol) in DMF (10 mL) were added cesium carbonate (1591 mg, 4.88 mmol) and UT-indazole (192 mg, 1.627 mmol) at ambient temperature. The mixture was stirred at 100 °C for 8 h. LCMS showed the major peak was the product. The resulting solution was quenched25958 with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of 0 ~ 75% ethyl acetate in petroleum ether to afford l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lH-pyrazol-l-yl)ethanol. MS ESI calculated for CI8HI8N5O [M + H]+320.36, found 320.05.

[0248] Step 5: To a mixture of l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lJ / -pyrazol-l- yl)ethanol (200 mg, 0.626 mmol) in DCM (15 mL) was added DMP (1062 mg, 2.505 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 8 h. The resulting solution was quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of 0 ~ 8% methanol in dichloromethane to afford l -(3-( IT / -indazol- l -yl)pyridin-2-yl)-2-(5-methyl- IT / -pyrazol- l - yl)ethanone. MS ESI calculated for CisHieNsO [M + H]+, 318.34, found 318.55.

[0249] Step 6: To a mixture of l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lJ / -pyrazol-l- yl)ethanone (35 mg, 0.110 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (9.18 pl, 0.221 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuum to afford crude product. The crude product was quenched with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford (£)-l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lJ / - pyrazol-l-yl)ethanone oxime. MS ESI calculated for CisHnNeO [M + H]+, 333.36, found 333.20.

[0250] Step 7: To a mixture of (£)-l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(5-methyl-lJT- pyrazol-l-yl)ethanone oxime (37 mg, 0.089 mmol) in ethanol (4 mL) were added ammonium acetate (0.128 mL, 1.781 mmol) and zinc (6.53 pl, 0.712 mmol) at ambient temperature. The mixture was stirred at 60 °C for 16h. The resulting mixture was concentrated in vacuum to afford crude product. The residue was purified by Prep-HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19x250 mm 10 u; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 20% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound, Example 11, l -(3-( IT / -indazol- l -yl)pyridin-2-yl)-2-(5-methyl- l 7 / -pyrazol- l - yl)ethanamine. MS ESI calculated for Ci8Hi9N6 [M + H]+, 319.38, found 319.10.25958EXAMPLE 12(S or 7?)-l-(3- indazol-l-yl)pyridin-2-yl)-2-(oxazol-2-yl)ethanamine

[0251] Step 1 : To a mixture of oxazol-2-ylmethanol (1 g, 10.09 mmol) in THF (20 mL) was added triphenylphosphine (5.29 g, 20.18 mmol) at room temperature. After CB (6.69 g, 20.18 mmol) was added and stirred for 16 h at room temperature. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous of ammonium chloride (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PEZEtOAc = 1 : 1 to afford 2-(bromomethyl) oxazole. MS ESI calculated for CLHjBrNO [M + H]+161.95 found 161.90.

[0252] Step 2 : To a mixture of 2-(bromomethyl) oxazole (156 mg, 0.965 mmol) in DCM (10 mL) were added l-(3-(U / -indazol-l-yl) pyridin-2-yl)-A-(diphenylmethylene)methanamine (250 mg, 0.644 mmol), KOH (361 mg, 6.44 mmol), TBAI (23.77 mg, 0.064 mmol) and K2CO3 (889 mg, 6.44 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature then diluted with DCM (100 mL), washed with saturated aqueous of ammonium chloride (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford l-(3-(U / -indazol-l-yl) pyridin- 2-yl)-7V-(diphenylmethylene)-2-(oxazol-2-yl) ethanamine. MS ESI calculated for C30H24N5O [M + H]+470.19 found 470.25.

[0253] Step 3 : To a mixture of I -(3-( IT / -indazol-l -yl) pyridin-2-yl)-A-(diphenylmethylene)-2- (oxazol-2-yl) ethanamine (40 mg, 0.085 mmol) in DCM (2 mL) was added HC1 in dioxane (0.341 mL, 0.341 mmol) at room temperature. After the resulting mixture was stirred for 30 min at room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC under the following conditions: Column: XBridge C18 OBD Prep Column, 100A, 10 pm, 19 mm x 250 mm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 50% B in 5.08 min; 210 / 254 nm; to afford the mixture of products, which was further separated under the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM=3: l(10 mM NH3- MEOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate:20 mL / min; Gradient: 10% B to 10%25958B in 19 min; 254 / 220 nm; (fast peak) to afford the title compound, Example 12, (5 or / ?)-l-(3- (UT-indazol-l-yl)pyri din-2 -yl)-2-(oxazol-2-yl)ethanamine, MS ESI calculated for C17H16N5O [M + H]+306.13 found 306.10.

[0254] And slow peak to afford isomeric compound, (R or 5)-l-(3-(U / -indazol-l-yl)pyridin-2- yl)-2-(oxazol-2-yl)ethanamine. MS ESI calculated for C17H16N5O [M + H]+, 306.13 found 306.10.EXAMPLE 13(S or R)- 1 -(3 -( U / -indazol- 1 -y Dpyri din-2 -yl)-2-(4-methyli soxazol-3 -yBethanamine

[0255] Step 1 : To a mixture of ethyl 4-methylisoxazole-3-carboxylate (1 g, 6.45 mmol) in MeOH (40 mL) was added LiBEp (0.421 g, 19.34 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with saturated aqueous of ammonium chloride (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PEZEA = 1 : 1 to afford (4-methylisoxazol-3-yl)methanol. MS ESI calculated for CsHsNCL [M + H]+, 114.05 found 114.00.

[0256] Step 2 : To a mixture of (4-methylisoxazol-3-yl)methanol (300 mg, 2.65 mmol) in DMF (3 mL) was added TEA (0.739 mL, 5.30 mmol) at 0 °C. A solution of MsCl (0.310 ml, 3.98 mmol) in DMF (0.5 mL) was added. After the resulting mixture was stirred for 1 h at 0 °C, it was quenched with water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated under reduced pressure to afford (4-methylisoxazol-3-yl)methyl methanesulfonate. MS ESI calculated for CeHioNCLS [M + H]+192.03 found 192.05.

[0257] Step 3 : To a mixture of (4-methylisoxazol-3-yl)methyl methanesulfonate (148 mg, 0.772 mmol) in DCM (8 mL) were added l-(3-(lJ / -indazol-l-yl)pyridin-2-yl)-7V- (diphenylmethylene)methanamine (200 mg, 0.515 mmol), KOH (289 mg, 5.15 mmol), TBAI (19.02 mg, 0.051 mmol) and K2CO3 (712 mg, 5.15 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature then filtered. The filtrate was quenched with25958 water (50 mL) and extracted with DCM (5 x 30 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to affordl-(3-(U / -indazol-l-yl)pyridin-2-yl)-7V-(diphenylmethylene)-2- (4-methylisoxazol-3-yl)ethanamine. MS ESI calculated for C31H26N5O [M + H]+484.21 found 484.25.

[0258] Step 4 : To a mixture of l-(3-(lJ7-indazol-l-yl)pyri din-2 -yl)-7V-(diphenylmethylene)-2- (4-methylisoxazol-3-yl)ethanamine (110 mg, 0.227 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (0.227 mL, 0.227 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC under the following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 10 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient:20% B to 45% B in 5.8 min; 210 / 254 nm; to afford a racemic mixture which was further separated with the following conditions: Column: CHIRALPAK IE, 3 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM = 3: 1(10 mM NH3-MEOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 45 mL / min; Gradient: 10% B to 10% B in 10 min; 220 / 254 nm; to afford isomeric compound (R or S)-l-(3-(lH- indazol-l-yl)pyridin-2-yl)-2-(4-methylisoxazol-3-yl)ethanamine. MS ESI calculated for CI8HI8N5O [M + H]+, 320.14 found 320.10.

[0259] And to afford the title compound, Example 13, (S or A)-l-(3-(U7-indazol-l-yl)pyridin- 2-yl)-2-(4-methylisoxazol-3-yl)ethanamine. MS ESI calculated for CI8HI8NSO [M + H]+, 320.14 found 320.10.EXAMPLE 14(R or M-l-(3- indazol-l-yl)pyridin-2-yl)-2-(4-methylisothiazol-3-yl)ethanamine

[0260] Step 1 : To a mixture of 4-bromoisothiazole-3-carboxylic acid (1 g, 4.81 mmol) in EtOH (10 mL) was added sulfuric acid (0.047 g, 0.481 mmol) at room temperature. After stirring for 30 min at 60°C, the mixture was diluted with EtOAc (200 mL), and washed with saturated aqueous of ammonium chloride (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford ethyl 4-25958 bromoisothiazole-3-carboxylate. MS ESI calculated for CeEEBrNCES [M + H]+, 235.93 found 235.95.

[0261] Step 2 : To a mixture of ethyl 4-bromoisothiazole-3-carboxylate (850 mg, 3.60 mmol) in 1,4-dioxane (10 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2260 mg, 18.00 mmol), K2CO3 (995 mg, 7.20 mmol) and Pd(dtbpf)C12 (235 mg, 0.360 mmol) at room temperature. After stirring for 2 h at 80 °C, the mixture was diluted with EtOAc (200 mL), washed with saturated aqueous of ammonium chloride (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in PE to afford ethyl 4-methylisothiazole-3-carboxylate. MS ESI calculated for C7H10NO2S [M + H]+172.04 found 172.00.

[0262] Step 3 : To a mixture of ethyl 4-methylisothiazole-3-carboxylate (500 mg, 2.92 mmol) in MeOH (10 mL) were added LiBEL (318 mg, 14.60 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature then concentrated under reduced pressure. The mixture was diluted with EtOAc (200 mL), washed with saturated aqueous of ammonium chloride (4 x 25 mL). The organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc = 1 : 1 to afford (4-methylisothiazol-3-yl)methanol. MS ESI calculated for C5H8NOS [M + H]+130.02 found 129.95.

[0263] Step 4 : To a mixture of (4-methylisothiazol-3-yl) methanol (70 mg, 0.542 mmol) in DMF (1 mL) was added TEA (0.151 ml, 1.084 mmol) at 0 °C. A solution of MsCl (0.063 ml, 0.813 mmol) in DMF (0.5 mL) was added and stirred for 1 h at 0 °C. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous of ammonium chloride (50 mL). The organic layer was washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (4-methylisothiazol-3-yl) methyl methanesulfonate. MS ESI calculated for C6H10NO3S2 [M + H]+208.00 found 208.10.

[0264] Step 5 : To a mixture of (4-methylisothiazol-3-yl) methyl methanesulfonate (96 mg, 0.463 mmol) in DCM (5 mL) were added l-(3-(17 / -indazol-l-yl) pyridin-2-yl)-A- (diphenylmethylene)methanamine (120 mg, 0.309 mmol), KOH (173 mg, 3.09 mmol), TBAI (11.41 mg, 0.031 mmol) and K2CO3 (427 mg, 3.09 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature and then filtered. The filtrate was concentrated under reduced pressure to afford l-(3-(U / -indazol-l-yl) pyridin-2-yl)-A-(diphenylmethylene)-2- (4-methylisothiazol-3-yl) ethanamine. MS ESI calculated for C31H26N5S [M + H]+, 500.18 found 500.20.25958

[0265] Step 6 : To a mixture of l-(3-(lJ / -indazol-l-yl)pyridin-2-yl)-7V-(diphenylmethylene)-2- (4-methylisothiazol-3-yl)ethanamine (100 mg, 0.200 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (0.200 mL, 0.200 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient: 20% B to 50% B in 6 min;210 / 254 nm; to afford the racemic mixture which was further separated by Prep-Chiral under the following conditions: Column: CHIRALPAK IC, 2 x 25cm, 5pm; Mobile Phase A: Hex: DCM =3: 1 (10 mM NH3-MEOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 13 min; 254 / 220 nm; (fast peak) to afford the title compound, Example 14, (S or A)-l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(4-methylisothiazol-3- yl)ethanamine. MS ESI calculated for CisHisNsS [M + H]+336.12 found 336.10, and (slow peak) to afford isomeric compound (R or 5)-l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(4- methylisothiazol-3-yl)ethanamine. MS ESI calculated for CisHisNsS [M + H]+336.12 found 336.10.EXAMPLES 15-19

[0266] Compounds 15-19 were prepared according to the following procedure:1. To a 96 well plate in the glove box was added 60 pl of the diphenylimine starting material (N- ((3-(lH-indazol-l-yl)pyridin-2-yl)methyl)-l,l-diphenylmethanimine) stock solution [prepared by mixing 1000 mg of N-((3-(lH-indazol-l-yl)pyridin-2-yl)methyl)-l,l-diphenylmethanimine with 5.15 mL of THF],2. The plate was sealed and put in a precooled tumble stirrer (—40 °C).3. The reaction solutions were stirred for ~15 mins at -40 °C.4. At -40 °C, 72 pl of NaHMDS stock solution [prepared by mixing 482 mg of NAHMDS with 5.26 mL of THF] was added.5. The plate was sealed and the reaction mixtures were allowed to stir at -40 °C for 45 min.6. 110 pl of the alkyl halide stock solutions were added to the reaction wells.7. The plate was sealed and the reaction mixture was allowed to stir at -40 °C for 2.5 h8. The chiller was turned off and the reaction mixtures were allowed to warm to room temperature overnight.9. 60 pl of isopropanol was added to the reaction mixtures.2595810. The reaction plate was taken out of the glove box and 60 pl of 4M HCl / di oxane and 60 pl of HPLC grade water was added to each reaction.11. The resulting mixtures were allowed the stir at room temperature overnight.12. The reaction mixtures were concentrated using the Genevac in the glove box.13. The reaction mixtures were transferred to a 96 well filter plate using 150 pl of HPLC grade water and 1500 pl of DMSO. The mixtures were filtered using vacuum into a 96 well deep well plate which was sealed and purified using reverse phase methods.25958(S or A)-l-(3-(17 / -indazol-l-yl) pyridin-2-yl)-2-(2,4-difluorophenyl) ethanamine

[0267] Step 1: To a mixture of 3-fluoropicolinaldehyde (10 g, 80 mmol) in DCM (100 mL) were added cesium carbonate (31.3 g, 96 mmol) and 2-methylpropane-2-sulfinamide (11.63 g, 96 mmol) at room temperature. After the resulting mixture was stirred at 40 °C at 16 h, it was diluted with water (400 mL) and extracted with ethyl acetate (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column using a gradient of 0 to 47% EtOAc in PE to afford (£)-A-((3-fluoropyri din-2 -yl) methylene)-2-methylpropane-2-sulfinamide. MS ESI calculated for C10H14FN2OS [M + H]+, 229.07, found 229.00.

[0268] Step 2 : To a mixture of (£)-A-((3-fluoropyridin-2-yl) methylene)-2-methylpropane-2- sulfinamide (6 g, 26.3 mmol) in DMF (60 ml) were added cesium carbonate (8.56 g, 26.3 mmol) and UT-indazole (3.10 g, 26.3 mmol) at room temperature. The reaction was stirred at room temperature for 16 h and then diluted with water (400 mL) and extracted with ethyl acetate (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column using a gradient of 0 to 70% EtOAc in PE to afford (£)-A-((3-(17 / -indazol-l-yl)pyridin-2-yl)methylene)- 2-methylpropane-2-sulfinamide. MS ESI calculated for C17H19N4OS [M + H]+, 327.12, found 327.10.

[0269] Step 3: To a solution of (£)-A-((3-(17 / -indazol-l-yl)pyridin-2-yl)methylene)-2- methylpropane-2-sulfmamide (1 g, 3.06 mmol) in anhydrous THF (5 mL) was added (2,4- difluorobenzyl) magnesium bromide (0.850 g, 3.68 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and quenched with saturated NH4CI (50 mL). The mixture was extracted with ethyl acetate (3 x 200 mL), and the combined organic layers were washed with brine (300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column using a gradient of 0 to 100% EtOAc in PE to afford A-(l-(3-(17 / -indazol-l-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)ethyl)-2- methylpropane-2-sulfmamide. MS ESI calculated for C24H25F2N4OS [M + H]+, 455.16, found 455.15.25958

[0270] Step 4: To a mixture of A-(l-(3-(U / -indazol-l-yl) pyridin-2-yl)-2-(2,4- difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (350 mg, 0.770 mmol) in DCM (5 mL) was added HC1 (4 M in dioxane, 5 mL, 20.00 mmol) at room temperature. The reaction was stirred at room temperature for 1 h then concentrated in vacuum. The residue was purified by / Vc -HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm, 10 p; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% to 50% B in 6 min; 210 / 254 nm; to afford the racemic product. The racemic product was resolved by Chiral / c -HPLC with the following conditions: Column: Lux 5u Cellulose-4, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex (8 mmol / L NH3 MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 20% B in 18.5 min; 220 / 254 nm; (fast peak) to afford the title compound, Example 20, (S or A)-l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(2,4- difhiorophenyl)ethanamine. MS ESI calculated for C20H16F2N4 [M + H]+, 351.13, found 351.05.

[0271] And (slow peak) to afford isomeric compound, (R or 5)-l-(3-(U7-indazol-l-yl) pyridin- 2-yl)-2-(2,4-difluorophenyl) ethanamine. MS ESI calculated for C20H16F2N4 [M + H]+, 351.13, found 351.10.EXAMPLE 21(S or R)- 1 -(3 -(1 JT-indazol- 1 -yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3 -methylpiperidin- 1 -yDethan- 1 - amine hydrochloride

[0272] Step 1: (S)-l -(2, 2-dimethoxyethyl)-4,4-difluoro-3 -methylpiperidine. To a solution of (S)-4,4-difluoro-3 -methylpiperidine hydrochloride (1.5g, 8.74 mmol) and 2 -bromo- 1,1- dimethoxyethane (1.446 ml, 12.24 mmol) in DMF (10 ml) was added DIPEA (4.58 ml, 26.2 mmol). The mixture was heated to 60 °C, stirred overnight, then cooled to RT and 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, eluting with (0-50% ethyl acetate / hexane) to give the title compound.

[0273] Step 2: (S)-2-(4,4-difluoro-3 -methylpiperidin- l-yl)acetaldehy de hydrochloride. To a solution of (S)-l -(2, 2-dimethoxyethyl)-4,4-difluoro-3 -methylpiperidine (1.2g, 5.37 mmol) in 1,4-25958 dioxane (15 ml) was added 37% HC1 in H2O (6ml, 73.1 mmol). The mixture was heated to 70 °C and stirred for 5 hours and concentrated in vacuo to give the title compound.

[0274] Step 3: (S)-N-(2-(4,4-difluoro-3-methylpiperidin-l-yl)ethylidene)-2-methylpropane-2- sulfinamide. To a solution of (S)-2-(4,4-difluoro-3-methylpiperidin-l-yl)acetaldehyde hydrochloride (1.2g, 5.62 mmol) in DCE (20 ml) was added 2-methylpropane-2-sulfinamide (0.681 g, 5.62 mmol) and titanium(iv) ethoxide (1.922 g, 8.42 mmol). The mixture was heated to 80 °C and stirred for 1 hour, cooled to rt and added 0.5 ml H2O. The mixture was stirred at rt for 1 hour, filtered through a pad of Celite to remove the solid. After washed with extra ethyl acetate, the combined filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with (0-60% ethyl acetate / hexane) to give the title compound. LCMS m / z (M+H): calculated 281.4, observed 281.5.

[0275] Step 4: N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S)-4,4-difhioro-3-methylpiperidin-l- yl)ethyl)-2-methylpropane-2-sulfinamide. To a solution of l-(2-iodopyridin-3-yl)-lH-indazole (250 mg, 0.779 mmol) in THF (8 ml) at -78 °C was added 1.3 M isopropylmagnesium chloride lithium chloride complex in THF (0.611 ml, 0.794 mmol). The mixture was stirred at -78 °C for 30 minutes, then warmed to 0 °C, followed by addition of solution of N-((E)-2-((S)-4,4-difluoro- 3-methylpiperidin-l-yl)ethylidene)-2-methylpropane-2-sulfinamide (131 mg, 0.467 mmol) in 1ml THF, then the reaction mixture was warmed to rt and stirred overnight. The reaction was quenched with satutrated aqueous NH4CI, 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, eluting with (0-100% ethyl acetate / hexane to give the title compound. LCMS m / z (M+H): calculated 476.6, observed 476.6.

[0276] Step 5: tert-butyl ((S or A)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3- methylpiperidin-l-yl)ethyl)carbamate To a solution of N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2- ((S)-4,4-difluoro-3-methylpiperidin-l-yl)ethyl)-2-methylpropane-2-sulfmamide (110 mg, 0.231 mmol) in MeOH (0.5 ml) was added 4 M HC1 in 1,4-dioxane (0.5 ml, 2.00 mmol). The mixture was stirred at rt for Ih and concentrated in vacuo. The residue was dissolved in DCM (2 ml), added (BOC)2O (0.081 ml, 0.347 mmol) and EtsN (0.129 ml, 0.925 mmol). The resulting mixture was stirred at rt for 3 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with (0-100% ethyl acetate / hexane) to give a mixture which was further separated by SFC (AS-H column, 45% MeOH as co-solvent) to give the title compound (second eluted fraction). LCMS m / z (M+H): calculated 472.5, observed 472.5.

[0277] Step 6: (S or A)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3- methylpiperidin-l-yl)ethan-l -amine hydrochloride To a solution of tert-butyl ((S or R)-l-(3-(lH-25958 indazol-l-yl)pyri din-2 -yl)-2-((S)-4,4-difluoro-3-methylpiperi din- l-yl)ethyl)carbamate (44 mg, 0.093 mmol) in MeOH (0.5ml) was added 4 M HC1 in 1,4-dioxane (0.5ml, 2.000 mmol)). The mixture was stirred at rt for 2 hours and concentrated under reduced presurre to give the title compound Example 21 (second eluted fraction). LCMS m / z (M+H): calculated 372.4, observed 372.5.EXAMPLE 22(S or7?)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or 7?)-4,4-difluoro-2-methylpiperidin-l- yl)ethan-l -amine hydrochloride

[0278] Step 1 : N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(4,4-difluoro-2-methylpiperidin-l- yDethyl)- 1 , 1 -diphenylmethanimine To a solution of 4,4-difluoro-2-methylpiperidine hydrochloride (331 mg, 1.931 mmol) in DMF (3 ml) in a tube was added paraformaldehyde (87 mg, 2.70 mmol), cesium carbonate (1006 mg, 3.09 mmol) and N-((3-(lH-indazol-l-yl)pyridin-2- yl)m ethyl)- 1,1 -diphenylmethanimine (300 mg, 0.772 mmol), and the tube was sealed. The mixture was heated to 90 °C, stirred overnight, then cooled to rt and partitioned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated to give the title compound.

[0279] Step 2: l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(4,4-difluoro-2-methylpiperidin-l- yDethan-l -amine To a solution of N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(4,4-difluoro-2- methylpiperi din- l-yl)ethyl)- 1,1 -diphenylmethanimine (414 mg, 0.773 mmol) in MeOH (2 ml) was added 4.0 M HCI in 1,4-dioxane (2 ml, 8.00 mmol). The mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with (0-5% 2N NH3 in MeOH / DCM) to give the title compound. LCMS m / z (M+H): calculated 372.4, observed 372.5.

[0280] Step 3: tert-butyl ((S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-4,4-difluoro- 2-methylpiperidin-l-yl)ethyl)carbamate To a solution of l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2- (4,4-difluoro-2-methylpiperidin-l-yl)ethan-l -amine (90 mg, 0.242 mmol) in CH2Q2 (2 ml) was added (BOC)2O (0.084 ml, 0.363 mmol) and EtsN (0.051 ml, 0.363 mmol). The mixture was stirred at rt for 4 hours and concentrated in vacuo. The residue was purified by SFC (AD column,2595810% MeOH co-solvent) to give the title compound (second eluted fraction). LCMS m / z (M+H): calculated 472.5, observed 472.5.

[0281] Step 4: (S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-4,4-difluoro-2- methylpiperidin-l-yl)ethan-l -amine hydrochloride To a solution of tert-butyl ((S or R)-l-(3-(lH- indazol-l-yl)pyri din-2 -yl)-2-((S or R)-4,4-difluoro-2-methylpiperidin-l-yl)ethyl)carbamate (compound from step 3) (22 mg, 0.047 mmol) in MeOH (0.5 ml) was added 4.0 M HC1 in 1,4- dioxane (0.5 ml, 2.000 mmol). The mixture was stirred at rt for 2 hours and concentrated in vacuo to give the title compound, Example 22. LCMS m / z (M+H): calculated 372.4, observed 372.4.EXAMPLE 23(S or7?)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or 7?)-3,3-difluoro-4-methylpyrrolidin-l- yDethan-l -amine hydrochloride

[0282] Step 1 : N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(3 -difhioro-4-methylpyrrolidin-l- yPethyl)- 1 , 1 -diphenylmethanimine To a tube containing a solution of 3,3-difluoro-4- methylpyrrolidine hydrochloride (304 mg, 1.931 mmol) in 2-propanol (6 ml) was added paraformaldehyde (74.8 mg, 2.317 mmol), cesium carbonate (1006 mg, 3.09 mmol) and N-((3- (IH-indazol-l-yl)pyri din-2 -yl)m ethyl)- 1,1 -diphenylmethanimine (300 mg, 0.772 mmol)), and the tube was sealed. The mixture was heated to 100 °C, stirred overnight, then cooled to rt and partitioned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated to give the title compound.

[0283] Step 2: tert-butyl ((S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-4,4-difluoro- 2-methylpiperidin-l-yl)ethyl)carbamate To a solution of N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)- 2-(3, 3 -difluoro-4-methylpyrrolidin-l-yl)ethyl)- 1,1 -diphenylmethanimine (403mg, 0.773 mmol) in MeOH (1 ml) was added 4M HCI in 1,4-dioxane (1 ml, 4.00 mmol). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was redissoved in MeOH (1 ml), followed by addition of EtsN (0.431 ml, 3.09 mmol) and (BOC)2O (422 mg, 1.931 mmol). The mixture was stirred at rt for 3 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with (0-40% ethyl acetate / hexane) to give a racemate25958 which was further separated by SFC (AS-H column, 20% EtOH with 0.2% DIPA as co-solvent) to give the title compound (second eluted fraction). LCMS m / z (M+H): calculated 457.5, observed 457.5.

[0284] Step 3: (S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-3,3-difluoro-4- methylpyrrolidin-l-yl)ethan-l -amine hydrochloride To a solution of tert-butyl ((S or R)-l-(3- (IH-indazol-l-yl)pyri din-2 -yl)-2-((S or R)-4,4-difluoro-2-methylpiperidin-l-yl)ethyl)carbamate (26 mg, 0.057 mmol) in MeOH (0.5 ml) was added 4 M HC1 in 1,4-dioxane (0.014 ml, 0.057 mmol). The mixture was stirred at rt for 2 hours and concentrated in vacuo, to give the title compound, Example 23. LCMS m / z (M+H): calculated 358.4, observed 358.4.(S or A)-l-(3- indazol-l-yl)pyridin-2-yl)-2-(( or A)-3 -(trifluorom ethoxy )pyrrolidin-l- yDethan-l -amine

[0285] Step 1: N-(l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(3-(trifluoromethoxy)pyrrolidin-l- yl)ethyl)-l,l-diphenylmethanimine. To a tube containing a solution of 3-(trifluorom ethoxy )pyrroli dine hydrochloride (185 mg, 0.965 mmol) in 2-propanol (2 ml) was added paraformaldehyde (37.4 mg, 1.158 mmol), cesium carbonate (503 mg, 1.545 mmol) and N-((3-(lH-indazol-l-yl)pyridin-2-yl)methyl)-l,l-diphenylmethanimine (150 mg, 0.386 mmol), and the tube was sealed. The mixture was heated to 100 °C, stirred overnight, then cooled to rt and partitioned between ethyl acetate and water. The separated organic phase was dried over Na2SO4, filtered and concentrated to give the title compound.

[0286] Step 2: tert-butyl ((S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-3- (trifluoromethoxy) pyrrolidin-l-yl)ethyl)carbamate. To a solution of N-(l-(3-(lH-indazol-l- yl)pyridin-2-yl)-2-(3 -(trifluoromethoxy)pyrrolidin- 1 -yl)ethyl)- 1 , 1 -diphenylmethanimine (215 mg, 0.387 mmol) in MeOH (1 ml) was added 4 M HC1 in 1,4-dioxane (1 ml, 4.00 mmol). The mixture was stirred at rt for 2 hours and concentrated in vacuo. The residue was redissolved in MeOH (1 ml), followed by addition of EtsN (0.216 ml, 1.548 mmol) and ((BOC)2O (169 mg, 0.774 mmol). The mixture was stirred at rt for 3 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with (0-40% ethyl acetate / 25958 hexane) to give a mixture which was further separated by SFC (AS-H column, 20% EtOH with 0.2% DIPA as co-solvent) to give the title compound (first eluted fraction). LCMS m / z (M+H): calculated 492.5, observed 492.5.

[0287] Step 3: (S or R)-l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S or R)-3- (trifluoromethoxy)pyrrolidin-l-yl)ethan-l-amine. To a solution of tert-butyl (l-(3-(lH-indazol-l- yl)pyridin-2-yl)-2-(3-(trifluoromethoxy)pyrrolidin-l-yl)ethyl)carbamate (from Example 24, Step 2) (13 mg, 0.026 mmol) in MeOH (0.25ml) was added 4M HC1 in 1,4-di oxane (0.25ml, 1.000 mmol). The mixture was stirred at rt for 2h and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (0-5% 2N NH3 in MeOH / DCM) to give title compound, Example 24. LCMS m / z (M+H): calculated 392.4, observed 392.4.EXAMPLE 25(S or R)- 1 -(3 -( UT-indazol- 1 -yDpyri din-2 -yl)-2-(3 -fluorophenoxy)ethan- 1 -amine, 2,2,2- trifluoroacetate

[0288] Step 1 : To a solution of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2- hydroxyethyl)carbamate (220 mg, 0.621 mmol) in toluene (4 mL) were added l-fluoro-3- iodobenzene (207 mg, 0.931 mmol), Rockphos Pd G3 ([(2-Di-tert-butylphosphino-3-methoxy-6- methyl-2',4',6'-triisopropyl-l,l'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate)(52.0 mg, 0.062 mmol) and cesium carbonate (405 mg, 1.241 mmol) at room temperature under N2. The reaction was stirred at 90 °C for 16 h. The solvent was removed, and the residue was purified by silica gel column chromatography, eluting with 0 ~ 65% EtOAc in PE to give racemic tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(3- fhiorophenoxy)ethyl)carbamate. ESI calculated for C25H26FN4O3 [M + H]+, 449.19, found 449.20.

[0289] Step 2 : The racemic material from Step 1 was separated by prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane (0.5% 2M NH3 in MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% to 10% in 33 min; Wave Length: 220 / 254 nm, to give the fast peak (single isomer), tert-butyl (l-(3-(UT- indazol- 1 -yl)pyri din-2 -yl)-2-(3 -fluorophenoxy )ethyl)carbamate. ESI calculated for C25H26FN4O3 [M + H]+, 449.19, found 449.20. And the slow peak (single isomer), tert-butyl (l-(3-(177-indazol-25958 l-yl)pyridin-2-yl)-2-(3-fluorophenoxy)ethyl)carbamate. ESI calculated for C25H26FN4O3 [M + H]+, 449.19, found 449.20.

[0290] Step 3: A mixture of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(3- fluorophenoxy)ethyl)carbamate (60 mg, 0.134 mmol, fast peak from Step 2) in DCM (10 mL) was added TFA (10.00 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuum to afford the isomeric product (R or 5)-l-(3- (UT-indazol-l-yl)pyri din-2 -yl)-2-(3-fluorophenoxy)ethan-l -amine, 2,2,2-trifluoroacetate. ESI calculated for C20H18FN4O [M + H]+, 349.14, found 349.10.

[0291] Step 4: A mixture of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(3- fluorophenoxy)ethyl)carbamate (30 mg, 0.067 mmol, slow peak from Step 2) in DCM (10 mL) was added TFA (10.00 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuum to afford the title compound, Example 25, (5 or >)- l -(3-( IT / -indazol- l -yl)pyridin-2-yl)-2-(3-fluorophenoxy)ethan- l -amine, 2,2,2-trifluoroacetate. ESI calculated for C20H18FN4O [M + H]+, 349.14, found 349.10.EXAMPLE 26(S or R)- 1 -(3 -( 1 JT-indazol- 1 -yDpyri din-2 -yD- ^-methyl- ^-fS , 3 ,3 -trifluoropropyDethane- 1,2- diamine 2,2,2-trifluoroacetate

[0292] Step 1 : Into a 8-mL vial purged and maintained with an inert atmosphere of argon, were placed nickel(II) chloride ethylene glycol dimethyl ether complex (0.120 g, 0.547 mmol), 4,4'-di- tert-butyl-2,2'-bipyridine (0.147 g, 0.547 mmol) and DMA (6 mL). The mixture was stirred at 60 °C for 30 min. In an another 40 mL vial, purged and maintained with an inert atmosphere of argon, were placed 1 -(2 -brom opyri din-3 -yl)-U7-indazole (1.5 g, 5.47 mmol), 3- (((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.78 g, 8.21 mmol), CS2CO3 (5.35 g, 16.42 mmol) and (Ir[DF(CF3)ppy]2(dtbpy))PFe (0.061 g, 0.055 mmol) in 1,4-di oxane (24 mL). The resulting mixture was stirred at room temperature for 5 min. The previous reaction mixture was transferred to this 40 mL vial via syringe. The resulting mixture was irradiated with blue LED for 20 h at ambient temperature. The reaction was quenched with brine (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were25958 dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1-60% ethyl acetate in PE to give benzyl tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)ethane-l,2- diyl)dicarbamate. MS ESI calculated for C27H30N5O4 [M + H]+, 488.22, found 488.30

[0293] Step 2 : To a mixture of benzyl tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)ethane- l,2-diyl)dicarbamate (1.6 g, 3.28 mmol) in THF (10 mL) was added Pd / C (1.048 g, 9.84 mmol) at room temperature under argon atmosphere. The suspension was degassed under vacuum and purged with H2 several times, and then it was stirred under 1 atm of H2 at room temperature for 3 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by c -HPLC under the following conditions; Column: SunFire Prep Cl 8 OBD Column, 19 x 150 mm, 5 pm, 10 nm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 15% B to 50% B in 6 min, 210 nm; to give tert-butyl (l-(3-(lrt-indazol-l-yl)pyridin-2-yl)-2- aminoethyl)carbamate. MS ESI calculated for C19H24N5O2 [M + H]+, 354.19, found 354.25.

[0294] Step 3 : To a solution of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2- aminoethyl)carbamate (200 mg, 0.566 mmol) in EtOH (5 mL) was added 3,3,3-trifluoropropanal (127 mg, 1.132 mmol) at room temperature. The reaction was stirred at 40 °C for 0.5 h. Then the sodium cyanoborohydride (0.095 mL, 1.698 mmol) was added to the mixture. The reaction was stirred at 40 °C for 0.5 h. Saturated aq. NH4CI (30 mL) was added to the mixture, and the inorganic precipitate was filtered through a pad of Celite. The filtrate was extracted with ethyl acetate (3 x 50 mL), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4.The mixture was concentrated in vacuum to afford crude which was purified by silica gel column chromatography, eluting with 20 % EtOAc in PE to give tert-butyl ( I -(3-( lrt-indazol- l - yl)pyridin-2-yl)-2-((3,3,3-trifluoropropyl)amino)ethyl)carbamate. ESI calculated for C22H27F3N5O2 [M + H]+, 450.20, found 450.25.

[0295] Step 4: To a solution of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-((3,3,3- trifluoropropyl)amino)ethyl)carbamate (50 mg, 0.111 mmol) in EtOH (5 mL) was added formaldehyde at room temperature. The reaction was stirred at room temperature for 0.5 h. Then sodium cyanoborohydride (0.019 mL, 0.334 mmol) was added to the reaction mixture. The reaction was stirred at 40 °C for 0.5 h. The mixture was quenched by saturated aq. NH4CI (15 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over Na2SO4, filtered. The filtrate was concentrated in vacuo to give the residue. The residue was purified by silica gel column chromatography, eluting with 40% EtOAc in PE to give racemic tert-butyl (l-(3-(lrt-indazol-l-yl)pyridin-2-yl)-2-(methyl(3,3,3-25958 trifluoropropyl)amino)ethyl)carbamate. ESI calculated for C23H29F3N5O2 [M + H]+, 464.22, found 464.30.

[0296] Step 5 : The racemic material from Step 4 was separated by / vc -chiral-HPLC with the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 pm; Mobile Phase A: Hexane (0.5% 2M NHs-MeOH), Mobile Phase B: IP A; Flow rate: 20 mL / min; Gradient: 15% to 15% in 8 min. to give the fast peak (single isomer), tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2- yl)-2-(methyl(3,3,3-trifluoropropyl)amino)ethyl)carbamate. ESI calculated for C23H29F3N5O2 [M + H]+, 464.22, found 464.25. And to give the slow peak (single isomer), tert-butyl (l-(3-(lrt- indazol-l-yl)pyridin-2-yl)-2-(methyl(3,3,3-trifluoropropyl)amino)ethyl)carbamate. ESI calculated for C23H29F3N5O2 [M + H]+, 464.22, found 464.30.

[0297] Step 6: To a solution of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2-(methyl(3,3,3- trifluoropropyl)amino)ethyl)carbamate (10 mg, 0.022 mmol, from step 5, single isomer, fast peak) in DCM (5 mL) was added TFA (5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuum to afford isomeric product, (R or S)- 1 -(3 -( UT-indazol- 1 -yl)pyridin-2-yl)-7V2-methyl-7V2-(3 , 3 ,3 -trifluoropropyl)ethane- 1,2- diamine 2,2,2-trifluoroacetate. ESI calculated for C18H21F3N5 [M + H]+, 364.17, found 464.10.

[0298] Similarly, to a solution of tert-butyl (l-(3-(U / -indazol-l-yl)pyridin-2-yl)-2- (methyl(3,3,3-trifluoropropyl)amino)ethyl)carbamate (10 mg, 0.022 mmol, from step 2, single isomer, slow peak) in DCM (5 mL) was added TFA (5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuum to afford the title compound, Example 26, (S or 7?)-l-(3-(U / -indazol-l-yl)pyridin-2-yl)-7V2-methyl-A2-(3,3,3- trifluoropropyl)ethane-l,2-diamine 2,2,2-trifluoroacetate. ESI calculated for C18H21F3N5 [M + H]+, 364.17, found 464.15.(M-l-(3-(3-(2,3-dihydrobenzorb1[L41dioxin-5-yl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yDethanamine25958

[0299] Step 1 : To a mixture of 7V-((5)-l-(3-(3-bromo-lJ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin- 2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.201 mmol) in toluene (1.5 mL) and water (0.300 mL) were added (2,3-dihydrobenzo[b][l,4]dioxin-5-yl)boronic acid (36.1 mg, 0.201 mmol), potassium phosphate (42.6 mg, 0.201 mmol) and 1, l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (13.08 mg, 0.020 mmol) at ambient temperature under argon. The reaction was stirred at 60 °C for 16 h. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 80mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column using a gradient of 0% - 20% methanol in dichloromethane to afford (5)-7V-((5)-l-(3-(3-(2,3-dihydrobenzo[b][l,4]dioxin- 5-yl)-lJ7-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfmamide. MS ESI calculated for C31H32N5O3S [M + H]+554.67, found 554.20.

[0300] Step 2: To a mixture of (5)-7V-((S)-l-(3-(3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-177- indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (50 mg, 0.090 mmol) in di chloromethane (5 mL) was added hydrogen chloride (4 M in l,4-dioxane)(l mL, 4 mmol) at rt. The reaction was stirred at ambient temperature for Ih. LCMS showed major was product. The resulted solution was concentrated in vacuum to afford crude product. The residue was purified by reverse phase with the following conditions: Column, Cl 8, 80 g, mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile. Gradient: 2% B to 70% B in 35 min; Detector, UV 254 nm. to afford the title compound, Example 27, (S)- 1 -(3 -(3 -(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-5-yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C27H24N5O2 [M + H]+450.19, found 450.10.EXAMPLE 28(M-l-(3-(3-phenyl-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2- trifluoroacetate25958

[0301] Step 1 : A mixture of phenylboronic acid (36.7 mg, 0.301 mmol), (5)-A-((5)-l-(3-(3- bromo-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.201 mmol), potassium phosphate (85 mg, 0.401 mmol) and 1, l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (13.08 mg, 0.020 mmol) in toluene (1 mL) and water (0.1 mL) was stirred at 60 °C overnight. The reaction mixture was quenched with water (10 mL), and the mixture was extracted with EtOAc (5 x 10 mL). The combined organic layers were washed with brine (8 mL), dried over Na?SO4 and filtered. The filtrate was concentrated under reduced pressure to afford (5)-2-methyl-A-((5)-l -(3 -(3 -phenyl- UT-indazol-1 -yl)pyri din-2 -yl)-2- (pyridin-2-yl)ethyl)propane-2-sulfinamide. MS ESI calculated for C29H30N5OS [M + H]+496.21, found 496.25.

[0302] Step 2: To a solution of (5)-2-methyl-A-((5)-l-(3-(3-phenyl-177-indazol-l-yl)pyridin-2- yl)-2-(pyridin-2-yl)ethyl)propane-2-sulfinamide (40 mg, 0.081 mmol) in DCM (1 mL) was added HC1 (4 M in dioxane, 0.020 mL, 0.081 mmol) at room temperature under the atmosphere of argon. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19x 150 mm 5 pm 10 nm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20 B to 50 B in 4.3 min; 210 / 254 nm; to afford the title compound, Example 28, (5)-l-(3-(3-phenyl-177-indazol-l- yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C25H22N5 [M + H]+392.18, found 392.15.EXAMPLE 29(M-l-(3-(3-cyclopropyl-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2- trifluoroacetate

[0303] Step 1 : To a stirred solution of (5)-A-((5)-l-(3-(3-bromo-lZ / -indazol-l-yl)pyridin-2-yl)- 2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.401 mmol), 1, l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (26.2 mg, 0.040 mmol) and potassium phosphate25958(187 mg, 0.883 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL) was added 2-cyclopropyl- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (101 mg, 0.602 mmol) at room temperature under argon atmosphere. The reaction mixture was stirred at 60 °C for 16 h and quenched with water (10 mL). The mixture was extracted with ethyl acetate (5 x 20 mL), and the combined organic layers were washed with brine (8 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give (5)-A-((5)-l -(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyri din-2-yl)-2- (pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C26H30N5OS [M + H]+, 460.21, found 460.20.

[0304] Step 2: To a solution of1 -(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyri din-2 -yl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.326 mmol) in DCM (2 mL) was added hydrogen chloride (4 M in dioxane, 2 mL, 8.00 mmol) at 25°C under argon atmosphere. The reaction was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm 5 pm 10 nm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 5 B to 45 B in 6 min; 254 nm; to afford the title compound, Example 29, (5)- 1 -(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyridin-2-yl)-2-(pyri din-2 - yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C22H22N5 [M + H]+, 356.18, found 356.15.EXAMPLE 30(M-l-(3-(3-cyclobutyl-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2- trifluoroacetate

[0305] Step 1: To a mixture of (5)-A-((5 -l-(3-(3-bromo-17 / -indazol-l-yl)pyridin-2-yl)-2- (pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 1.404 mmol), nickel(II) iodide (43.9 mg, 0.140 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (37.7 mg, 0.140 mmol), zinc (184 mg, 2.81 mmol) and tetrabutylammonium iodide (130 mg, 0.351 mmol) in DMPU (14 mL) were added bromocyclobutane (284 mg, 2.107 mmol) and pyridine (11.11 mg, 0.140 mmol) at room25958 temperature under argon atmosphere. The reaction mixture was stirred at 40 °C for 16 h, LCMS indicated -10% product. The mixture was filtered through a Celite pad. The filtrate was diluted with ethyl acetate (100 mL) and washed with water (10 x 30 mL). The organic layers were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography, eluting with 0 - 10% MeOH in DCM to give the crude product). Then the crude product (70 mg, 50% purity) was purified by RP-CombiFlash with the following conditions: Column: 40 g, Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B hold 5 min, 0% B to 40% B in 30 min; 210 / 254 nm. The product-containing fractions were collected and evaporated under reduced pressure to afford (5)-A-((5)-l-(3-(3-cyclobutyl-17 / -indazol-l-yl)pyridin-2-yl)-2- (pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C27H32N5OS [M + H]+, 474.22, found 474.50.

[0306] Step 2: To a solution of (5)-A-((5 - 1 -(3 -(3 -cyclob utyl-l / / -indazol-l-yl)pyri din-2 -yl)-2- (pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (30 mg, 0.057 mmol) in DCM (2 mL) was added HC1 (4 M in 1,4-di oxane, 2 mL) at room temperature. The reaction was stirred 2 h, and the solvent was removed. The residue was purified by Prep-HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm, 10 pl; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 50% B in 6 min; 210 / 254 nm. The product-containing fractions were collected and evaporated under reduced pressure to afford the title compound, Example 30, (5)- 1 -(3 -(3 -cyclobutyl- UT-indazol-1- yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C23H24N5 [M + H]+370.20, found 370.15.EXAMPLE 31(M-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)((5 or A)-5,6,7,8-tetrahydroquinolin-8- yDmethanamine

[0307] Step 1 : To a mixture of 5,6,7,8-tetrahydroquinoline (72.0 mg, 0.540 mmol) in THF (2 mL) was added / / -BuLi (2.5 M in hexane, 0.22 mL, 0.567 mmol) at -78 °C. The reaction was25958 stirred at -78 °C for 0.5 h. Then to this mixture was added (5, E)-N-((3 -(3 -cyclopropyl- 1H- indazol-l-yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (99 mg, 0.270 mmol). Then the reaction was warmed to room temperature and stirred for 1 h. The resulting solution was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product (5)-A-((15 -(3-(3- cyclopropyl-lZ / -indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methyl)-2- methylpropane-2-sulfmamide. MS ESI calculated for C29H34N5OS [M + H]+, 500.24, found 500.40.

[0308] Step 2: To a mixture of (5)-A-((15)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2- yl)(5,6,7,8-tetrahydroquinolin-8-yl)methyl)-2-methylpropane-2-sulfinamide (150 mg, 0.300 mmol) in DCM (5 mL) was added hydrochloric acid (4 ml, 16.00 mmol) at room temperature. The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19x250 mm 10 u; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 40% B in 6 min; 210 / 254 nm; fast peak fractions were collected, combined and concentrated under reduced pressure to give the title compound Example 31, (5)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)((A or S)-5, 6,7,8- tetrahydroquinolin-8-yl)methanamine. MS ESI calculated for C25H26N5 [M + H]+, 396.21, found 396.10.

[0309] Slower peak fractions were combined and concentrated under reduced pressure to give the isomeric (5)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)((5 or R)-5, 6,7,8- tetrahydroquinolin-8-yl)methanamine. MS ESI calculated for C25H26N5 [M + H]+, 396.21, found 396.10.EXAMPLE 32l-(3-(3-cyclobutyl-lZ / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethanamine25958

[0310] To a stirred mixture of 3 -cyclobutyl- I / / -indazole (63.8 mg, 0.370 mmol) in DMF (10 mL) were added Ni, A2-bis(5-methyl-[l,l'-biphenyl]-2-yl)oxalamide (56.6 mg, 0.135 mmol), 1- (3-bromopyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethanamine (100 mg, 0.337 mmol), copper (I) iodide (32.0 mg, 0.168 mmol) and K2CO3 (93 mg, 0.673 mmol) under nitrogen atmosphere. The resulting mixture was warmed to 110 °C and stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC under the following conditions: Column: XBridge C18 OBD Prep Column, 100A, 10 pm, 19 mm x 250 mm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 80% B in 5.8 min; 254 / 210 nm. to afford racemic l-(3-(3- cyclobutyl-l / 7-indazol- 1 -yl)pyri din-2 -yl)-2-(5-fluoropyrimidin-2-yl)ethanamine 2,2,2- trifluoroacetate. The racemic mixture was separated by Chiral-Prep-HPLC under the following conditions: Column: Phenomenex Lux 5 pm Cellulose-4, AXIA Packed, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex (8 mmol / L NHs.MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 25 min; 220 / 254 nm. fast peak fractions were collected and concentrated to afford the isomeric compound, 1 -(3 -(3 -cyclobutyl- l / / -indazol-l-yl)pyri din-2 -yl)- 2-(5-fluoropyrimidin-2-yl)ethanamine. MS ESI calculated for C22H22FN6 [M + H]+, 389.18, found 389.10.

[0311] And (slow peak) fractions were collected and concentrated to afford the title compound Example 32, l-(3-(3-cyclobutyl-l / 7-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2- yl)ethanamine. MS ESI calculated for C22H22FN6 [M + H]+, 389.18, found 389.15.EXAMPLE 33(M-l-(3-(3-(3,3-difluorocyclobutyl)-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine

[0312] Step 1 : To a mixture of 3,3-difluorocyclobutanecarboxylic acid (5 g, 36.7 mmol) in DCM (120 mL) were added HATU (27.9 g, 73.5 mmol) and DIEA (19.25 mL, 110 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 30min, and then N,O- dimethylhydroxylamine hydrochloride (5.38 g, 55.1 mmol) was added at ambient temperature.25958After the resulting mixture was stirred at ambient temperature for 16 h, it was quenched with water (100 mL) and extracted with DCM (3 x 150 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE - 0 to 30% to afford 3,3-difluoro-A-methoxy-A- methylcyclobutanecarboxamide. MS ESI calculated for C7H12F2NO2 [M + H]+, 180.08, found 180.05.

[0313] Step 2 : To a mixture of l-bromo-2-fluorobenzene (117 mg, 0.670 mmol) in THF (5 mL) was added / / -BuLi (2.5 M in hexane, 0.246 mL, 0.614 mmol) at -78 °C under argon. The resulting mixture was stirred at -78 °C for 30 min. Then to the mixture was added 3,3-difluoro-A- methoxy-A-methylcyclobutanecarboxamide (100 mg, 0.558 mmol) at -78 °C under argon. The resulting mixture was warmed to ambient temperature and stirred for 1 h. TLC showed the starting material was consumed completely. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative TLC (developed by EtOAc / PE = 1 : 8) to afford (3,3- difluorocyclobutyl)(2-fluorophenyl)methanone.

[0314] Step 3 : To a mixture of (3,3-difluorocyclobutyl)(2-fluorophenyl)methanone (2.27 g, 10.60 mmol) in ethanol (20 mL) was added hydrazine hydrate (80% in water) (20 mL, 10.60 mmol) at room temperature. The reaction was stirred at 80 °C for 2 h and then concentrated under vacuum to afford ((3,3-difluorocyclobutyl)(2-fluorophenyl)methylene)hydrazine. MS ESI calculated for C11H12F3N2 [M + H]+, 229.09, found 229.10.

[0315] Step 4 : A mixture of ((3,3-difluorocyclobutyl)(2-fluorophenyl)methylene)hydrazine (2.2 g, 8.00 mmol) and ethylene glycol (30 mL, 539 mmol) was stirred at 150 °C for 16 h. The resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, washed with brine (2 x 200mL), dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE = 0 ~ 10% to afford 3-(3,3-difluorocyclobutyl)-lJ / -indazole. MS ESI calculated for C11H11F2N2 [M + H]+209.08, found 209.05.

[0316] Step 5: To a mixture of (5)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethanamine (200 mg, 0.719 mmol) in DMF (5 mL) were added copper (I) iodide (13.69 mg, 0.072 mmol), potassium carbonate (199 mg, 1.438 mmol), BPMPO (60.5 mg, 0.144 mmol) and 3-(3,3- difluorocyclobutyl)-lJ / -indazole (225 mg, 1.079 mmol) at ambient temperature under argon. The resulting mixture was stirred at 110 °C for 16 h and diluted with water (20 mL). The mixture was25958 extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum, and the residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound, Example 33, (5)-l-(3-(3-(3,3-difluorocyclobutyl)-lJ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C23H22F2N5 [M + H]+, 406.18, found 406.10.EXAMPLE 34(M-l-(3-(3-cyclopentyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2- trifluoroacetate

[0317] Step 1: To a mixture of (5)-l-(3-(3-bromo-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine (90 mg, 0.228 mmol) in toluene (1.0 mL) and water (0.5 mL) were added Pd(PPhs)4 (26.4 mg, 0.023 mmol), potassium phosphate (194 mg, 0.913 mmol) and cyclopent-1- en-l-ylboronic acid (77 mg, 0.685 mmol) at ambient temperature under argon. The reaction was stirred at 100 °C for 16 h and then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of MeOH / DCM = 0 ~ 10% to afford (5)-l-(3-(3-(cyclopent-l-en-l-yl)-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine. MS ESI calculated for C24H24N5 [M + H]+, 382.20, found 382.15.

[0318] Step 3: To a mixture of (5 -l-(3-(3-(cyclopent-l-en-l-yl)-177-indazol-l-yl)pyridin-2- yl)-2-(pyridin-2-yl)ethanamine (60 mg, 0.157 mmol) in methanol (10 mL) was added Pd-C (10% on carbon, wetted with ca. 55% water) (167 mg, 0.157 mmol) at ambient temperature. The mixture was degassed with EE three times and stirred for 16 h at room temperature under the atmosphere of EE (1.5 atm). The resulting solution was filtered. The filtrate was concentrated under reduced pressure to afford crude product. The residue was purified by Prep-HPLC with the25958 following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to afford the title compound, Example 34, (5)-l-(3-(3-cyclopentyl-lH-indazol- l-yl)pyridin-2-yl)-2-(pyri din-2 -yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C24H26N5 [M + H]+, 384.20, found 384.10.EXAMPLE 35(S or A)-l-(3-(3-cyclobutyl-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine

[0319] Step 1 : To a mixture of 3 -cyclobutyl- IJT-indazole (174 mg, 1.010 mmol) and l-(3- fluoropyridin-2-yl)ethanone (141 mg, 1.010 mmol) in DMF (3 mL) was added CS2CO3 (658 mg, 2.021 mmol). The reaction mixture was stirred for 2 h at room temperature then quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated brine (5 x 10 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with 30% EtOAc in PE to afford 1 -(3 -(3 -cyclobutyl- IJT-indazol-l -yl)pyridin-2- yl)ethanone. MS ESI calculated for CisHisNsO [M + H]+292.14, found 292.15.

[0320] Step 2: To a mixture of l-(3-(3-cyclobutyl-l / / -indazol-l-yl)pyridin-2-yl)ethanone (200 mg, 0.686 mmol), 2-bromo-5-fluoropyridine (145 mg, 0.824 mmol), chloro[(4,5- bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-l, l-biphenyl)]palladium (II) (61.0 mg, 0.069 mmol) and Xantphos (39.7 mg, 0.069 mmol) in 1,4-Dioxane (6 mL) was added sodium tert-butoxide (132 mg, 1.373 mmol). The reaction mixture was stirred for 16 h at 80 °C. The reaction was quenched with saturated NH4CI (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated brine (3 x 5 mL), dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with 40% EtOAc in PE to afford 1 -(3 -(3 -cyclobutyl- 1H- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanone. MS ESI calculated for C23H20FN4O [M + H]+387.15, found 387.15.25958

[0321] Step 3: To a mixture of l-(3-(3-cyclobutyl-l / Z-indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethanone (130 mg, 0.336 mmol) in MeOH (1 mL) was added hydroxylamine hydrochloride (117 mg, 1.682 mmol). The reaction mixture was stirred for 2 h at 28 °C. The reaction mixture was quenched with water (20 mL) and extracted with DCM (4 x 10 mL). The combined organic layers were washed with saturated brine (2 x 5 mL), dried over anhydrous Na2SO4 and then concentrated under reduced pressure to afford (£)- 1 -(3 -(3 -cyclobutyl- H- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanone oxime. MS ESI calculated for C23H21FN5O [M + H]+402.17, found 402.30.

[0322] Step 4: To a mixture of (£)-l-(3-(3-cyclobutyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethanone oxime (140 mg, 0.349 mmol) in MeOH (2 mL) were added zinc (57.0 mg, 0.872 mmol) and ammonium acetate (134 mg, 1.744 mmol). The reaction mixture was stirred for 16 h at 40 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with / Vc -HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (10 M / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 50% B in 6 min; 210 / 254 nm; to afford a racemic mixture which was separated further with Chiral-HPLC under the following conditions: Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM = 3 : l(10mM NH3-MEOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: 2% B to 2% B in 16 min; 220 / 254 nm; fast peak fractions were combined and evaporated to afford Example 35, (5 or K)- 1 -(3 -(3 -cyclobutyl- 1H- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine. MS ESI calculated for C23H23FN5 [M + H]+388.19, found 388.15.

[0323] And slow peak fractions were combined and evaporated to afford isomeric compound (R or 5)-l-(3-(3-cyclobutyl-U / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine. MS ESI calculated for C23H23FN5 [M + H]+388.19, found 388.15.EXAMPLE 3625958(M-l-(3-(3-cyclohexyl-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine 2,2,2- trifluoroacetate

[0324] Step 1: To a mixture of (5)-l-(3-(3-bromo-lJ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine (80 mg, 0.203 mmol) in toluene (1.0 mL) and water (0.5 mL) were added Pd(PPh3)4 (23.45 mg, 0.020 mmol), K3PO4 (172 mg, 0.812 mmol) and cyclohex- 1-en-l- ylboronic acid (77 mg, 0.609 mmol) at ambient temperature under argon. The reaction was stirred at 100 °C for 16 h and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of MeOH / DCM = 0 ~ 10% to afford (5)-l-(3-(3-(cyclohex-l-en-l-yl)-17 / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl). MS ESI calculated for C25H26N5 [M + H]+, 396.21, found 396.20.

[0325] Step 2: To a mixture of (5 -l-(3-(3-(cyclohex-l-en-l-yl)-177-indazol-l-yl)pyridin-2-yl)- 2-(pyridin-2-yl)ethanamine (80 mg, 0.202 mmol) in methanol (10 mL) was added Pd-C (10% on carbon, wetted with ca.55% water) (215 mg, 0.202 mmol) at ambient temperature. The mixture was degassed with H2 three times and stirred for 16 h at room temperature under the atmosphere of H2 (1.5 atm). The resulting solution was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound Example 36, (5)- 1 -(3 -(3 -cyclohexyl- IJT-indazol-l -yl)pyri din-2 -yl)-2-(pyri din-2 - yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C25H28N5 [M + H]+, 398.23, found 398.10.EXAMPLE 37(M-l-(3-(3-(bicyclori.L 11pentan-l-yl)-lZ / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine

[0326] Step 1 : Into a 4 mL vial were placed nickel (II) chloride hexahydrate (4.81 mg, 0.020 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (5.43 mg, 0.020 mmol) in DMA (1 mL). The resulting mixture was stirred at room temperature for 30 min. Into an another 50 mL vial were25958 placed (Ir[dF(CF3)ppy]2(dtbpy))PFe (22.69 mg, 0.020 mmol), CS')- / c / 7-butyl (1 -(3 -(3 -bromo- 177- indazol-l-yl)pyri din-2 -yl)-2-(pyridin-2-yl)ethyl)carbamate (100 mg, 0.202 mmol), ISfeCCh (21.44 mg, 0.202 mmol) and bicyclo[l. l.l]pentan-l-yltrifluoro-14-borane, potassium (52.8 mg, 0.303 mmol) in 1,4-dioxane (4 mL) and the resulting mixture was stirred at room temperature for5 min. The previous reaction mixture was transferred to this vial via syringe. After the resulting mixture was irradiated with blue LED for 3 h at ambient temperature, it was diluted with brine (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to dryness. The residue was purified by silica gel column chromatography, eluting with 0 ~ 40% ethyl acetate in petroleum ether to give CS')- / c77-butyl (l-(3-(3-(bicyclo[l. l.l]pentan-l-yl)-lJ7-indazol- l-yl)pyridin-2-yl)-2-(pyri din-2 -yl)ethyl). MS ESI calculated for C29H32N5O2 [M + H]+, 482.25, found 482.30.

[0327] Step 2: To a solution of (A')- / c77-butyl (l-(3-(3-(bicyclo[l.l.l]pentan-l-yl)-l / / -indazol- l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethyl)carbamate (30 mg, 0.062 mmol) in DCM (2 mL) was added HC1 (4 M in ethyl acetate, 2.000 mL) at room temperature. After the reaction was stirred for 3 h, the solvent was removed and the residue was purified by / Vc -HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B in6 min; 210 / 254 nm. to give the title compound Example 37, (5)-l-(3-(3-(bicyclo[l.l. l]pentan-l- yl)-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C24H24N5 [M + H]+, 382.20, found 382.20.EXAMPLE 38 AND 391 -(1 -(2-((M- 1 -amino-2-(pyri din-2 -yl)ethyl)pyri din-3 -yl)- 1 J7-indazol-3 -yl)-2,2,2-trifluoroethanol and 1 -( 1 -(2-((S)- 1 -amino-2-(pyridin-2-yl)ethyl)pyri din-3 -yl)- 1 JT-indazol -3 -yl)-2,2,2- tri fluoroethanol25958

[0328] Step 1: To a solution of (5)-tert-butyl (l-(3-(3-formyl-U / -indazol-l-yl)pyridin-2-yl)-2- (pyridin-2-yl)ethyl)carbamate (150 mg, 0.338 mmol) in DMSO (6 mL) was added trimethyl(trifluoromethyl)silane (96 mg, 0.676 mmol) at room temperature. The resulting solution was stirred for 4 h, then quenched with saturated sodium bicarbonate solution (80 mL) and extracted with ethyl acetate (4 x 60 mL). The combined organic layers were washed with brine (4 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of 0 ~ 50% ethyl acetate in petroleum ether to afford tert-butyl ((15)-2-(pyridin-2-yl)-l-(3-(3- (2, 2, 2-trifluoro-l -hydroxy ethyl)- U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate. MS ESI calculated for C26H27F3N5O3 [M + H]+, 514.20, found 514.21.

[0329] Step 2: To a solution of tert-butyl ((15)-2-(pyridin-2-yl)-l-(3-(3-(2,2,2-trifluoro-l- hy droxy ethyl)- Irt-indazol- 1 -yl)pyri din-2 -yl)ethyl)carbamate (30 mg, 0.058 mmol) in DCM (3 mL) was added hydrogen chloride (4 M in 1,4-dioxane) (3 mL, 12.00 mmol) at room temperature. The reaction mixture was stirred for 0.5 h at room temperature under nitrogen protection. The solvent was removed under reduced pressure. The residue was purified by Prep- HPLC, eluting with a gradient of 0 ~ 40% acetonitrile in water (0.01% trifluoroacetic acid) to give the product as mixture of isomers. Then the mixture of isomers was separated by Chiral- Prep-HPLC under the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM = 3: 1 (10 mM NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 2% B to 2% B in 20 min; 220 / 254 nm; to give fast peak as title compound, (single isomer), Example 38, l-(l-(2-((5)-l-amino-2-(pyri din-2 -yl)ethyl)pyri din-3 -yl)-lrt- indazol-3-yl)-2,2,2-trifhioroethanol. MS ESI calculated for C21H19F3N5O [M + H]+, 414.15, found 414.10.

[0330] And the slow peak (single isomer), title compound Example 39, l-(l-(2-((5)-l-amino-2- (pyri din-2 -yl)ethyl)pyri din-3 -yl)-lrt-indazol-3-yl)-2, 2, 2-trifluoroethanol. MS ESI calculated for C21H19F3N5O [M + H]+, 414.15, found 414.10.EXAMPLE 4025958 l-(3-(3-(2,2-difluorocyclopropyl)-lJ / -indazol-l-yl)pyridin-2-yl)-2-(3,5-difluoropyridin-2- yDethanamine

[0331] A mixture of 3-(2,2-difluorocyclopropyl)-U / -indazole (50 mg, 0.257 mmol), potassium carbonate (107 mg, 0.772 mmol), BPMPO (21.66 mg, 0.051 mmol), Cui (4.90 mg, 0.026 mmol) and l-(3-bromopyridin-2-yl)-2-(3,5-difluoropyridin-2-yl)ethanamine (81 mg, 0.257 mmol) in DMF (1 mL) was stirred for 2 h at 110 °C. The reaction was quenched with water (30 mL) and extracted with DCM (5 x 30 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous ISfeSCL, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC, eluted with a gradient of acetonitrile: water (0.01% trifluoroacetic acid) - 0: 1 to 1 :3 to afford the title compound Example 40, l-(3-(3- (2,2-difluorocyclopropyl)-lZ / -indazol-l-yl)pyridin-2-yl)-2-(3,5-difluoropyridin-2-yl)ethanamine (fast peak), MS ESI calculated for C22H18F4N5 [M + H]+428.14 found 428.05.

[0332] And isomeric compound l-(3-(3-(2,2-difluorocyclopropyl)-17 / -indazol-l-yl)pyridin-2- yl)-2-(3,5-difluoropyridin-2-yl)ethanamine (slow peak), MS ESI calculated for C22H18F4N5 [M + H]+428.14 found 428.05.EXAMPLE 41 AND 42

[0333] Step 1 : To a mixture of 3 -fluorocyclobutanecarboxylic acid (2 g, 16.93 mmol) in DCM (40 mL) were added HATU (12.88 g, 33.9 mmol) and DIEA (8.87 mL, 50.8 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 30 min, and then to the mixture was added A,O-dimethylhydroxylamine hydrochloride (2.478 g, 25.4 mmol) at ambient temperature. After the reaction was stirred at ambient temperature for 16 h, it was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by reverse phase with the followingconditions: Column, C18, 120 g, 24 x 180 mm; mobile phase: acetonitrile in water (0.05% TFA), 34%-95% in 8 min; Detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure to give 3-fluoro-A-methoxy-A- methylcyclobutanecarboxamide. MS ESI calculated for C7H13FNO2 [M + H]+, 162.09, found 162.10

[0334] Step 2 : To a mixture of l-bromo-2-fluorobenzene (1.086 g, 6.20 mmol) in THF (15 mL) was added w-BuLi (2.5M in hexane, 2.482 mL, 6.20 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 1 h, and then to the mixture was added 3-fluoro-A-methoxy-A- methylcyclobutanecarboxamide (1.0 g, 6.20 mmol) at -78 °C. The reaction was stirred at ambient temperature for 2 h. The resulting solution was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE = 0 ~ 50% to afford (3-fhiorocyclobutyl)(2-fluorophenyl)methanone. MS ESI calculated for C11H11F2O [M + H]+, 197.07, found 197.00.

[0335] Step 3 : To a mixture of (3-fluorocyclobutyl)(2-fluorophenyl)methanone (670 mg, 3.41 mmol) in ethanol (10 mL) was added hydrazine hydrate (10 mL, 3.41 mmol) at ambient temperature. The mixture was stirred at 80 °C for 16 h and then concentrate in vacuum to afford crude product. To the crude product was added ethylene glycol (30 mL, 3.41 mmol). The reaction was stirred at 150 °C for 16h. The resulting solution was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE = 0 ~ 50% to afford 3-(3-fluorocyclobutyl)- UT-indazole (fast peak, cis or trans). MS ESI calculated for C11H12FN2 [M + H]+, 191.09, found 191.10.

[0336] And 3-(3-fluorocyclobutyl)-U / -indazole (slow peak, trans or cis). MS ESI calculated for C11H12FN2 [M + H]+, 191.09, found 191.10.

[0337] Step 4 : To a mixture of (5)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethanamine (fast peak, 100 mg, 0.360 mmol) in DMF (2 mL) were added BPMPO (30.2 mg, 0.072 mmol), K2CO3 (99 mg, 0.719 mmol), Cui (6.85 mg, 0.036 mmol) and 3-(3-fluorocyclobutyl)-U / -indazole (75 mg, 0.395 mmol) at ambient temperature. The resulting mixture was stirred at 110 °C for 2 h and then concentrated in vacuum. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 u; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to afford the title compound (single isomer) Example 41, (5)- 1 -(3 -(3 -(3 -fluorocyclobutyl)- 1JT- indazol-l-yl)pyri din-2 -yl)-2-(pyri din-2 -yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C23H23FN5 [M + H]+, 388.18, found 388.05.

[0338] To a mixture of (5)- 1 -(3 -brom opyri din-2 -yl)-2-(pyri din-2 -yl)ethanamine (slow peak, 100 mg, 0.360 mmol) in DMF (2 mL) were added BPMPO (30.2 mg, 0.072 mmol), K2CO3 (99 mg, 0.719 mmol), Cui (6.85 mg, 0.036 mmol) and 3 -(3 -fluorocyclobutyl)- UT-indazole (75 mg, 0.395 mmol) at ambient temperature under argon. The reaction was stirred at 110 °C for 2 h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm lOu; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% to 50% B in 6 min; 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give the isomeric title compound (single isomer) Example 42, (5)-l-(3-(3-(3-fluorocyclobutyl)-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine 2,2,2-trifluoroacetate. MS ESI calculated for C23H23FN5 [M + H]+, 388.18, found 388.05.EXAMPLE 43

[0339] (5 or R)- 1 -(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyridin-2-yl)-2-(4-methylthiazol-2- yl)ethanamine

[0340] Step 1: To a mixture of (4-methylthiazol-2-yl) methanol (1 g, 7.74 mmol) in DMF (10 mL) was added TEA (2.158 mL, 15.48 mmol) at room temperature. A solution of Ms-Cl (0.905 mL, 11.61 mmol) in DMF (ImL) was added at 0°C and stirred for 2 h at 0 °C. The mixture was diluted with DCM (3 xlOO mL), washed with saturated aqueous of ammonium chloride (200 mL). The organic layer was washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure to afford (4-methylthiazol-2-yl) methyl methanesulfonate. MS ESI calculated for C6H10NO3S2 [M + H]+208.00 found 208.25.25958

[0341] Step 2: To a mixture of l-(3-bromopyridin-2-yl)-7V-(diphenylmethylene) methanamine (339 mg, 0.965 mmol) in DCM (8 mL) were added (4-methylthiazol-2-yl) methyl methanesulfonate (200 mg, 0.965 mmol), TBAI (35.6 mg, 0.096 mmol), K2CO3 (1334 mg, 9.65 mmol) and KOH (541 mg, 9.65 mmol) at room temperature. After the reaction mixture was stirred for 16 h at room temperature, it was filtered. The filtrate was quenched with water (50 mL) and extracted with DCM (5 x 30 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to afford l-(3-bromopyridin-2-yl)-A-(diphenylmethylene)-2-(4-methylthiazol- 2-yl) ethanamine. MS ESI calculated for C24H2iBrN3S [M + H]+462.06 found 462.15.

[0342] Step 3 : To a mixture of l-(3-bromopyridin-2-yl)-A-(diphenylmethylene)-2-(4- methylthiazol-2-yl) ethanamine (400 mg, 0.865 mmol) in DCM (4 mL) was added 4 M HC1 in dioxane (431 mg, 3.46 mmol) at room temperature. The resulting mixture was stirred for 30min at room temperature and then concentrated under reduced pressure. The residue was purified by RP -flash, eluted with 80% ACN in water (0.1% TFA) to afford l-(3-bromopyridin-2-yl)-2-(4- methylthiazol-2-yl) ethanamine. MS ESI calculated for CnHnBrNsS [M + H]+297.99 found 298.05.

[0343] Step 4 : To a mixture of l-(3-bromopyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine (200 mg, 0.671 mmol) in DMF (4 mL) were added 3-cyclopropyl-U / -indazole (106 mg, 0.671 mmol), Cui (12.77 mg, 0.067 mmol), K2CO3 (185 mg, 1.341 mmol) and BPMPO (56.4 mg, 0.134 mmol) at room temperature. The reaction mixture was stirred for 2 h at 110 °C then purified by / Vc -HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient:20% B to 50% B in 6 min; 210 / 254 nm; to afford the racemic mixture which was separated with chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2.0 cm x 25 cm; Mobile Phase A: Hex (8mmol / L NHs.MeOH)— HPLC, Mobile Phase B: IP A— HPLC; Flow rate:20 mL / min; Gradient: 10% B to 10% B in 22 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford isomeric compound, (R or 5)-l-(3-(3- cyclopropyl-U7-indazol-l-yl)pyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine. MS ESI calculated for C21H22N5S [M + H]+376.15 found 376.05.

[0344] And slow peak fractions were combined and concentrated to afford the title compound Example 43, (5 or A)-l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(4-methylthiazol-2- yl)ethanamine. MS ESI calculated for C21H22N5S [M + H]+376.15 found 376.05.25958EXAMPLE 44 AND 45single isomer, fast peak single isomer, slow peak(lM-l-(3-(3-(3,3-difluorocyclopentyl)-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine

[0345] Step 1 : To a mixture of 3, 3 -difluorocyclopentanecarboxylic acid (1 g, 6.66 mmol) in DCM (20 mL) were added HATU (5.07 g, 13.32 mmol) and DIEA (3.49 mL, 19.98 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 30 min, and then to the mixture was added A,O-dimethylhydroxylamine hydrochloride (0.975 g, 9.99 mmol) at ambient temperature. After the reaction was stirred at ambient temperature for 16 h, it was quenched with water (20mL) and extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE = 0 ~ 50% to afford 3,3-difluoro-A-methoxy-A- methylcyclopentanecarboxamide. MS ESI calculated for C8H14F2NO2 [M + H]+, 194.09, found 194.10.

[0346] Step 2: To a mixture of l-bromo-2-fluorobenzene (1.196 g, 6.83 mmol) in THF (20 mL) was added w-BuLi (2.5M in Hexane) (0.401 g, 6.26 mmol) at -78 °C under argon. The resulting mixture was stirred at -78 °C for 1 h, and then to the mixture was added 3,3-difluoro-A- methoxy-A-methylcyclopentanecarboxamide (1.1 g, 5.69 mmol) at -78 °C. The reaction was stirred at ambient temperature for 1 h. The resulting solution was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of DCM / PE = 0 ~ 25% to afford (3,3-difluorocyclopentyl)(2-fluorophenyl)methanone.

[0347] Step 3 : To a mixture of (3,3-difluorocyclopentyl)(2-fluorophenyl)methanone (1.34 g, 5.87 mmol) in ethanol (30 mL) was added hydrazine hydrate (80% in water) (30 mL, 5.87 mmol) at ambient temperature. The reaction was stirred at 80 °C for 16 h and then concentrated in25958 vacuum to afford ((3,3-difluorocyclopentyl)(2-fluorophenyl)methylene)hydrazine. MS ESI calculated for C12H14F3N2 [M + H]+, 243.10, found 243.15.

[0348] Step 4 : A mixture of ((3,3-difluorocyclopentyl)(2-fluorophenyl)methylene)hydrazine (2.01 g, 4.40 mmol) and ethylene glycol (30 mL, 538 mmol) was stirred at 150 °C for 16 h. The resulting solution was quenched with water (20mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc / PE = 0 ~ 20% to afford 3 -(3,3- difluorocyclopentyl)-l / Z-indazole. MS ESI calculated for C12H13F2N2 [M + H]+223.10, found 223.10.

[0349] Step 5: To a mixture of (5)-l-(3-bromopyridin-2-yl)-2-(pyridin-2-yl)ethanamine (200 mg, 0.719 mmol) in DMF (2 mL) were added BPMPO (60.5 mg, 0.144 mmol), K2CO3 (199 mg, 1.438 mmol), Cui (13.69 mg, 0.072 mmol) and 3-(3,3-difluorocyclopentyl)-17 / -indazole (176 mg, 0.791 mmol) at ambient temperature under argon. The resulting mixture was stirred at 110 °C for 2 h and then diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum, and the residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the product as mixture of isomers. The product mixture was separated by preparative chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2.0 cm I.D. * 25 cm L; Mobile Phase A: Hex (0.2% IP A), Mobile Phase B: IP A; Flow rate: 20 mL / min; Gradient: 10% to 10% B in 26 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford the title compound, Example 44 (single isomer), (15 -l-(3-(3-(3,3- difluorocyclopentyl)-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C24H24F2N5 [M + H]+, 420.19, found 420.10.

[0350] And slow peak fractions were combined and concentrated to afford Example 45 (single isomer), (15)-l-(3-(3-(3,3-difluorocyclopentyl)-U / -indazol-l-yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine. MS ESI calculated for C24H24F2N5 [M + H]+, 420.19, found 420.10.25958l-(3-(3-cyclopropyl-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine

[0351] To a mixture of 1 -(3 -brom opyri din-2 -yl)-2-(5-fluoropyri din-2 -yl)ethanamine (200 mg, 0.675 mmol) in DMF (4 mL) were added BPMPO (56.8 mg, 0.135 mmol), K2CO3 (187 mg, 1.351 mmol), Cui (12.86 mg, 0.068 mmol) and 3 -cyclopropyl- UT-indazole (118 mg, 0.743 mmol) at ambient temperature under argon. The reaction was stirred at 110 °C for 2 h under argon and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum, and the residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 p; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min;Gradient: 30% to 65% B in 6 min; 210 / 254 nm; to afford the racemic product. The racemic product was resolved by preparative CHIRAL-HPLC with the following conditions: Column: Lux 5u Cellulose-4, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex (8mmol / L NH3 MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% B in 41 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford Example 46, 1 -(3 -(3 -cyclopropyl- 1H- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine. MS ESI calculated for C22H21FN5 [M + H]+, 374.16, found 374.05.

[0352] And slow peak fractions were combined and concentrated to afford isomeric compound, l-(3-(3-cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine. MS ESI calculated for C22H21FN5 [M + H]+, 374.16, found 374.05.25958EXAMPLE 47(S or R)- 1 -(3 -(3 -cyclopropyl- U / -indazol- 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine

[0353] Step 1: To a mixture of (E)-N-((3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyridin-2- yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.819 mmol) in THF (15 mL) was added allylmagnesium bromide (1.228 mL, 1.228 mmol) at 0 °C under argon. The reaction was stirred at 0 °C for 1 h under argon. The resulting solution was quenched with saturated NH4CI (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 0: 1 to 4: 1 to afford 7V-( 1 -(3 -(3 -cyclopropyl- 1 JT-indazol- 1 -yl)pyridin-2-yl)but-3 -en- 1 -yl)-2-methylpropane-2- sulfinamide. MS ESI calculated for C23H28N4OS [M + H]+, 409.20, found 409.20.

[0354] Step 2 : To a mixture of V-(1 -(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyridin-2-yl)but-3-en- l-yl)-2-methylpropane-2-sulfinamide (260 mg, 0.636 mmol) in dichloromethane (10 mL) was added HC1 (4 M in 1,4 dioxane) (10 mL, 40.0 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 u; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% to 60% B in 5.8 min; 254 / 210 nm; to afford the racemic product. The racemic product was separated by preparative CHIRAL-HPLC with the following conditions: Column: CHIRALPAK-AD-H- UL001, 20*250 mm, 5 pm; Mobile Phase A: Hex (8 mmol / L NHs.MeOH), Mobile Phase B: IP A; Flow rate: 20 mL / min; Gradient: 5% B in 20 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford isomeric compound, (R or 5)- 1 -(3 -(3 -cyclopropyl- 1JT- indazol-l-yl)pyri din-2 -yl)but-3-en-l -amine. MS ESI calculated for C19H20N4 [M + H]+, 305.17, found 305.15.

[0355] And slow peak fractions were combined and concentrated to afford the title compound Example 47, (5 or / ?)-l-(3-(3-cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)but-3-en-l-amine. MS ESI calculated for C19H20N4 [M + H]+, 305.17, found 305.15.25958EXAMPLE 48l-(3-(3-cyclopropyl-17 / -indazol-l-yl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)ethanamineStep 1: To a stirred mixture of 2,6-dimethylpyridine (162 mg, 1.514 mmol) in THF (8 mL) was added butyllithium (0.646 mL, 1.615 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h, then (£)-7V-((3 -(3 -cyclopropyl- IJT-indazol-l -yl)pyridin-2- yl)methylene)-2-methylpropane-2-sulfinamide (370 mg, 1.010 mmol) was added. The mixture was stirred for 2 h and then it was quenched by water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic fractions were washed with brine (3 x 15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 1-10% methanol in dichloromethane to afford 7V-(l-(3-(3-cyclopropyl-lJ / -indazol-l-yl)pyridin-2-yl)-2-(6- methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C27H32N5OS [M + H]+, 474.22, found 474.30.Step 2: To a stirred mixture of 7V-(1 -(3 -(3 -cyclopropyl- UT-indazol-l -yl)pyridin-2-yl)-2-(6- methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (360 mg, 0.760 mmol) in DCM (4 mL) was added hydrogen chloride (1.900 mL, 7.60 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h then concentrated under reduced pressure. The residue was purified by / c -HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B in 6 min; 210 / 254 nm; to afford l-(3-(3- cyclopropyl- 1 JT-indazol- 1 -yl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)ethanamine 2,2,2- trifluoroacetate as a racemic mixture. The racemic mixture was separated by Chiral-HPLC under the following conditions: Column: Lux 5 pm Cellulose-4, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex (8 mmol / L NHs.MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 25 min; 254 / 220 nm; fast peak fractions were combined and concentrated to afford the title compound Example 48, l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(6-25958 methylpyridin-2-yl)ethanamine. MS ESI calculated for C23H24N5 [M + H]+, 370.20, found 370.10.

[0356] And slow peak fractions were combined and concentrated to afford the isomeric compound, 1 -(3 -(3 -cyclopropyl- 177-indazol-l -yl)pyri din-2 -yl)-2-(6-methylpyri din-2 - yl)ethanamine. MS ESI calculated for C23H24N5 [M + H]+, 370.20, found 370.10.EXAMPLE 496-(2-amino-2-(3 -(3 -cyclopropyl- U / -indazol-l-yl)pyridin-2-yl)ethyl)picolinonitrile

[0357] Step 1 : To a solution of diisopropylamine (0.076 mL, 0.546 mmol) in THF (25 mL) was added butyllithium (2.5 M in hexane, 0.196 mL, 0.491 mmol) at -78 °C under argon atmosphere, then 2-bromo-6-methylpyridine (0.094 g, 0.546 mmol) in THF (2 mL) was added and the reaction was stirred for 30 min at -78 °C. Then (£)-A-((3 -(3 -cyclopropyl- UT-indazol-1- yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.1 g, 0.273 mmol) in THF (2 mL) was further added into the reaction at -78 °C, the reaction was stirred for 1 h at this temperature. The reaction mixture was quenched by saturated NH4CI (50 mL) and extracted with ethyl acetate (3 x 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography with a gradient of 0 ~ 100% ethyl acetate in petroleum ether to give A-(2-(6- bromopyri din-2 -yl)- 1 -(3 -(3 -cyclopropyl- UT-indazol- 1 -yl)pyridin-2-yl)ethyl)-2-methylpropane-2- sulfinamide. MS ESI calculated for C26H29BrNsOS [M + H]+, 538.12, found 538.10.

[0358] Step 2 : To a mixture of A-(2-(6-brom opyridin-2-yl)-l -(3 -(3 -cyclopropyl- UT-indazol-1- yl)pyri din-2 -yl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 1.671 mmol), (oxybis(2,l- phenylene))bis(diphenylphosphine) (180 mg, 0.334 mmol), allylpalladium (II) chloride dimer (61.2 mg, 0.167 mmol) and K4[Fe(CN)e]H2O (652 mg, 1.671 mmol) in DMA (10 mL) was added water (5 mL) at room temperature, then the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with ethyl acetate (120 mL) and washed with brine (8 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography with a25958 gradient of 0 ~ 100% ethyl acetate in petroleum ether to give 7V-(2-(6-cyanopyridin-2-yl)-l-(3-(3- cyclopropyl- 1 JT-indazol- 1 -yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C27H29N6OS [M + H]+, 485.20, found 485.35.

[0359] Step 3 : To a solution of 7V-(2-(6-cyanopyridin-2-yl)-l -(3 -(3 -cyclopropyl- 1 / Z-indazol-l- yl)pyri din-2 -yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.238 mmol) in DCM (3 mL) was added HC1 (4 M in 1,4-dioxane, 3.00 mL) at 25 °C. The reaction was stirred for 2 h. The solvent was removed, and the residue was purified by / Vc -HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm, 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 50% B in 6 min; 210 / 254 nm. to give the fast peak 6-(2-amino-2-(3 -(3 -cyclopropyl- IJT-indazol-l- yl)pyridin-2-yl)ethyl)picolinonitrile 2,2,2-trifluoroacetate. MS ESI calculated for C23H21N6 [M + H]+, 381.17, found 381.15. And to give the slow peak 6-(2-amino-2-(3 -(3 -cyclopropyl- 1JT- indazol-l-yl)pyri din-2 -yl)ethyl)picolinamide 2,2,2-trifluoroacetate. MS ESI calculated for C23H23N6O [M + H]+, 399.19, found, 399.15.

[0360] Step 4 : The racemic nitrile (fast peak from Step 3) was separated by Chiral-Prep-HPLC under the following conditions: Column: Reg-AD, 30 x 250 mm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: IP A; Flow rate: 45 mL / min; Gradient: 20% B to 20% B in 24 min; 220 / 254 nm. fractions were combined and concentrated to give the fast peak (single isomer), isomeric compound, 6-(2-amino-2-(3 -(3 -cyclopropyl- UT-indazol-1 -yl)pyridin-2- yl)ethyl)picolinonitrile. MS ESI calculated for C23H21N6 [M + H]+, 381.17, found, 381.15.

[0361] And the slow peak fractions were combined and concentrated to give the slow peak (single isomer), title compound Example 49, 6-(2-amino-2-(3 -(3 -cyclopropyl- UT-indazol-1- yl)pyri din-2 -yl)ethyl)picolinonitrile. MS ESI calculated for C23H21N6 [M + H]+, 381.17, found, 381.15.EXAMPLE 50(S or A)-l-(3-(3-cyclopropyl-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine2,2,2-trifluoroacetate25958

[0362] Step 1: To a mixture of 2,5-dimethylpyridine (246 mg, 2.292 mmol) in THF (15 mL) was added w-butyllithium (2.5M in hexane) (0.873 mL, 2.183 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 1 h under argon. Then to the mixture was added a solution of (£)-A-((3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)methylene)-2-methylpropane-2- sulfmamide (400 mg, 1.091 mmol) in THF (1 mL) at -78 °C under argon. The reaction was warmed to ambient temperature and stirred for 2 h under argon. The resulting solution was quenched with saturated NH4CI (50 mL) and extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, washed with brine (2 x 150mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 0: 1 to 2: 1 to afford 7V-(l-(3-(3-cyclopropyl-U7-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2- yl)ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C27H31N5OS [M + H]+, 474.22, found 474.20.

[0363] Step 2 : To a mixture of 7V-(l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(5- methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 0.781 mmol) in dichloromethane (10 mL) was added hydrogen chloride (4 M in 1,4-dioxane) (0.195 mL, 0.781 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% to 50% B in 6 min; 210 / 254 nm; to afford 1 -(3 -(3 -cyclopropyl- UT- indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine. MS ESI calculated for C23H23N5 [M + H]+, 370.20, found 370.25.

[0364] Step 3: To a mixture of l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(5- methylpyridin-2-yl)ethanamine (260 mg, 0.704 mmol) in di chloromethane (10 mL) were added tri ethylamine (0.196 mL, 1.407 mmol) and BOC-anhydride (0.245 mL, 1.056 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution was diluted with water (20 mL), and the mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column with a gradient of EtOAc: PE - 0: 1 to 1 : 1 to afford racemic product. The racemic mixture was separated by CHIRAL-HPLC with the following conditions: Column: CHIRALPAK ADH, 2*25 cm, 5 pm; Mobile Phase A: Hex (8mmol / L NHs.MeOH) C, Mobile Phase B: EtOH; Flow rate:20 mL / min; Gradient: 10% B in 23 min; 220 / 254 nm; fast peak fractions were combined to afford25958 tert-butyl (l-(3-(3-cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2- yl)ethyl)carbamate. MS ESI calculated for C23H31N5O2 [M + H]+, 470.25, found 470.15.

[0365] And slow peak fractions were combined to afford tert-butyl (l-(3-(3-cyclopropyl-UT- indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethyl)carbamate. MS ESI calculated for C23H31N5O2 [M + H]+, 470.25, found 470.15.

[0366] Step 4: To tert-butyl (l-(3-(3-cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5- methylpyridin-2-yl)ethyl)carbamate (fast peak from Step 3, 90 mg, 0.192 mmol) in dichloromethane (4 mL) was added HC1 (4 M in 1,4-dioxane) (3 mL, 12.00 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% to 55% B in 6 min; 210 / 254 nm; to afford isomeric compound, (R or 5)-l-(3-(3- cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine 2,2,2- trifluoroacetate. MS ESI calculated for C23H23N5 [M + H]+, 370.20, found 370.10.

[0367] Step 5 : To a mixture of tert-butyl (1 -(3 -(3 -cyclopropyl- lrt-indazol-1 -yl)pyri din-2 -yl)-2- (5-methylpyridin-2-yl)ethyl)carbamate (slow peak from Step 3, 80 mg, 0.170 mmol) in dichloromethane (4 mL) was added HC1 (4 M in 1,4-dioxane) (2 mL, 8.00 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution was concentrated in vacuum to afford crude product. The residue was purified by preparative HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% to 55% B in 6 min; 210 / 254 nm; to afford the title compound Example 50, (S or R)-l-(3-(3- cyclopropyl-l / / -indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine 2,2,2- trifluoroacetate. MS ESI calculated for C23H23N5 [M + H]+, 370.20, found 370.10.EXAMPLE 51(S or A)-l-(3-(3-cyclopropyl-lJ / -indazol-l-yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine25958

[0368] Step 1 : A mixture of diisopropylamine (133 mg, 1.310 mmol) in THF (6 mL) was degassed with nitrogen for 3 times and stirred at room temperature for 5 min. w-butyllithium (79 mg, 1.228 mmol, 2.5 M in hexane) was added dropwise to the mixture under N2 at -78 °C. The mixture was warmed to 0 °C and stirred at 0 °C for 0.5 h. Then after cooling the reaction mixture to -78 °C, 2,4-dimethylpyridine (132 mg, 1.228 mmol) was added and stirred at -78 °C for 0.5 h. (£)-A-((3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)methylene)-2-methylpropane-2- sulfmamide (300 mg, 0.819 mmol) was added dropwise to the mixture. The mixture was diluted with EtOAc (500 mL), washed with ammonium chloride (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc = 1 : 1 to afford A-(l-(3-(3-cyclopropyl-U / -indazol-l-yl) pyridin-2-yl)-2-(4- methylpyridin-2-yl) ethyl)-2-methylpropane-2-sulfinamide. MS ESI calculated for C27H32N5OS [M + H]+474.22 found 474.20.

[0369] Step 2 : To a mixture of A-(l-(3-(3-cyclopropyl-U / -indazol-l-yl) pyridin-2-yl)-2-(4- methylpyridin-2-yl) ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.317 mmol) in DCM (3 mL) was added 4 M HC1 in dioxane (39.5 mg, 0.317 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The mixture was filtered; the filtrate was concentrated under reduced pressure. The residue was purified by HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 u; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient: 10% B to 40% B in 6 min; 210 / 254 nm; to afford l-(3-(3-cyclopropyl-U / -indazol-l-yl) pyridin-2-yl)-2-(4- methylpyridin-2-yl) ethanamine. MS ESI calculated for C23H24N5 [M + H]+370.20, found 370.10.

[0370] Step 3: To a mixture of l-(3-(3-cyclopropyl-U / -indazol-l-yl)pyridin-2-yl)-2-(4- methylpyridin-2-yl)ethanamine (120 mg, 0.325 mmol) in DCM (3 mL) were added di-tert-butyl dicarbonate (78 mg, 0.357 mmol) and triethylamine (65.7 mg, 0.650 mmol) at room temperature. After stirring for 2 h at room temperature the mixture was diluted with EtOAc (200 mL), washed with ammonium chloride (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluting with PEZEA = 1 : 1 to afford the racemic mixture of product. The residue was separated with chiral-HPLC under the following conditions: Column: Reg-AD, 30*250mm,5pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate:40 mL / min; Gradient:20 B to 20 B in 17 min; 254 / 220 nm; to afford tert-butyl (l-(3-(l-cyclopropyl-6-fluoro-l / / -indazol-3-yl)pyridin-2-yl)-2-(4-25958 methylpyridin-2-yl)ethyl)carbamate (fast peak, single isomer); and to afford tert-butyl (l-(3-(l- cyclopropyl-6-fluoro- IT / -indazol-3-yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethyl)carbamate (slow peak, single isomer). MS ESI calculated for C28H32N5O2 [M + H]+, 470.25 found 470.30.

[0371] Step 4 : To a mixture of tert-butyl (l-(3-(l-cyclopropyl-6-fluoro-U / -indazol-3- yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethyl)carbamate (fast peak from Step 3, 60 mg, 0.123 mmol) in DCM (2 mL) was added TFA (90.48 pL, 1.23 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The mixture was concentrated under reduced pressure to afford isomeric compound (R or 5)- 1 -(3 -(3 -cyclopropyl- UT-indazol-1- yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine. MS ESI calculated for C23H24N5 [M + H]+370.20, found 370.10.

[0372] Step 5 : To a mixture of / crt-butyl (l-(3-(l-cyclopropyl-6-fluoro-17 / -indazol-3- yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethyl)carbamate (slow peak from Step 3, 60 mg, 0.123 mmol) in DCM (2 mL) was added TFA (140.03 mg, 1.23 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The mixture was concentrated under reduced pressure to afford the title compound Example 51, (5 orA)-l-(3-(3-cyclopropyl- UT-indazol- l-yl)pyridin-2-yl)-2-(4-methylpyri din-2 -yl)ethanamine. MS ESI calculated for C23H24N5 [M + H]+370.20, found 370.10.EXAMPLE 52(R or M- 1 -(3 -(3 -(3 ,3 -difluorocyclobutyl)- Irt-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yDethan-l -amine

[0373] Step 1 : To a mixture of l-(3-bromopyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l-amine (313 mg, 1.057 mmol) in DMF (5 mL) were added 3-(3,3-difluorocyclobutyl)-U / -indazole (200 mg, 0.961 mmol), copper(i) iodide (18.29 mg, 0.096 mmol), BPMPO (81 mg, 0.192 mmol) and K2CO3 (266 mg, 1.921 mmol) at ambient temperature under argon. The reaction was stirred at 110 °C for 16 h under argon. The resulting solution was added Silica Thiol (5 g) and stirred at ambient temperature for 1 h. The mixture was filtered. The filtrate was concentrated in vacuum25958 to afford crude product. The residue was purified by reverse phase chromatography with the following conditions: Column, Cl 8, 80 g, 19 x 150 mm; mobile phase: acetonitrile in Water (0.05% TFA), 2% - 70% in 35 min; Detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure to give racemic l-(3-(3-(3,3- difluorocyclobutyl)-lA-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l-amine.

[0374] Step 2 : The racemic product was resolved by chiral -PREP -HPLC with the following conditions: Column: Reg-AD, 30*250 mm, 5pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: 8 B to 8 B in 50 min; 254 / 220 nm; fast eluting fractions were combined and concentrated to afford the title compound Example 52, (5 orR)- 1 -(3 -(3 -(3 ,3 -difluorocyclobutyl)- 1 A-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan- 1 -amine. MS ESI calculated for C23H21F3N5 [M + H]+, 424.17, found 424.05.

[0375] And slow eluting fractions were processed as above to afford isomeric compound, (R orS)- 1 -(3 -(3 -(3 ,3 -difluorocyclobutyl)- 1 A-indazol- 1 -yl)pyri din-2 -yl)-2-(5-fluoropyri din-2 -yl)ethan- 1 -amine. MS ESI calculated for C23H21F3N5 [M + H]+, 424.17, found 424.05.EXAMPLE 53(M-l-(3-(3-cyclobutyl-5-fluoro-lA-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine

[0376] To a stirred mixture of 3-cyclobutyl-5-fluoro-lA-indazole (200 mg, 1.051 mmol) in DMF (5 mL) were added K2CO3 (363 mg, 2.63 mmol), (5)-l-(3-bromopyridin-2-yl)-2-(pyridin- 2-yl)ethanamine (351 mg, 1.262 mmol), copper (I) iodide (40.0 mg, 0.210 mmol) and Al, A2- bis(5-methyl-[l,l'-biphenyl]-2-yl)oxalamide (177 mg, 0.421 mmol) under nitrogen atmosphere. The resulting mixture was warmed to 110 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 * 250 mm 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B in 6 min; 210 / 254 nm to afford the title compound Example 53, (5)-l-(3-(3-cyclobutyl-5- fluoro-lA-indazol-l-yl)pyri din-2 -yl)-2-(pyridin-2-yl)ethanamine. MS ESI calculated for C23H23FN5 [M + H]+, 388.19, found 388.10.25958EXAMPLE 54 AND 55l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-lJ / -indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol

[0377] The title compounds 54 and 55 were prepared using procedures similar to those described for Example 38, using appropriate starting materials and purification conditions described earlier. Those conditions resulted in isomeric compound (single isomer), l-(l-(2-(l- amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)-2,2,2-trifluoroethan-l-ol, MS ESI calculated for C23H19F7N5O3 [M + H]+, 432.13, found 431.95; title compound Example 54 (single isomer), l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-l -indazol-3-yl)- 2,2,2-trifluoroethan-l-ol, MS ESI calculated for C21H18F4N5O [M + H]+, 432.13, found 432.00; title compound Example 55 (single isomer), l-(l-(2-(l-amino-2-(5-fluoropyridin-2- yl)ethyl)pyridin-3-yl)-177-indazol-3-yl)-2,2,2-trifluoroethan-l-ol., MS ESI calculated for C21H18F4N5O [M + H]+432.13, found 432.00; and isomeric compound (single isomer), l-(l-(2- (l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-lJ7-indazol-3-yl)-2,2,2-trifluoroethan-l-ol, MS ESI calculated for C21H18F4N5O [M + H]+, 432.13, found 432.00.(S or 7?)-l-(3-(3-cyclobutyl-5-fluoro- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yDethanamine25958

[0378] Step 1 : Into a 20-mL vial purged and maintained with an inert atmosphere of argon, were placed NiCh 6H2O (0.151 g, 0.635 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.170 g, 0.635 mmol) in DMA (5 mL) was stirred at room temperature for 30 min. Into an another 50 mL vial, purged and maintained with an inert atmosphere of argon, were placed tert-butyl 3-bromo-5- fluoro-lA-indazole-1 -carboxylate (2 g, 6.35 mmol), cyclobutyltrifluoro-14-borane, potassium salt (1.028 g, 6.35 mmol), Ir[dF(CF3)ppy]2(dtbpy)PFe (0.712 g, 0.635 mmol) and lSfeCCL (1.345 g, 12.69 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at room temperature for 5 min. The previous reaction mixture was transferred to this vial via syringe. The resulting mixture was irradiated with blue LED for 3 h at ambient temperature. The reaction was quenched with brine (35 mL) and extracted with EtOAc (3 x 65 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to dryness. The residue was purified by silica gel column chromatography, eluting with 0 ~ 50% ethyl acetate in PE to give tert-butyl 3-cyclobutyl-5-fluoro-lA-indazole-l-carboxylate. MS ESI calculated for C16H20FN2O2 [M + H + MeCN]+, 291.14, found 332.05.

[0379] Step 2 : To a solution of tert-butyl 3-cyclobutyl-5-fluoro-lA-indazole-l-carboxylate (1.1 g, 3.79 mmol) in DCM (10 mL) was added HC1 (4 M in dioxane) (10.00 mL) at room temperature. The reaction was stirred for 2 h. The solvent was removed, and the residue was diluted with saturated NaHCCL aq. (35 mL) and extracted with ethyl acetate (3 x 65 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to dryness. The residue was purified by silica gel column chromatography, eluting with 0 ~ 50% ethyl acetate in PE to give 3-cyclobutyl-5-fluoro-lH- indazole. MS ESI calculated for C11H12FN2 [M + H]+, 191.09, found 191.10.

[0380] Step 3 : To a stirred mixture of 3-cyclobutyl-5-fluoro-lA-indazole (400 mg, 2.103 mmol) in DMF (10 mL) were added Al, A2-bis(5-methyl-[l,l'-biphenyl]-2-yl)oxalamide (354 mg, 0.841 mmol), l-(3-bromopyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine (747 mg, 2.52 mmol), copper (I) iodide (80 mg, 0.421 mmol) and K2CO3 (727 mg, 5.26 mmol) under nitrogen atmosphere. The resulting mixture was warmed to 110°C and stirred for 2 h. The reaction mixture was filtered via diatomite and washed with MeOH (5 x 20 mL). The filtrate was concentrated in vacuum to give a residue which was purified by Prep-HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 50% B in 6 min; 210 / 254 nm; to give the racemic product. The racemic product was separated by Chiral - Prep-HPLC under the following conditions: Column: Phenomenex Lux-Cellulose-2, 3 x 15 cm, 5 pm; Mobile Phase A: Hexane (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20- I l l -25958 mL / min; Gradient: 20% B in 20 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford the fast peak, title compound Example 56, (5 orA)-l-(3-(3-cyclobutyl-5- fluoro-l / Z-indazol-l-yl)pyri din-2 -yl)-2-(5-fluoropyri din-2 -yl)ethanamine. MS ESI calculated for C23H22F2N5 [M + H]+, 406.18, found 406.05.

[0381] And slow peak fractions were combined and concentrated to afford the slow peak, isomeric compound, (R or 5)-l-(3-(3-cyclobutyl-5-fluoro-lJ / -indazol-l-yl)pyridin-2-yl)-2-(5- fhioropyridin-2-yl)ethanamine. MS ESI calculated for C23H22F2N5 [M + H]+, 406.18, found 406.05.EXAMPLE 57(S or R)- 1 -(1 -(2-( 1 -amino-2-(5-fluoropyridin-2-yl)ethyl)pyri din-3 -yl)- 1 J / -indazol-3 - yllcyclobutan- 1 -ol

[0382] Step 1 : To a mixture of l-(17 / -indazol-3-yl)cyclobutan-l-ol (200 mg, 1.063 mmol) in DMF (5 mL) were added l-(3-bromopyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l-amine (472 mg, 1.594 mmol), BPMPO (89 mg, 0.213 mmol), copper(i) iodide (20.24 mg, 0.106 mmol) and K2CO3 (294 mg, 2.125 mmol) at ambient temperature under argon. The reaction was stirred at 110 °C for 16 h. To the resulting solution was added silica thiol (5 g) and stirred at ambient temperature for 1 h. The mixture was filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by prep-HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19*250mm 10pm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% to 50% B in 6 min; 210 / 254 nm. The collected fractions were combined and concentrated under reduced pressure to give l-(l-(2-(l- amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-177-indazol-3-yl)cyclobutan-l-ol. MS ESI calculated for C23H23FN5O [M + H]+, 404.18, found 404.00.

[0383] Step 2 : To a mixture of l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)- 17 / -indazol-3-yl)cyclobutan-l-ol (150 mg, 0.372 mmol) in dichloromethane (10 mL) were added TEA (0.104 mL, 0.744 mmol) and BOC2O (0.129 mL, 0.558 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting solution quenched with water25958(30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x lOOmL), dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 0: 1 to 4: 1 to afford racemic tert-butyl (2-(5-fluoropyridin-2-yl)-l-(3-(3-(l- hydroxycyclobutyl)-l / Z-indazol-l-yl)pyridin-2-yl)ethyl)carbamate.

[0384] Step 3 : The racemic product from step 2 was resolved by chiral-PREP-HPLC with the following conditions: Column: CHIRALPAK-AD-H-UL001, 20x250mm, 5 pm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B in 12 min; 220 / 254 nm; to afford tert-butyl (2-(5-fluoropyridin-2-yl)-l-(3-(3-(l- hydroxycyclobutyl)-U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate (fast eluting, single isomer). MS ESI calculated for C28H31FN5O3 [M + H]+, 504.23, found 504.30.

[0385] And to afford tert-butyl (2-(5-fluoropyridin-2-yl)-l-(3-(3-(l-hydroxycyclobutyl)-UT- indazol-l-yl)pyridin-2-yl)ethyl)carbamate (slow eluting, single isomer). MS ESI calculated for C28H31FN5O3 [M + H]+, 504.23, found 504.30.

[0386] Step 4: To a mixture of tert-butyl (2-(5-fluoropyridin-2-yl)-l-(3-(3-(l- hydroxycyclobutyl)-U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate (49 mg, 0.097 mmol, fast eluting peak from Step 3) in dichloromethane (5 mL) was added TFA (2 mL, 26.0 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The solvent was removed and the residue was lyophilized to give the isomeric compound, (R or 5)-l-(l-(2-(l- amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-U / -indazol-3-yl)cyclobutan-l-ol. MS ESI calculated for C23H23FN5O [M + H]+, 404.18, found 404.05.

[0387] To a mixture of tert-butyl (2-(5-fluoropyridin-2-yl)-l-(3-(3-(l-hydroxycyclobutyl)-UT- indazol-l-yl)pyridin-2-yl)ethyl)carbamate (48 mg, 0.095 mmol, slow eluting peak from Step 3) in dichloromethane (5 mL) was added TFA (2 mL, 26.0 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 2 h. The solvent was removed and the residue was lyophilized to give the title compound Example 57, (5 or A)-l-(l-(2-(l-amino-2-(5-fluoropyridin- 2-yl)ethyl)pyridin-3-yl)-U / -indazol-3-yl)cyclobutan-l-ol. MS ESI calculated for C23H23FN5O [M + H]+, 404.18, found 404.05.25958EXAMPLE 58(M-l-(3-(3-cyclobutyl-4-fluoro-l / / -indazol-l-yl) pyri din-2 -yl)-2-(pyridin-2-yl)ethan-l -amine

[0388] To a mixture of 3-cyclobutyl-4-fluoro- l / / -indazole (200 mg, 1.051 mmol) in DMF (4 mL) were added (5)- 1 -(3 -brom opyri din-2 -yl)-2-(pyri din-2 -yl) ethan-l-amine (292 mg, 1.051 mmol), copper(I) iodide (40.0 mg, 0.210 mmol), BPMPO (177 mg, 0.421 mmol) and K2CO3 (291 mg, 2.103 mmol) at room temperature. The reaction mixture was stirred for 2 h at 110 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC under the following conditions: Column: Atlantis Prep T3 OBD Column, 19x250 mm 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient:30% B to 60% B in 6 min; 210 / 254 nm; to afford the title compound Example 58, (5)-l-(3-(3-cyclobutyl-4-fluoro-l / / -indazol-l-yl) pyridin-2-yl)-2-(pyridin-2- yl)ethan-l -amine.EXAMPLE 59(R or M- 1 -(3 -(3 -cyclobutyl-4-fluoro- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yDethan-l -amine

[0389] Step 1 : To a mixture of 4-fluoro-lH-indazole (5 g, 36.7 mmol) in acetonitrile (40 ml) was added NBS (7.19 g, 40.4 mmol) at room temperature. The reaction was stirred at room temperature for 1 h under argon. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford crude product. The residue was purified by silica gel column using a gradient of 0% - 18 % EtOAc in25958PE to afford 3-bromo-4-fluoro-l / Z-indazole. MS ESI calculated for CyHsBrFN? [M + H]+214.95, found 215.05.

[0390] Step 2: To a solution of 3-bromo-4-fluoro-lJ / -indazole (923 mg, 4.29 mmol) in DCM (10 mL) were added triethylamine (869 mg, 8.59 mmol) and di-tert-butyl dicarbonate (1405 mg, 6.44 mmol) at room temperature. The resulting solution was stirred for 1.5h at room temperature under nitrogen atmosphere. The reaction solution was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 0: 1 to 1 : 1 to afford tert-butyl 3 -bromo-4-fluoro-lZZ-indazole-l -carboxylate. MS ESI calculated for CnHisBrF^Ch [M + H-100]+215.01, found 215.25.

[0391] Step 3 : Into a 40-mL vial purged and maintained with an inert atmosphere of argon, were placed nickel(II) chloride (285 mg, 2.199 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (53.7 mg, 0.200 mmol) in DMA (6 mL) was stirred at 60 °C room temperature for 30 min. Into an another 40 mL vial, purged and maintained with an inert atmosphere of argon, were placed tert- butyl 3 -bromo-4-fluoro-lJT-indazole-l -carboxylate (630 mg, 1.999 mmol), cyclobutyltrifluoro- 14-borane, potassium salt (324 mg, 1.999 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PFe (224 mg, 0.200 mmol) and ISfeCCL (636 mg, 6.00 mmol) in 1,4-Dioxane (24 mL). The resulting mixture was stirred at room temperature for 5 min. The previous reaction mixture was transferred to this vial via syringe. The resulting mixture was irradiated with blue LED for 16 h at ambient temperature. The mixture was quenched by water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic fractions were washed with brine (3 x lOOmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1-30% EtOAc in PE to tert-butyl 3- cyclobutyl-4-fluoro-U / -indazole-l -carboxylate. MS ESI calculated for C16H20FN2O2 [M + H]+291.14, found 291.20.

[0392] Step 4 : A mixture of tert-butyl 3 -cyclobutyl-4-fluoro-U / -indazole-l -carboxylate (500 mg, 1.722 mmol) in DCM (10 mL) was added 4 M HC1 in dioxane (1073 mg, 8.61 mmol) at room temperature. The reaction was quenched with saturated ISfeCCL (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford 3-cyclobutyl-4-fluoro-U / -indazole. MS ESI calculated for Ci 1H12FN2 [M + H]+191.09, found 191.15.

[0393] Step 5 : To a mixture of 3 -cyclobutyl -4-fluoro-UT-indazole (200 mg, 1.051 mmol) in DMF (4 mL) were added l-(3-bromopyridin-2-yl)-2-(5-fluoropyridin-2-yl) ethan-l-amine (311 mg, 1.051 mmol), copper(I) iodide (40.0 mg, 0.210 mmol), K2CO3 (290 mg, 2.10 mmol) and25958BPMPO (177 mg, 0.421 mmol) at room temperature. The reaction mixture was stirred for 2 h at 110 °C. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate:20 mL / min; Gradient:25% B to 55% B in 6 min; 254 / 210 nm; to afford the product as racemic mixture. The racemic mixture was separated by chiral-HPLC with the following conditions: Column: LUX 5pm Cellulose-2, 2.12 x 25 cm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate:20 mL / min; Gradient:20% B to 20% B in 15 min; 220 / 254 nm; fast peak fractions were combined and concentrated to afford the title compound Example 59, (5 or A)-l-(3-(3-cyclobutyl-4-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5- fhioropyridin-2-yl)ethan-l -amine. MS ESI calculated for C23H22F2N5 [M + H]+406.18 found 406.10.

[0394] And slow peak fractions were combined and concentrated to afford the isomeric compound, (R or 5)-l-(3-(3-cyclobutyl-4-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C23H22F2N5 [M + H]+, 406.18 found 406.10.EXAMPLE 60l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-U / -indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol

[0395] Step 1 : A mixture of tert-butyl 5-fluoro-3-formyl-U / -indazole-l-carboxylate (4.2 g, 15.89 mmol) and Na2CO3 (3.37 g, 31.8 mmol) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere. Then TMFCF3 (4.71 mL, 31.8 mmol) was added dropwise with stirring. The reaction was quenched with water (500 mL) at room temperature. The resulting mixture was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified with silica gel chromatography under the following conditions: Column:25958 silica-CS Column 120 g; Mobile Phase A: PE, Mobile Phase B: EtOAc; Flow rate: 60 mL / min; Gradient: 0% B to 30% B in 40 min; 254 / 280 nm. The fractions containing the desired product were collected at 13% B and concentrated under reduced pressure. This resulted in tert-butyl 6- fluoro-3 -(2, 2, 2 -tri fluoro- 1 -hydroxy ethyl)- lrt-indazole-1 -carboxylate.

[0396] Step 2 : To a mixture of tert-butyl 5-fluoro-3-(2,2,2-trifluoro-l-hydroxyethyl)-U / - indazole-1 -carboxylate (5.56 g, 13.31 mmol) in DCM (20 mL) was added 4 M HC1 in dioxane (20 mL, 80 mmol) at room temperature and stirred for 2 h. The reaction was quenched with saturated Na2CO3 (400 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column using a gradient of 0% - 35 % EtOAc in DCM to afford 2,2,2-trifluoro-l-(5-fluoro-lJ7- indazol-3-yl)ethanol. MS ESI calculated for C9H7F4N2O [M + H]+235.04, found 235.00.

[0397] Step 3 : To a mixture of 2,2,2-trifhioro-l-(5-fhioro-lJ / -indazol-3-yl)ethanol (500 mg, 2.135 mmol), l-(3-bromopyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine (759 mg, 2.56 mmol), A7,A2-bis(6-methyl-[l,l'-biphenyl]-3-yl)oxalamide (359 mg, 0.854 mmol), copper (I) iodide (81 mg, 0.427 mmol) and K2CO3 (590 mg, 4.27 mmol) in DMF (40 mL) was stirred for 16 h at 110 °C under nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm 10 pm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B in 6 min; 210 / 254 nm. The product-containing fractions were combined, concentrated under reduced pressure. The residue was further separated by chiral HPLC under the following conditions: Column: LUX 5 pm Cellulose-2, 2.12 x 25 cm; Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate:35 mL / min; Gradient:20% B to 20% B in 6.5 min; 220 / 254 nm; to afford l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5- fluoro-U / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol, peak 1 (fast peak, RT1 = 4.543 min) and 1-(1- (2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-U / -indazol-3-yl)-2,2,2- trifluoroethan-l-ol, peak 2 (slow peak, RT2 = 6.126 min).

[0398] Step 4 : To a mixture of l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5- fluoro-U / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol (peak 1 from Step 3, 100 mg, 0.177 mmol) and TEA (0.124 mL, 0.887 mmol) in DCM (1 mL) was added BOC2O (0.041 mL, 0.177 mmol). The reaction mixture was concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with 30% EtOAc in PE to afford a mixture which was separated by chiral HPLC under the following conditions: Column: LUX 5 pm Cellulose-2, 2.12 x 25cm;25958Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: IP A; Flow rate:20 mL / min; Gradient: 10% B to 10% B in 16 min; 220 / 254 nm; to afford single isomer tert-butyl (l-(3-(5- fluoro-3 -(2,2,2-trifluoro- 1 -hydroxy ethyl)- 1 JT-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethyl)carbamate (peak 1, RT1 = 9.526 min), and single isomer tert-butyl (l-(3-(5-fluoro-3- (2, 2, 2-trifluoro-l -hydroxy ethyl)- 17 / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethyl)carbamate (peak 2, RT2 = 12.929 min).

[0399] Step 5: To a mixture of tert-butyl (l-(3-(5-fluoro-3-(2,2,2-trifluoro-l-hydroxyethyl)- U / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethyl)carbamate (single isomer, peak 1 from step 4, 40 mg, 0.073 mmol) in DCM (1 mL) was added TFA (0.112 mL, 1.456 mmol). The reaction mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure to afford the title compound as single isomer, Example 60, l-(l-(2-(l-amino-2- (5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lJ / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol. MS ESI calculated for C2IHI7F5N5O [M + H]+450.13, found 449.95.

[0400] Step 6: To a mixture of tert-butyl (l-(3-(5-fluoro-3-(2,2,2-trifluoro-l-hydroxyethyl)- U / -indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethyl)carbamate (single isomer, peak 2 from step 4, 40 mg, 0.073 mmol) in DCM (1 mL) was added TFA (0.112 mL, 1.456 mmol). The reaction mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure to afford isomeric compound (single isomer), l-(l-(2-(l-amino-2-(5- fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lJ / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol. MS ESI calculated for C2IHI7F5N5O [M + H]+450.13, found 450.00.EXAMPLE 61l-(l-(2-(l-amino-2-cyclobutylethyl)pyridin-3-yl)-lJ / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol 2,2,2-tri fluoroacetate

[0401] Step 1 : To a stirred mixture of 3 -bromopicolinic acid (1.9 g, 9.41 mmol) in DCM (90 mL) were added HATU (7.15 g, 18.81 mmol), N, O-dimethylhydroxylamine hydrochloride (1.376 g, 14.11 mmol) and diisopropylamine (2.86 g, 28.2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h. The reaction mixture was25958 quenched by water (90 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic fractions were washed with brine (3 x 150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1 ~ 10% methanol in di chloromethane to afford 3-bromo- A-methoxy-A-methylpicolinamide. MS ESI calculated for CsHioBrlSbCL [M + H]+, 244.98, found 244.90.

[0402] Step 2 : To a stirred mixture of 3-bromo-A-methoxy-A-methylpicolinamide (1.6 g, 6.53 mmol) in THF (30 mL) was added (cyclobutylmethyl)magnesium bromide (15.67 mL, 7.83 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (3 x 45 mL). The combined organic fractions were washed with brine (3 x 45 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1 ~ 10% methanol in dichloromethane to afford l-(3-bromopyridin-2-yl)-2-cyclobutylethan- 1-one.

[0403] Step 3 : To a stirred mixture of l-(3-bromopyridin-2-yl)-2-cyclobutylethan-l-one (148 mg, 0.582 mmol) in MeOH (5 mL) were added sodium cyanoborohydride (110 mg, 1.747 mmol) and ammonium acetate (449 mg, 5.82 mmol) under nitrogen atmosphere. The resulting mixture was warmed to 65 °C and stirred for 2 h. The reaction mixture was quenched by water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (3 x 15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 ~ 10% methanol in di chloromethane to afford l-(3- bromopyridin-2-yl)-2-cyclobutylethan-l -amine. MS ESI calculated for CnHieBrN? [M + H]+, 255.04, found 254.95.

[0404] Step 4 : To a stirred mixture of l-(3-bromopyridin-2-yl)-2-cyclobutylethan-l-amine (520 mg, 2.038 mmol) in DMF (5 mL) were added K2CO3 (704 mg, 5.09 mmol), BPMPO (343 mg, 0.815 mmol), 2,2,2-trifhioro-l-(lJ / -indazol-3-yl)ethan-l-ol (441 mg, 2.038 mmol) and copper(I) iodide (78 mg, 0.408 mmol) under nitrogen atmosphere. The resulting mixture was warmed to 130 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase with the following conditions: mobile phase A: water (0.05% TFA), mobile phase B: MeCN, 5% ~ 95% in 45 min; Detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure to give 1- ( 1 -(2-(l -amino-2-cy cl obutylethyl)pyri din-3 -yl)- 1 JT-indazol-3 -yl)-2,2,2-trifluoroethan- 1 -ol.25958

[0405] Step 5 : To a stirred mixture of l-(l-(2-(l-amino-2-cyclobutylethyl)pyridin-3-yl)-UT- indazol-3-yl)-2,2,2-trifluoroethan-l-ol (300 mg, 0.768 mmol) in DCM (10 mL) were added triethylamine (233 mg, 2.305 mmol) and di-tert-butyl dicarbonate (335 mg, 1.537 mmol) at 25 °C nitrogen atmosphere. The resulting mixture was stirred for 2 h. The reaction mixture was quenched by water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic fractions were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 ~ 10% MeOH in DCM to afford / c / 7-butyl(2-cyclobutyl- 1 -(3 -(3 -(2,2,2-trifluoro- 1 -hydroxy ethyl)- 1 JT-indazol- 1 -yl)pyridin-2-yl)ethyl)carbamate.

[0406] Step 6: The mixture of terLbutyl(2-cyclobutyl-l-(3-(3-(2,2,2-trifluoro-l-hydroxyethyl)- U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate (250 mg, 0.255 mmol) was separated by Chiral- prep-HPLC under the following conditions: Column, IC, 0.46 x 10 cm; 5 pm; mobile phase; Hex (0.1% DEA): IP A = 95: 5; Detector, UV 254 nm.

[0407] The first peak provided terLbutyl(2-cyclobutyl-l-(3-(3-(2,2,2-trifluoro-l-hydroxyethyl)- U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate.

[0408] The second peak provided terLbutyl(2-cyclobutyl-l-(3-(3-(2,2,2-trifluoro-l- hydroxy ethyl)- 1 JT-indazol- 1 -yl)pyridin-2-yl)ethyl)carbamate.

[0409] The third peak provided tert-butyl(2-cy cl obutyl-1 -(3 -(3 -(2,2,2-trifluoro- 1- hydroxy ethyl)- 1 JT-indazol- 1 -yl)pyridin-2-yl)ethyl)carbamate.

[0410] The fourth peak provided tert-butyl(2-cy cl obutyl-1 -(3 -(3 -(2,2,2-trifluoro- 1- hydroxy ethyl)- 1 JT-indazol- 1 -yl)pyridin-2-yl)ethyl)carbamate.

[0411] Step 7: To a stirred mixture of te / 7-butyl(2-cyclobutyl-l-(3-(3-(2,2,2-trifluoro-l- hydroxyethyl)-U / -indazol-l-yl)pyridin-2-yl)ethyl)carbamate (second peak, from step 6, 30 mg, 0.061 mmol) in DCM (4.00 mL) was added HC1 (4 M in dioxane, 4.00 mL) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h. The residue was purified by Prep- HPLC with the following conditions: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm, 10 pm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 15% B to 50% B; 210 / 254 nm to give the title compound (single isomer) Example 61, 1 -(1 -(2-( 1 -amino-2-cy cl obutylethyl)pyri din-3 -yl)- 1 JT-indazol-3 -yl)-2,2,2-trifluoroethan- 1 -ol 2,2,2-trifluoroacetate. MS ESI calculated for C20H22F3N4O [M + H]+, 391.17, found 391.05.

[0412] Similarly, peaks 1, 3 and 4 from step 6 were processed separately as described above to provide the isomeric compounds (each single isomer), l-(l-(2-(l-amino-2- cyclobutylethyl)pyridin-3-yl)-U / -indazol-3-yl)-2,2,2-trifluoroethan-l-ol 2,2,2-trifluoroacetate.25958(R or A')- 1 -(3 -(4-fluoro-3 -( 1 -(trifluoromethyl)cyclopropyl)- 1 A-indazol- 1 -yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethan- 1 -amine

[0413] Step 1 : To a mixture of l-(trifluoromethyl)cyclopropane-l -carboxylic acid (1.5 g, 9.73 mmol) in DCM (20 mL) were added N, (9-dimethylhydroxylamine (0.892 g, 14.60 mmol), HATU (7.40 g, 19.47 mmol) and AA-diisopropylethylamine (3.77 g, 29.2 mmol) at room temperature under argon. The reaction was stirred at room temperature for 16 h, then diluted with water (400 mL) and extracted with DCM (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel column using a gradient of 0 - 10% MeOH in DCM to afford A-methoxy-A-methyl- 1 -(trifluoromethyl)cy cl opropane-1 -carboxamide. MS ESI calculated for C7H11F3NO2 [M + H]+, 198.07, found 198.05.

[0414] Step 2: To a mixture of 2-bromo-l,3-difhiorobenzene (1.8 g, 9.33 mmol) in THF (20 mL) was added w-butyllithium (2.5 M in hexane) (3.7 mL, 9.33 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h at -78 °C. Then A-m ethoxy -A-m ethyl- 1 -(trifluoromethyl) cyclopropane- 1 -carboxamide (1.2 g, 6.09 mmol) was added to the mixture at -78 °C. The reaction mixture was stirred for 1 h at -78 °C. The reaction mixture was quenched by saturated aq. NH4CI (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with brine (100 mL), dried over ISfeSCU and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel column chromatography, eluting with 1 ~ 23% EtOAc in PE to give (2,6-difluorophenyl)(l-(trifluoromethyl)cyclopropyl)methanone.

[0415] Step 3 : To a mixture of (2,6-difluorophenyl) (1 -(trifluoromethyl) cyclopropyl)methanone (600 mg, 2.398 mmol) in EtOH (10 mL) was added N2H4.H2O (5 mL) at room temperature. The mixture was stirred at 80 °C for 14 h, then concentrated in vacuum to afford a residue. The residue was purified by silica gel column chromatography, eluting with 1 ~ 18% EtOAc in PE to give 4-fluoro-3-(l -(trifluoromethyl) cyclopropyl)- lA-indazole. MS ESI calculated for C11H9F4N2 [M + H]+, 245.06, found 245.15.25958

[0416] Step 4 : To a stirred mixture of 4-fluoro-3-(l-(trifluoromethyl)cyclopropyl)-l / / -indazole (180 mg, 0.737 mmol) and CS2CO3 (480 mg, 1.474 mmol) in DMF (4 mL) were added A1, 7V2- bis(5-methyl-[l,l'-biphenyl]-2-yl)oxalamide (62.0 mg, 0.147 mmol), 1 -(3 -brom opyri din-2 -yl)-2- (5-fluoropyridin-2-yl)ethan-l -amine (175 mg, 0.590 mmol), and copper(I) iodide (14.04 mg, 0.074 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was warmed to 100 °C and stirred for 16 h. The solid was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by A7J-CombiFlash under the following conditions: C18, 330 g, Mobile Phase A: water (1% TFA), Mobile Phase B: acetonitrile, gradient: 0 ~ 40% B in 40 min, Flow rate: 100 mL / min, detector: 254 nm, to afford the racemic 1 -(3 -(4-fluoro-3 -( 1 -(trifluoromethyl)cyclopropyl)- 17 / -i ndazol - 1 -yl)pyridin-2-yl)-2- (5-fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C23H19F5N5 [M + H]+, 460.15, found 460.10.

[0417] Step 5: The racemic material from step 4, l-(3-(4-fluoro-3-(l- (trifluoromethyl)cyclopropyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine was separated by chiral-HPLC under the following conditions: Column: Lux Cellulose - 2, Column Size: 4.6 x 100 mm, 3 pm, Mobile Phase: Hex (0.1% DEA): EtOH = 80: 20, Flow rate: 1.0 mL / min. Fast peak fractions were combined and concentrated to give the title compound Example 62, (S or R)-l-(3-(4-fluoro-3-(l-(trifluoromethyl)cyclopropyl)-lH-indazol-l-yl)pyridin- 2-yl)-2-(5-fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C23H19F5N5 [M + H]+, 460.15, found 460.10.

[0418] And slow peak fractions were combined and concentrated to give the isomeric compound, (R or 5)-l-(3-(4-fluoro-3-(l-(trifluoromethyl)cyclopropyl)-lA-indazol-l-yl)pyridin- 2-yl)-2-(5-fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C23H19F5N5 [M + H]+, 460.15, found 460.05.EXAMPLE 63(R or M-l -(3 -(4-fluoro-3-(l -(trifluoromethyl) cyclobutyD-UT-indazol-l-yl) pyridin-2-yl)-2-(5- fluoropyridin-2-yl) ethan-1 -amine25958

[0419] Step 1 : To a mixture of l-(trifluoromethyl)cyclobutane-l -carboxylic acid (3 g, 17.84 mmol) in DCM (20 mL) were added N, (9-dimethylhydroxylamine (2.180 g, 35.7 mmol), HATU (10.18 g, 26.8 mmol) and A, A-diisopropylethylamine (6.92 g, 53.5 mmol) at room temperature under argon. The reaction was stirred at room temperature for 16 h, then diluted with water (400 mL) and extracted with DCM (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to afford a residue. The residue was purified by silica gel column using a gradient of 0 ~ 5% MeOH in DCM to afford A-methoxy-A-methyl-l-(trifluoromethyl)cyclobutane-l-carboxamide. MS ESI calculated for C8H13F3NO5 [M + H]+, 212.08, found 212.15.

[0420] Step 2: To a mixture of 2-bromo-l,3-difhiorobenzene (1.2 g, 6.22 mmol) in THF (20 mL) was added w-butyllithium (2.5 M in hexane) (3.7 mL, 9.33 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h, followed by addition of A-methoxy -N-m ethyl- 1- (trifluoromethyl) cyclobutane- 1 -carboxamide (1.970 g, 9.33 mmol) at -78 °C. The reaction was stirred for 1 h, then quenched by saturated aq. NH4CI aqueous (100 mL), and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum to afford a residue. The residue was purified by silica gel column chromatography, eluting with 1—10 % EtOAc in PE to give (2, 6-difluorophenyl)(l-(trifluoromethyl)cy cl obutyl)m ethanone. MS ESI calculated for C12H10F5O [M + H]+, 265.06, found 265.06.

[0421] Step 3 : To a mixture of (2,6-difluorophenyl)(l-(trifluoromethyl)cyclobutyl)methanone (1.1 g, 4.16 mmol) in EtOH (6 mL) was added N2H4-H2O (3 mL) at room temperature. The mixture was stirred at 80 °C for 14 h, then was concentrated in vacuum to afford a residue. The residue was purified by silica gel column chromatography, eluting with 1 ~ 15% EtOAc in PE to give 4-fluoro-3-(l -(trifluoromethyl) cyclobutyl)- 1 / / -indazole. MS ESI calculated for C12H11F4N2 [M + H]+, 259.08, found 259.15.

[0422] Step 4 : To a mixture of 4-fluoro-3-(3-(trifluoromethyl)cyclobutyl)-lA-indazole (300 mg, 1.162 mmol) in DMF (3 mL) were added potassium carbonate (321 mg, 2.324 mmol), BPMPO (98 mg, 0.232 mmol), copper(I) iodide (22.13 mg, 0.116 mmol) and l-(3-bromopyridin- 2-yl)-2-(5-fluoropyrimidin-2-yl)ethan-l -amine (380 mg, 1.278 mmol) at room temperature under argon. The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by AP-CombiFlash under the following conditions: C18, 330 g, Mobile Phase A: water (1% TFA), Mobile Phase B: acetonitrile, gradient: 0 ~ 40% B in 40 min, Flow rate: 100 mL / min, detector: 254 nm, to give racemic l-(3-(4-fluoro-3-(l-(trifluoromethyl)cyclobutyl)-lA-indazol-l-yl)pyridin-2-yl)-2-(5-25958 fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C24H21F5N5 [M + H]+, 474.16, found 474.20.

[0423] Step 5: The racemic material from step 4, l-(3-(4-fluoro-3-(l- (trifluoromethyl)cyclobutyl)- IH-indazol-l -yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan- 1 - amine was resolved by Prep-chiral-HPLC with following condition: Column: Lux 5 pm Cellulose-2, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex (0.3% isopropylamine), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% to 10% in 26 min. Fast peak fractions were combined and concentrated to give the title compound Example 63, (S or R)-l-(3-(4-fluoro-3-(l- (trifluoromethyl)cyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine. ESI calculated for C24H21F5N5 [M + H]+, 474.16, found 474.15.

[0424] And slow peak fractions were combined and concentrated to give the isomeric compound, (R or 5)- 1 -(3 -(4-fluoro-3-(l -(trifluoromethyl) cyclobutyl)- lA-indazol-l-yl) pyridin-2- yl)-2-(5-fluoropyridin-2-yl) ethan-1 -amine. ESI calculated for C24H21F5N5 [M + H]+, 474.16, found 474.15.EXAMPLE 64(R or M-l-(3-(4-fhioro-3-(spiro[2.31hexan-5-yl)-l.H-indazol-l-ylpyridin-2-yl)-2-(5-fluoropyridin- 2-yl)ethan- 1 -amine

[0425] Step 1 : To a mixture of spiro [2.3] hexane-5-carboxylic acid (800 mg, 6.34 mmol) in DCM (20 mL) were added A, O-dimethylhydroxylamine (775 mg, 12.68 mmol), HATU (3617 mg, 9.51 mmol) and A, A-diisopropylethylamine (2459 mg, 19.02 mmol) at room temperature under argon. The reaction was stirred at room temperature for 16 h, then diluted with water (400 mL) and extracted with DCM (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography using a gradient of 0 - 16% EtOAC in PE to afford A-methoxy-A-methyl spiro [2.3] hexane-5-carboxamide. MS ESI calculated for C9H16NO2 [M + H]+, 170.11, found 170.25.25958

[0426] Step 2 : To a mixture of 2-bromo-l,3-difluorobenzene (1 g, 5.18 mmol) in THF (20 mL) was added zz-butyllithium (3.11 mL, 7.77 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 0.5 h. Then A-methoxy-A-methyl spiro [2.3] hexane-5- carboxamide (800 mg, 4.73 mmol) was added to the mixture at -78 °C. The reaction mixture was stirred at-78 °C for 1 h. The reaction mixture was quenched by saturated aq. NH4CI (50 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. The solid was filtered, and the filtrate was concentrated in vacuum to afford residue. The residue was purified by silica gel column chromatography, eluting with 0 ~ 30% EtOAc in PE to give (2,6-difluorophenyl) ( / ?zro[2.3]hexan-5-yl)methanone. MS ESI calculated for C13H13F2O [M + H]+, 223.09, found 223.15.

[0427] Step 3 : To a solution of (2,6-difluorophenyl) (spiro [2.3] hexan-5-yl)m ethanone (1 g, 4.50 mmol) in EtOH (4 mL) was added hydrazine (4 mL, 4.50 mmol) at room temperature. The reaction was stirred at 80 °C for 14 h. The solvent was concentrated in vacuum to afford a residue. The residue was diluted with 10 mL ethane- 1,2-diol and stirred at 150 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (6 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum to afford a residue. The residue was purified by silica gel column chromatography, eluting with 1-18% EtOAc in PE to give 4-fluoro-3-(.s / w<9 [2.3]hexan-5-yl)-lA-indazole. MS ESI calculated for C13H14FN2 [M + H]+, 217.11, found 217.45.

[0428] Step 4: To a mixture of 4-fluoro-3-( / ?zro[2.3]hexan-5-yl)-lA-indazole (217 mg, 1 mmol) in DMF (3 mL) were added potassium carbonate (320 mg, 2.312 mmol), BPMPO (97 mg, 0.231 mmol), copper(I) iodide (22.02 mg, 0.116 mmol) and l-(3-bromopyridin-2-yl)-2-(5- fluoropyrimidin-2-yl) ethan-l-amine (378 mg, 1.272 mmol) at room temperature under argon. The reaction was stirred at 110 °C for 2 h. The solid was filtered out, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by RP- CombiFlash under the following conditions: C18, 40 g, Mobile Phase A: water (1% TFA), Mobile Phase B: acetonitrile, gradient: 0 - 40% to give racemic l-(3-(4-fluoro-3- ( / ?zro[2.3]hexan-5-yl)-lA-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l -amine. MS ESI calculated for C25H24F2N5 [M + H]+, 432.19, found 432.25.

[0429] Step 5: The racemic material from step 4, I -(3-(4-fluoro-3-(.s / WY>[2.3]hexan-5-yl)- l A- indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l -amine was separated by the prep- chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 pm; Mobile Phase A: HEX: DCM = 3: 1 (0.4% isopropylamine), Mobile Phase B: EtOH; Flow rate: 1 mL / min; Gradient: 2 % to 2% in 15 min. The fast peak fractions were combined and25958 concentrated to give the fast peak, title compound Example 64, (5 or A)-l-(3-(4-fluoro-3- (spiro\2.3~\ hexan-5-yl)- I T / -indazol- l -yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan- l -amine.MS ESI calculated for C25H24F2N5 [M + H]+, 432.19, found 432.20.

[0430] And slow peak fractions were combined and concentrated to give the slow peak, isomeric compound, (R or 5)-l-(3-(4-fluoro-3-(spiro[2.3]hexan-5-yl)-lJ7-indazol-l-ylpyridin-2- yl)-2-(5-fluoropyridin-2-yl)ethan-l-amine. MS ESI calculated for C25H24F2N5 [M + H]+, 432.19, found 432.25.EXAMPLE 65 AND 661 -(3 -(4-fluoro-3 -(spiro 12,21 pentan- 1 -yl)- 1 / / -indazol - 1 -yl)pyridin-2-yl)-2-(5 -fluoropyri din-2 - yllethan-l -amine 2,2,2-trifluoroacetate

[0431] Step 1 : To a mixture of ,s / WY>[2.2]pentane- l -carboxylic acid (1 g, 8.92 mmol) in DCM (20 mL) were added A,(9-dimethylhydroxylamine (1.090 g, 17.84 mmol), HATU (5.09 g, 13.38 mmol) and A,A-diisopropylethylamine (3.46 g, 26.8 mmol) at room temperature under argon. The reaction was stirred at room temperature for 16 h, then diluted with water (100 mL) and extracted with DCM (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford a residue, and the residue was purified by silica gel column using a gradient of 0 ~ 10% MeOH in DCM to afford N- methoxy-A-methyl / zzro[2.2]pentane-l -carboxamide. MS ESI calculated for CsHuNCLS [M + H]+, 156.09, found 156.00.

[0432] Step 2: To a mixture of 2-bromo-l,3-difluorobenzene (1.2 g, 6.22 mmol) in THF (20 mL) was added zz-butyllithium (3.73 mL, 9.33 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h at -78 °C. Then A-methoxy-A-methyl / ?zro[2.2]pentane-l-carboxamide (0.965 g, 6.22 mmol) was added to the mixture at -78 °C. The reaction mixture was stirred for 1 h at -78 °C, then quenched by saturated NH4CI aq. (100 mL), and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to afford a residue, and the residue was purified by silica gel column chromatography and eluted with 1—12 % EtOAc in PE to give (2,6-difluorophenyl)25958(spiro [2.2] pentan-l-yl) methanone. MS ESI calculated for C12H11FO2 [M + H]+, 209.07, found 209.15.

[0433] Step 3 : To a mixture of (2,6-difluorophenyl)( / ?zro[2.2]pentan-l-yl)methanone (800 mg, 3.84 mmol) in EtOH (6 mL) was added N2H4.H2O (3 mL) at room temperature. The mixture was stirred at 80°C for 14 h. The mixture was concentrated in vacuum to afford crude product (£)- ((2,6-difluorophenyl)(spiro[2.2]pentan-l-yl)methylene) hydrazine. MS ESI calculated for C12H13F2O2 [M + H]+, 223.10, found 223.20.

[0434] Step 4 : A mixture of (£)-((2,6-difluorophenyl) (spiro [2.2] pentan-l-yl) methylene) hydrazine (600 mg, 2.70 mmol) in ethane- 1,2-diol (6 mL, 2.70 mmol) was stirred at 150 °C for 14 h, then quenched by saturated NH4CI aq. (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to afford a residue, and the residue was purified by silica gel column chromatography and eluted with 1—28 % EtOAc in PE to give 4-fluoro-3-(.s / w'<9 [2.2]pentan-l-yl)-lA-. MS ESI calculated for C12H12FN2 [M + H]+, 203.09, found 203.00.

[0435] Step 5: To a stirred mixture of 4-fluoro-3-(.s / w<9 [2.2] pentan- l-yl)-lA-indazole (121.2 mg, 0.599 mmol) and K2CO3 (83 mg, 0.599 mmol) in DMF (3 mL) were added Al, A2-bis(5- methyl-[l,l'-biphenyl]-2-yl) oxalamide (252 mg, 0.599 mmol), l-(3-bromopyridin-2-yl)-2-(5- fluoropyridin-2-yl) ethan-l-amine (177 mg, 0.599 mmol), and copper(I) iodide (114 mg, 0.599 mmol) at room temperature under nitrogen atmosphere. The resulting mixtu...

Claims

25958WHAT IS CLAIMED IS:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof,wherein:R1is hydrogen, C3-6 cycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci- 4fluoroalkyl, and hydroxy; orR2is C1-6 alkyl, C1-6 alkenyl, C4-6 cycloalkyl, 5 to 10 membered heterocycloalkyl, aryl, or heteroaryl, 2 wherein R is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; provided that when R1is H, then R2is not substituted or unsubstitutedeach R3, R4, R5, and R6independently is hydrogen, halo, methyl or CF3; each Ra, Rb, Rc, and Rdis H; orRaand Rctaken together with the atoms to which they are attached form a five membered ring and each Rband Rdis H;n is 0 or 1; p is 0, 1, or 2; and r is 0, 1, or 2 z is 0 or 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is C3- 6 cycloalkyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci-4fluoroalkyl, and hydroxy.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l. l]pentanyl, spiro[2.3]hexyl, or spiro[2.2]pentyl, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci-4fluoroalkyl, and hydroxy.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R1is Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl having 5 to 10 ring atoms, and R1is substituted by 0, 1 or 2 substituents selected from the group consisting of fluoro, -CF, -CF2, -CF3 and hydroxy.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein is phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, or thiophenyl, pyrimidinyl, tetrahydroquinolinyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl, and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, - OCH3, and -OCF3.

8. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R2is w-propyl, phenyl, pyridyl, pyrazinyl, heterotetralinyl, thiazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazole, or thiophenols, and R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3.

9. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R2is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl and wherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R2is substituted by 1 or 2 substituents selected from the group consisting of halo, methyl, and cyano.

11. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R2is -CH2CH2CF3,2595812. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R5, and R6independently is hydrogen, methyl or fluoro.

13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein n is i and Raand Rctaken together with the atoms to which they are attached form a five membered ring and each Rband Rdis H.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, provided that when R1is H, then R2is not substituted or unsubstituted pyridyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, provided that when R1is H, then R2is not substituted or unsubstituted aryl and R2is not substituted or unsubstituted heteroaryl.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, of formula II:wherein:R1is hydrogen, Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, Ci- 4fluoroalkyl, and hydroxy; orR2is C4-6 cycloalkyl, 5 to 10 membered heterocycloalkyl, aryl, or heteroaryl, wherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; provided that if R1is H, then R2is not substituted or unsubstitutedeach R3, R4, R5, and R6independently is hydrogen or halo;p is 0, 1, or 2; r is 0, 1, or 2; and z is 0 or 1.

17. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, of formula III:wherein:R1is hydrogen, Cs-ecycloalkyl, aryl, or 5-10 membered heterocycloalkyl, wherein R1is substituted by 0, 1 or 2 substituents selected from the group consisting of halogen or Ci- 4fluoroalkyl, and hydroxy; orR2is C4-6 cycloalkyl, 5 to 10 membered heterocycloalkyl, aryl, or heteroaryl, provided that when R1is H, then R2is not substituted or unsubstitutedwherein R2is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of halo, methyl, phenyl, cyano, -OCH3, and -OCF3; each R3, R4, R5, and R6independently is hydrogen or halo; and p is 0 or 1.

18. The compound of claim 1 selected from the group consisting of l-(3-(lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine;1 -(2-(3 -phenylpyrrolidin-2-yl)pyri din-3 -yl)- IH-indazole;3-cyclopropyl-l-(2-(3-(5-fluoropyridin-2-yl)pyrrolidin-2-yl)pyridin-3-yl)-lH-indazole; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(5-fluoropyrimidin-2-yl)ethan-l -amine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(thiophen-2-yl)ethan-l -amine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(4-fluorophenyl)ethan-l -amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-3-(benzyloxy)propan-l-amine;3-(2-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-aminoethyl)benzonitrile; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(thiazol-2-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(5-methyl-lH-pyrazol-l-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(oxazol-2-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(4-methylisoxazol-3-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-(4-methylisothiazol-3-yl)ethanamine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-phenylethan-l -amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-cyclobutylethan-l-amine; l-(3-(lH-indazol-l-yl)pyri din-2 -yl)-2-cy cl ohexylethan-1 -amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethan-l-amine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-3-((2,3-dihydrobenzo[b][l,4]dioxin-5-yl)oxy)propan-l- amine; l-(3-(lH-indazol-l-yl) pyridin-2-yl)-2-(2,4-difluorophenyl) ethanamine; l-(3-(lH-indazol-l-yl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-methylpiperidin-l-yl)ethan-l-amine;25958 l-(3-(lH-indazol-l-yl)pyridin-2-yl)-(2-4,4-difluoro-2-methylpiperidin-l-yl)ethan-l -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-(2-3 ,3 -difluoro-4-methylpyrrolidin- 1 -yl)ethan- 1 -amine;1 -(3 -(IH-indazol- 1 -yl)pyridin-2-yl)-(2-3 -(trifluoromethoxy)pyrrolidin- 1 -yl)ethan- 1 -amine;1 -(3 -( 1 H-indazol- 1 -yl)pyridin-2-yl)-2-(3 -fluorophenoxy)ethan- 1 -amine; l-(3-(l / / -indazol-l-yl)pyridin-2-yl)-7V2-methyl-7V2-(3,3,3-trifluoropropyl)ethane-l,2-diamine;1 -(3 -(3 -(2,3 -dihydrobenzofb] [ 1 ,4]dioxin-5-yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;1 -(3 -(3 -phenyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyri din-2 -yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3 -(3 -cyclobutyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine; l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyrimidin-2-yl)ethanamine; l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3 -(3 -cyclopentyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;1 -(3 -(3 -cyclohexyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3 -(3 -(bicyclof 1.1.1 ]pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(l-(2-((S)-l-amino-2-(pyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)-2,2,2-tri fluoroethanol; l-(3-(3-(2,2-difluorocyclopropyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(3,5-difluoropyridin-2- yl)ethanamine; l-(3-(3-(3-fluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;1 -(3-(3 -cyclopropyl- lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylthiazol-2-yl)ethanamine;( 1 S)- 1 -(3 -(3 -(3,3 -difluorocy cl opentyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)-2-(5 -fluoropyridin-2-yl)ethanamine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine;1 -(3 -(3 -cyclopropyl - 1 H-indazol - 1 -yl)pyridin-2-yl)but-3 -en- 1 -amine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)ethanamine;6-(2-amino-2-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)ethyl)picolinonitrile; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-methylpyridin-2-yl)ethanamine; l-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)-2-(4-methylpyridin-2-yl)ethanamine; l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine;l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-lH-indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol; l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethanamine;1 -( 1 -(2-( 1 -amino-2-(5 -fluoropyridin-2-yl)ethyl)pyri din-3 -yl)- 1 H-indazol -3 -yl)cy clobutan- 1 -ol ; l-(3-(3-cyclobutyl-4-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lH-indazol-3-yl)-2,2,2- trifluoroethan- 1 -ol;1 -(1 -(2-( 1 -amino-2-cy cl obutylethyl)pyri din-3 -yl)- lH-indazol-3 -yl)-2,2,2-trifluoroethan- 1 -ol;1 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl)cyclopropyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5- fluoropyridin-2-yl)ethan- 1 -amine;1 -(3 -(4-fluoro-3 -(1 -(trifluoromethyl) cyclobutyl)- IH-indazol- 1 -yl) pyridin-2-yl)-2-(5- fluoropyridin-2-yl) ethan-1 -amine;1-(3-(4-fluoro-3-(spiro[2.3]hexan-5-yl)-lH-indazol-l-ylpyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;1 -(3 -(4-fluoro-3 -(spiro [2.2] pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine;2-(5-fluoropyridin-2-yl)-l-(3-(3-(3-(trifluoromethyl) cyclobutyl)-lH-indazol-l-yl) pyridin-2-yl) ethan-1 -amine; l-(3-(3-(3-(difluoromethyl)cyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethan-l- amine;1-(3-(3-cyclobutyl-4,7-difluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine 2,2,2-trifluoroacetate;2-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-5-fluoro-lH-indazol-3-yl)-l,l,l- trifluoropropan-2-ol; l-(3-(3-(3,3-difluorocyclobutyl)-4-methyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2- yl)ethan-l -amine; l-(3-(3-cyclobutyl-4-methyl-lH-indazol-l-yl)pyridin-2-yl)-2-(5-fluoropyridin-2-yl)ethan-l- amine; l-(l-(2-(l-amino-2-(5-fluoropyridin-2-yl)ethyl)pyridin-3-yl)-4-fluoro-lH-indazol-3-yl)-2,2- difluoroethan-l-ol; and l-(3-(3-cyclobutyl-lH-indazol-l-yl)-5-methylpyridin-2-yl)-2-(pyridin-2-yl)ethan-l-amine; or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 selected from the group consisting of (lS)-(3-(lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8-yl)methanamine;(5)- 1 -(3 -(3 -(2,3 -dihydrobenzofb] [ 1 ,4]dioxin-5-yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;(S)-l-(3-(3-phenyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)- 1 -(3 -(3 -cyclopropyl- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; (S)-l-(3-(3-cyclobutyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-(3-(3-cyclopropyl-lH-indazol-l-yl)pyridin-2-yl)(5,6,7,8-tetrahydroquinolin-8- yl)methanamine;(S)-l-(3-(3-(3,3-difluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; (S)-l-(3-(3-cyclopentyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)-l-(3-(3-cyclohexyl-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;(S)- 1 -(3 -(3 -(bicyclof 1.1.1 ]pentan- 1 -yl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyri din-2 - yl)ethanamine;(S)-l-(3-(3-(3-fluorocyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine;( 1 S)- 1 -(3 -(3 -(3,3 -difluorocyclopentyl)- IH-indazol- 1 -yl)pyridin-2-yl)-2-(pyridin-2- yl)ethanamine;(S)-l-(3-(3-cyclobutyl-5-fluoro-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethanamine; and (S)-l-(3-(3-(3-(difluoromethyl)cyclobutyl)-lH-indazol-l-yl)pyridin-2-yl)-2-(pyridin-2-yl)ethan- 1 -amine; or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-19 which is a 2,2,2-trifluoroacetate salt.

21. A pharmaceutical composition comprising the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A method of treating pain or another HCNl / HCN2-driven disease comprising administering a therapeutically effective amount a compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said pain or other HCNl / HCN2-driven disease is selected from the group consisting of inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) disorder and psychiatric disorder.

23. The method according to claim 22, wherein said inflammatory pain or 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), postoperative neuropathy, pudendal neuralgia, small fiber sensory neuropathy (SFSN), lower back pain, nerve damage following traumatic injury, fibromyalgia, and carpal tunnel syndrome.

24. The method according to claim 22, wherein said central nervous system (CNS) disorder or psychiatric disorder is selected from cognitive impairments associated with schizophrenia (CIAS), early infantile epileptic encephalopathies (EIEE), autism (sensory sensitivity), and mood disorders.

25. The method of any one of claims 22-24 wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof is administered orally to the subject.

26. Use of a compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof in therapy.

27. Use of a compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof for treating pain or another HCNl / HCN2-driven disease selected from the group consisting of inflammatory pain, neuropathic pain, tinnitus, central nervous system (CNS) and psychiatric disorders.

28. The use according to claim 27, wherein said inflammatory pain or 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), postoperative neuropathy, pudendal neuralgia, small fiber sensory neuropathy (SFSN), lower back pain, nerve damage following traumatic injury, fibromyalgia, and carpal tunnel syndrome.

29. The use according to claim 27, wherein said central nervous system (CNS) and psychiatric disorders are selected from cognitive impairments associated with schizophrenia25958(CIAS), early infantile epileptic encephalopathies (EIEE), schizophrenia, autism (sensory sensitivity), and mood disorders.

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