Spiro-oxindole compounds and their uses as therapeutic agents

(Field of invention) The present invention relates to spirooxyindole compounds. In particular, the present invention relates to sodium channel blockers and thus spirooxyindole compounds useful for treating sodium channel-mediated diseases or conditions such as pain, and other diseases and conditions associated with sodium channel mediation. ..

(Background of invention) Transmembrane proteins that trigger electrical potentials in electroactive sodium channels, nerves, muscles and other electrically excitable cells are essential components of normal sensations, movements, thoughts and behaviors (Non-Patent Document 1). .. These channels consist of highly processed alpha subunits associated with auxiliary beta subunits. The pore-forming alpha subunit is sufficient to exert channel function, but the motility and voltage dependence of channel opening and closing are partially modified by the beta subunit (Non-Patent Document 2). Each alpha subunit contains four homologous domains I-IV, each with six predictive transmembrane segments. The relative molecular weight of the alpha subunit of the sodium channel, including the voltage sensor that forms the ionic conductive pores and regulates the sodium ionic conduction, is 260,000. Electrophysiological records, biochemical purification and molecular cloning confirmed 10 different sodium channel alpha subunits and 4 beta subunits (Non-Patent Documents 3; and 4).

A prominent feature of sodium channels is their rapid activation and inactivation (voltage-dependent gate opening and closing) when the voltage applied to the plasma membrane of excitatory cells is depolarized, as well as conductive pores that are essential to the structure of proteins. Efficient and selective conduction of sodium ions through them (Non-Patent Document 5). At negative or hyperpolarizing membrane potentials, sodium channels close. After membrane depolarization, sodium channels open quickly and then inactivate. The channels carry current only in the open state, and once inactivated, they must return to the dormant state supported by membrane hyperpolarization before they can reopen. Different sodium channel subtypes differ in the voltage range in which they are active and inactive and in the active and inactive kinetics.

Sodium channels of proteins have been extensively studied and have been shown to be involved in numerous biological functions. Studies in this area have identified variants of the alpha subunit that can result in significant changes in channel function and activity, ultimately leading to major pathophysiological conditions. Because of this function, this family of proteins is considered to have important implications for therapeutic intervention. Na_v1.1 and Na_v1.2 is highly expressed in the brain (Raymond, CK et al., J. Biol. Chem. (2004), 279 (44): 46234-41) and is essential for normal brain function. In humans, Na_v1.1 and Na_vMutations in 1.2 can lead to severe epileptic conditions and sometimes mental decline (Rhodes, TH et al., Proc. Natl. Acad. Sci. USA (2004), 101 (30): 11147-52; Kamiya. , K. et al., J. Biol. Chem. (2004), 24 (11): 2690-8; Pereira, S. et al., Neurology (2004), 63 (1): 191-2). Thus, both channels are considered to be effective targets for the treatment of epilepsy (see International Publication No. 01/38564 Pamphlet).

Na_V1.3 is widely expressed throughout the body (Raymond, CK et al. Cited earlier). It has been demonstrated to have up-regulated expression in rat dorsal sensory nerves after nervous system injury (Hains, BD et al., J. Neurosci. (2003), 23 (26): 8881-92). Many experts in the field are Na_vWe consider 1.3 to be a suitable target for the treatment of pain (Lai, J. et al., Curr. Opin. Neurobiol. (2003), (3): 291-72003; Wood, JN et al., J. Neurobiol. (2004), 61 (1): 55-71; Chung, JM et al., Novartis Found Symp. (2004), 261: 19-27; discussion 27-31, 47-54).

Na_vExpression of 1.4 is effectively restricted to muscle (Raymond, CK et al., Listed above). Mutations in this gene have been shown to be deeply involved in muscle function, including paralysis (Tamaoka A., Intern. Med. (2003), (9): 769-70). Therefore, this channel is considered a target for the treatment of abnormal muscle contractions, spasms or paralysis.

Cardiac sodium channel, Na_v1.5 is predominantly expressed in the ventricles and atrium (Raymond, CK et al., Listed above) and can be found in synovial nodules, ventricular nodules, and possibly Purkinje cells. The rapid rise of the cardiac working potential and the rapid impulse conduction through the heart tissue are Na_vThis is due to the opening of 1.5. Thus, Na_V1.5 is the core of the heart arrhythmia. Human Na_VMutations in 1.5 result in, for example, QT3 prolongation (LQT3), Brugada syndrome (BS), genetic cardiac conduction deficiency, nocturnal sudden death syndrome (SUNDS) and sudden infant death syndrome (SIDS) (Liu, H). It becomes multiple arrhythmic syndromes such as Am.J.Pharmacogenomics (2003), 3 (3): 173-9). Sodium channel blocker therapy has been frequently used in the treatment of cardiac arrhythmias. Quinidine, the first antiarrhythmic drug discovered in 1914, is classified as a sodium channel blocker.

Na_V1.6 encodes a large number of widely dispersed potential-operated sodium channels found in the node of Ranvier neuronal axons throughout the central and peripheral nervous system (Caldwell, JH et al., Proc. Natl. Acad. Sci. USA (2000), 97 (10): 5616-20). No mutations detected in humans, but Na_V1.6 is thought to play a role in the development of symptoms associated with multiple sclerosis and has been considered a target for the treatment of this disease (Craner, MJ et al., Proc Natl Acad Sci USA (2004)). , 101 (21): 8168-73).

Na_V1.7 was initially cloned from a pheochromocytoma PC12 cell line (Toledo-Aral, JJ et al., Proc Natl. Acad. Sci USA (1997), 94: 1527-1532). Its presence in high concentrations in the growth cone of small-diameter neurons suggested that it could play a role in the transmission of nociceptive information. But Na_V1.7 is also expressed in neuroendocrine cells associated with the autonomic nervous system (Klugbauer, N. et al., EMBO J. (1995), 14 (6): 1084-90) and is associated with autonomic nervous processes. This has been challenged by experts in the field. The potential role in autonomous function is Na_V1.7 Demonstrated with the production of null mutants, Na in all sensory and exchange neurons_VThe removal of 1.7 results in a deadly perinatal phenotype (Nassar et al., Proc. Natl. Acad. Sci. USA (2004), 101 (34): 12706-11). On the other hand, Na in a subset of sensory nerves that are overwhelmingly noxious_V1.7 Deletion of expression demonstrated a role in the pain mechanism (Nassar et al., Supra). Active Na in a subset of neurons_V1.7 Further support for blockers is that two human genetic pain conditions, primary erythromelalgia and familial rectal pain pain, Na_VSupported by the discovery that it was shown to be located at 1.7 (Yang, Y. et al., J. Med. Genet. (2004), 41 (3): 171-4).

Na_VExpression of 1.8 is essentially limited to DRG (Raymond, CK et al., Supra). Na_VNo human mutations have been identified for 1.8. But Na_VThe 1.8-null mutant mice were viable, reproductive and normal in appearance. Significant insensitivity to harmful physical stimuli, a small deficiency in harmful temperature sensitivities, and delayed progression of inflammatory hyperalgesia tell researchers Na in pain signaling._VIt was suggested that 1.8 plays a major role (Akopian, AN et al., Nat. Neurosci. (1999), 2 (6): 541-8). Blocking this channel is widely accepted as a potential treatment for pain (Lai, J, et al., Supra; Wood, JN et al., Supra; Chung, JM et al., Supra). WO 03/037274A2 describes pyrazole-amides for the treatment of pain and chronic pain by blocking sodium channels associated with the onset or recurrence of central or peripheral nervous system conditions, especially those identified. And sulfonamines are described. WO 03/037890A2 contains piperidines for the treatment of pain and chronic pain by blocking sodium channels associated with the onset or recurrence of central or peripheral nervous system conditions, especially those identified. Have been described. The compounds, compositions and methods of these inventions are PN3 (Na)._V1.8) For specific applications for treating neuropathic or inflammatory pain by suppressing ion outflow through channels containing subunits.

Tetrodotoxin insensitive peripheral sodium channel Na discovered by Dib-Hajj, SD et al._V1.9 (see Dib-Hajj, SD et al., Proc. Natl. Acad. Sci. USA (1998), 95 (15): 8963-8) was shown to be present alone in the dorsal root ganglion. Na_V1.9 has been demonstrated to be the only member of the potential-actuated sodium channel superfamily, which is the basis for neurotrophine (BDNF) -induced depolarization and excitation and is ligand-mediated (Blum, R., Kafitz, KW, Konnerth, A., Nature (2002), 419 (6908): 687-93). The limited pattern of expression of this channel makes it a candidate for labeling for the treatment of pain (Lai, J, et al., Supra; Wood, JN et al., Supra; Chung, JM et al., Supra. ).

NaX is an putative sodium channel and has not been shown to be electroactive. In addition to expression in Schwann cells of the lung, heart, dorsal ganglion and peripheral nervous system, NaX is involved in nerve and ependymal cells in localized areas of the CNS, especially periventricular fluid homeostasis. Found in organs (Watanabe, E. et al., J. Neurosci. (2000), 20 (20): 7734-51). NaX-null mice showed abnormal intake of hypertonic saline in water-deficient and salt-deficient conditions. These findings indicate that NaX plays an important role in central sensing of fluid sodium concentration and regulation of salt ingestion behavior. Its expression pattern and function suggests that it is of interest for the treatment of cystic fibrosis and other related salt-regulating disorders.

Studies of the sodium channel blocker tetrodotoxin (TTX), which is used to reduce neuronal activity in certain areas of the brain, have shown potential applications in the treatment of addiction. Drug-paired stimuli induce drug craving and recurrence in addicts and drug-seeking behavior in rats. Functional completeness of the basal peach body (BLA) is required for recovery of cocaine-seeking behavior induced by cocaine conditioned stimuli (but not by cocaine itself). BLA plays a similar role in the recovery of heroin-seeking behavior. TTX induces BLA inactivation with respect to regulated and heroin-activated recovery of extinct heroin-seeking behavior in rat models (Fuchs, RA; and RE Psychopharmacology (2002) 160 (4): See 425-33).

This closely related family of proteins has long been recognized as a marker for therapeutic intervention. Sodium channels have been targeted by a variety of pharmaceutical agents. These include neurotoxins, antiarrhythmic agents, antiepileptic drugs and local anesthetics (Clare, JJ et al., Drug Discovery Today (2000) 5: 506-520). All current drugs that act on sodium channels have receptor sites on the alpha subunit. At least six different receptor sites have been identified for neurotoxins and one receptor site for local anesthetics and related drugs (Cestele, S. et al., Biochimie (2000), Vol.82, p883-892). ).

Small molecule sodium channel blockers or local anesthetics, and related antiepileptic and antiarrhythmic agents, interact with overlapping receptor sites located in the medial cavity of the pores of the sodium channel (Catterall, WA, Neuron (2000). ), 26: 13-25). Amino acid residues in the S6 segment from at least 3 of the 4 domains are involved in this complex drug receptor site, and the IVS6 segment plays a major role. These regions are highly conserved, so most sodium channel blockers known to date interact with all channel subtypes with comparable potential. Nonetheless, sufficient for the treatment of therapeutically selective sodium channel blockers and epilepsy (eg, lamotrignin, phenytoin and carbamazepine), and certain cardiac arrhythmias (eg, lidocaine, tocainide and mexiletine). It is possible to manufacture a treatment window. However, the potential and therapeutic index of these blockers are not optimal, and the usefulness of these compounds is limited in various therapeutic areas where sodium channel blockers are optimal. Management of acute and chronic pain Pharmacotherapy is central to the management of acute and chronic pain in all age groups, including newborns, toddlers and children. Pain drugs are listed by the American Pain Society in three main categories: 1) non-opioid analgesics-acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs), including salicylates (eg, aspirin). , 2) Opioid analgesics, and 3) Auxiliary analgesics.

Non-opioid analgesics such as acetaminophen and NSAIDs are useful for acute and chronic pain due to a variety of causes, including surgery, trauma, arthritis and cancer. Since acetaminophen has no anti-inflammatory activity, NSAIDs are applied to treat inflammation-related pain. Opioid drugs also have no anti-inflammatory activity. All NSAIDs suppress the enzyme cyclooxygenase (COX), thereby suppressing prostaglandin synthesis and reducing the inflammatory pain response. There are at least two COX isoforms, COX-1 and COX-2. Common non-selective COX inhibitors include ibuprofen and naproxen. The suppression of COX-1 found in platelets, GI tubes, kidneys and most other human tissues is thought to be associated with adverse effects such as gastrointestinal bleeding. Development of selective COX-2 NSAIDs such as celecoxib, valdecoxib and rofecoxib can reduce adverse profiles in the gastrointestinal tract and kidneys, in addition to the benefits of non-selective NSAIDs. However, there is currently evidence suggesting that chronic use of certain selective COX-2 inhibitors may result in an increased risk of stroke.

The American Pain Society recommends that repeated use of opioid analgesics be initiated based on pain-specific history and physical examination, including pain assessment. Due to the broad adverse profile associated with opiate use, treatment should include diagnosis, comprehensive interdisciplinary treatment planning, and proper and continuous monitoring of patients. In addition, it is recommended to add opioids to non-opioids to manage acute pain and cancer-related pain that does not respond to non-opioids alone. Opioid analgesics act as agonists for mu and kappa-type specific receptors in the central and peripheral nervous systems. Depending on the opioid drug and the mode of preparation or administration thereof, it can be made to have a shorter or longer duration. All opioid analgesics carry the risk of respiratory depression, liver dysfunction, addiction and addiction and are therefore not ideal for long-term or chronic pain management.

Numerous other classes of drugs may enhance the efficacy of opioids or NSAIDS and, in some circumstances, have independent analgesic activity or counteract the side effects of analgesics. Regardless of which of these effects the drug has, they are collectively referred to as "analgesic aids." Tricyclic antidepressants, antiepileptic drugs, local anesthetics, glucocorticoids, skeletal muscle relaxants, anticonvulsants, antihistamines, benzodiazepines, caffeine, local drugs (eg capsaicin), dextroamphetamine and phenothidine , All used clinically as an adjunct treatment or independently in pain treatment. In particular, antiepileptic drugs have been successful in treating pain conditions. For example, GABApentin with an unidentified therapeutic target is indicated for the treatment of neuropathic pain. In other clinical trials, attempts to establish that central neuropathic pain responds to ion channel blockers, such as calcium, sodium and / or NMDA (N-methyl-D-aspartate) channel blockers. Has been made. Currently, low-affinity NMDA channel blockers for the treatment of neuropathic pain are in development. The literature provides considerable preclinical electrophysiological evidence to support the use of NMDA antagonists in the treatment of neuropathic pain. Such agents have also been found to be used in controlling pain after resistance to opioid analgesia, especially in cancer patients.

Systemic analgesics such as NSAIDs and opioids should be distinguished from therapeutic agents that are only useful as local analgesics / anesthetics. Well-known topical analgesics, such as lidocaine and xylocaine, are non-selective ion channel blockers that can be fatal when administered systemically. Legitimate descriptions of non-selective sodium channel blockers can be found in Madge, D. et al., J. Med. Chem. (2001), 44 (2): 115-37.

Several sodium channel regulators are known for use as anticonvulsants or antidepressants, including, for example, carbamazepine, amitriptyline, lamotridin and riluzole, all of which are brain tetrodotoxin-sensitive (TTX-S) sodium channels. Target. Such TTX-S agents have dose-limited side effects, including dizziness, ataxia and drowsiness, primarily due to their action on the TTX-S channels in the brain. Role of sodium channels in pain Sodium channels are responsible for maintaining normal morbidity, including the long-recognized role that potential-actuated sodium channels play in the development of abnormal neuronal activity and neuropathic or pathological pain. It plays various series of roles. (Chung, JM et al.). Damage to peripheral nerves after trauma or disease is abnormal afferent, including altered sodium channel activity and ectopic secretion from axotomized afferents and the natural activity of sensitized intact nociceptors. It can result in the development of activity. These changes can lead to long-lasting abnormal hypersensitivity or allodynia to normal harmless stimuli. Examples of neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, chronic low back pain, illusionary limb pain, and cancer and chemotherapy-induced pain, chronic pelvic pain, complex local pain syndrome, and associated neuralgia. However, it is not limited to these.

There has been some success in treating neuropathic pain symptoms using medications such as gabapentin, and more recently pregabalin as a short-term first-line treatment. However, medications for neuropathic pain generally do not produce much success and respond poorly to commonly used pain-reducing drugs such as NSAIDS and opiates. Therefore, there is still a great need to investigate new treatments.<nplcit num="1"><text>Catterall, WA, Nature (2001), Vol.409, p988-990</text></nplcit><nplcit num="2"><text>Goldin et al., Neuron (2000), Vol.28, p365-368</text></nplcit><nplcit num="3"><text>Yu, FH et al., Sci.STKE (2004), 253</text></nplcit><nplcit num="4"><text>Yu, FH et al., Neurosci. (2003), 20: 7577-85</text></nplcit><nplcit num="5"><text>Sato, C., et al., Nature (2001), 409: 1047-1051</text></nplcit>

<p> Only a handful of powerful and effective sodium channel blockers remain with clinically minimal adverse events. There is also an unmet medical need to treat neuropathic pain and other sodium channel pathological conditions effectively and without adverse side effects. The present invention provides compounds that meet these clinical needs, methods of using these compounds, and compositions containing these compounds.</p>

<p> (Gist of the invention) The present invention relates to spirooxyindole compounds useful in the treatment and / or prevention of sodium channel-mediated diseases or conditions such as pain. The compounds of the present invention also include central nervous system conditions such as epilepsy, anxiety, depression and bipolar disease; cardiovascular conditions such as arrhythmias, atrial cells and ventricular fibrillation; lower limb immobility syndrome, essential tremor and muscle. Neuromuscular conditions such as paralysis or atrophy; neuroprotection against stroke, glaucoma, neurological trauma and multiple sclerosis; and channel diseases such as erythromyalgia and familial rectal pain syndrome It is also useful in the treatment of other (but not limited to) sodium channel-mediated diseases or conditions.</p><p> Therefore, in one aspect, the present invention is a compound represented by formula (I) as a stereoisomer, an enantiomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvent thereof. Provide Japanese or prodrugs.</p><p><chemistry num="6"><img file="JP5118627B2_D0001.tif" /></chemistry>(During the ceremony, j and k are 0, 1, 2 or 3, respectively; Q is -C (R)^1a) H-, -C (O)-, -O-, -S (O)_m-(Where m is 0, 1 or 2), -CF₂-, -C (O) O-, -C (O) N (R)⁵)-Or -N (R)⁵) C (O)-is; R^1aIs hydrogen or -OR⁵Is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; Or R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵, -R⁹-N (R)⁴) R⁵, Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl groups, respectively, as required, are alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; Or R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; Or R¹Is -R⁹-N (R)¹⁰) R¹¹, -R⁹-N (R)¹²) C (O) R¹¹Or -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, are alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl are substituted with one or more substituents selected from the group; Or R¹Is a heterocyclylalkyl or a heteroarylalkyl, wherein the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN, or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is 0, 1 or 2 independently and each n is 1 or 2 independently) may be substituted with one or more substituents selected from the group consisting of; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵Selected from the group consisting of (each m is 0, 1 or 2 independently and each n is 1 or 2 independently); Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aIs R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain. ) In another aspect, the invention presents a method of treating pain in mammals, especially humans, in which a therapeutically effective amount of the compound of the invention described above is administered to a mammal in need thereof. Provide a method to include.</p><p> In another aspect, the invention is one or more Nas._V1.1, Na_V1.2, Na_V1.3, Na_V1.4, Na_V1.5, Na_V1.6, Na_V1.7, Na_V1.8 or Na_V1.9 Provides a method of treating or alleviating the severity of a disease, condition or disorder associated with an activation or hyperactivity of the disease state. In another aspect, the invention presents a variety of sodium channel-mediated diseases or conditions, such as HIV-related pain, HIV treatment-induced neuropathy, trigeminal nerve pain, post-herpes infection nerve pain, acute pain, hypersensitivity, erythromelalgia. , Hypersensitivity bowel syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), muscular atrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis , Atherosclerosis, paroxysmal tension disorder, myasthenic syndrome, muscle tension, malignant hyperthermia, cystic fibromyalgia, pseudoaldosteronism, erythromelalgia, hypothyroidism, bipolar depression, anxiety, integration Ataxia, sodium channel toxin-related illness, familial erythromelalgia, primary erythromelalgia, familial erythromelalgia, cancer, epilepsy, partial and general tonic attacks, lower limb immobility syndrome, arrhythmia, fibromyalgia It provides a method for treating neuroprotection, sudden arrhythmia, atrial cells and ventricular fibrillation in ischemic conditions caused by pain, stroke, glaucoma or neurological trauma.</p><p> In another aspect, the invention is a method of treating various sodium channel-mediated diseases or conditions in mammals, especially humans, by suppressing ion outflow via voltage-gated sodium channels, in mammals in need thereof. , Provided are methods comprising administering a therapeutically effective amount of a previously described compound of the invention.</p><p> In another aspect, the invention provides a pharmaceutical composition comprising the compounds of the invention described above and a pharmaceutically acceptable excipient. In one embodiment, the invention relates to a pain-related disease or condition to be treated when the compound of the invention is administered to an animal, preferably a mammal, most preferably a human, in a pharmaceutically acceptable carrier. With respect to the pharmaceutical composition contained in an effective amount.</p><p> In another aspect, the invention is one or more compounds of the invention or one or more to increase the efficacy of existing or future drug treatments or reduce adverse events associated with accepted treatments. Other accepted therapies, or medications in combination with any combination of these, are provided. In one embodiment, the invention relates to a pharmaceutical composition that combines a compound of the invention with an established or future treatment for the applications listed in the invention.</p>

(Detailed description of the invention) Definition Certain chemical groups named herein are preceded by an abbreviation indicating the total number of carbon atoms present in the indicated chemical group. For example, C₇-C₁₂Alkyl represents the alkyl group specified below, with a total of 7-12 carbon atoms, C₄-C₁₂Cycloalkylalkyl represents the cycloalkylalkyl defined below, having a total of 4-12 carbon atoms. The total number of carbons in the abbreviation does not include the carbons present in the substituents of the listed groups. For example, the following terms have a meaning to display.

"C₁-C₁₀"Alkyl" refers to an alkyl radical as defined below, which contains 1 to 10 carbon atoms. C₁-C₁₀Alkyl radicals may be optionally substituted with respect to the alkyl group, as defined below.

"C₂-C₁₂"Alkynyl" refers to an alkynyl radical as defined below, which contains 2 to 12 carbon atoms. C₂-C₁₂The alkynyl radical may be optionally substituted with respect to the alkenyl group, as defined below.

"C₁-C₁₂"Alkoxy" refers to an alkoxy radical as defined below, which contains 1 to 12 carbon atoms. C₁-C₁₂The alkyl moiety of the alkoxy radical may optionally be substituted with respect to the alkyl group as defined below.

"C₂-C₁₂"Alkoxyalkyl" refers to an alkoxyalkyl radical as defined below, which contains 2 to 12 carbon atoms. C₂-C₁₂The alkyl moiety of the alkoxyalkyl radical may optionally be substituted with respect to the alkyl group as defined below.

"C₇-C₁₂"Aralkyl" refers to an aralkyl group containing 7 to 12 carbon atoms as defined below. C₇-C₁₂The aryl moiety of the aralkyl radical may be optionally substituted with respect to the aryl group as described below. C₇-C₁₂The alkyl moiety of the aralkyl radical may be optionally substituted with respect to the alkyl group as defined below.

"C₇-C₁₂"Aralkenyl" refers to an aralkenyl group as defined below, which contains 7 to 12 carbon atoms. C₇-C₁₂The aryl portion of the aralkyl radical may be optionally substituted with respect to the aryl group as described below. C₇-C₁₂The alkenyl moiety of the aralkyl radical may be optionally substituted with respect to the alkenyl group as defined below.

"C₃-C₁₂"Cycloalkyl" refers to a cycloalkyl radical as defined below, which has 3 to 12 carbon atoms. C₃-C₁₂Cycloalkyl radicals may optionally be substituted with respect to the cycloalkyl group as defined below.

"C₄-C₁₂"Cycloalkylalkyl" refers to a cycloalkylalkyl radical as defined below, which has 4 to 12 carbon atoms. C₄-C₁₂Cycloalkylalkyl radicals may optionally be substituted with respect to the cycloalkylalkyl group as defined below.

In addition to the above, the following terms used in the specification and the appended claims have the indicated meanings unless the opposite is stated.

"Amino" is -NH₂Say radicals.

"Cyano" refers to the -CN radical.

"Hydroxyl" refers to the -OH radical.

"Imino" refers to the = NH substituent.

"Nitro" is = NO₂Say radicals.

"Oxo" refers to the = O substituent.

"Tioxo" refers to the = S substituent.

"Trifluoromethyl" is -CF₃Say radicals.

"Alkyl" refers to a linear or branched hydrocarbon chain radical composed only of carbon and hydrogen atoms, which is unsaturated and contains 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Alternatively, it has 1 to 6 carbon atoms and is bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1 -Dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like can be mentioned. Unless otherwise specified herein, the alkyl group may optionally be substituted with one of the following groups: Alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O)_tOR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halo groups as required), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl. Alkyl; and each R¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alkenyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one double bond and 2 to 12 carbon atoms, preferably 1 to 8 carbon atoms. It has a number of carbon atoms and is bound to the rest of the molecule by a single bond, such as ethenyl, prope-1-nyl, bute-1-nyl, pente-1-nyl, penta-1,4-dienyl, etc. Be done. Unless otherwise specified herein, the alkenyl group may optionally be replaced by one of the following groups: Alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O)_tOR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halo groups as required), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl. Alkyl; and each R¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alkylene" or "alkylene chain" refers to a linear or branched divalent hydrocarbon chain that bonds the rest of the molecule to a radical group, consisting only of carbon and hydrogen, containing no unsaturated, 1-12. It contains radical atoms and includes, for example, methylene, ethylene, propylene, N-butylene and the like. The alkylene chain binds to the rest of the molecule via a single bond and to a radical group via a single bond. Bonding points of the alkylene chain with the rest of the molecule and with radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified herein, the alkylene chain may optionally be replaced by one of the following groups: Alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O)_tOR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halo groups as required), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl. Alkyl; and each R¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alkenylene" or "alkenylene chain" refers to a linear or branched divalent hydrocarbon chain that bonds the rest of the molecule to a radical group, consisting only of carbon and hydrogen and containing at least one double bond. , Has 2 to 12 carbon atoms, and includes, for example, ethenylene, propenylene, N-butenylene, and the like. The alkenylene chain binds to the rest of the molecule via a single bond and to a radical group via a double or single bond. Bonding points of the alkenylene chain with the rest of the molecule and with radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified herein, the alkenylene chain may optionally be replaced by one of the following groups: Alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O) OR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halo groups as required), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl. Alkyl; and each R¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alquinylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that bonds the rest of the molecule to a radical group, consisting only of carbon and hydrogen and containing at least one triple bond. It has 1 to 12 carbon atoms, and examples thereof include propynylene and n-butyylene. The alkynylene chain binds to the rest of the molecule via a single bond and to a radical group via a double or single bond. The junction of the alkynylene chain with the rest of the molecule and with the radical group can be mediated by one or any two carbons in the chain. Unless otherwise specified herein, the alkynylene chain may optionally be replaced by one of the following groups: Alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O)_tOR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halo groups as required), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl. Alkyl; and each R¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alkinyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one triple bond, 2 to 12 carbon atoms, preferably 1 to 8 carbon atoms. It has a carbon atom and is bonded to the rest of the molecule by a single bond, and examples thereof include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified herein, the alkynyl group may optionally be replaced by one of the following groups: Alkylate, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR¹⁴, -OC (O) -R¹⁴, -N (R)¹⁴)₂, -C (O) R¹⁴, -C (O) OR¹⁴, -C (O) N (R)¹⁴)₂, -N (R)¹⁴) C (O) OR¹⁶, -N (R)¹⁴) C (O) R¹⁶, -N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -S (O)_tOR¹⁶(Here t is 1-2), -S (O)_tR¹⁶(Where t is 0 ~ 2) and -S (O)_tN (R¹⁴)₂(Here t is 1-2), where each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R.¹⁶Are alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of which is not substituted unless otherwise stated.

"Alkoxy" is the formula: -OR_a(In the formula, R_aIs an alkyl radical as defined above), and contains 1 to 12 carbon atoms. The alkyl moiety of the alkoxy radical may optionally be substituted as defined above with respect to the alkyl radical.

"Alkoxyalkyl" is expressed by the formula: -R_a-OR_a(In the formula, each R_aIndependently refers to radicals (which are alkyl radicals as defined above). The oxygen atom may be attached to any carbon in either alkyl radical. Each alkyl moiety of the alkoxyalkyl radical may be optionally substituted with respect to the alkyl group as defined above.

"Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring structure composed only of hydrogen and carbon, containing 6 to 18 carbon atoms, and the ring structure is partially saturated. May be good. Aryl groups include, but are not limited to, fluorenyl, phenyl and naphthyl, for example. Unless otherwise specified herein, the term "aryl" or the prefix "al" (as in "aralkyl") may optionally be alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, Heteroaryl, Heteroarylalkyl, -R¹⁵-OR¹⁴, -R¹⁵-OC (O) -R¹⁴, -R¹⁵-N (R)¹⁴)₂, -R¹⁵-C (O) R¹⁴, -R¹⁵-C (O) OR¹⁴, -R¹⁵-C (O) N (R)¹⁴)₂, -R¹⁵-N (R)¹⁴) C (O) OR¹⁶, -R¹⁵-N (R)¹⁴) C (O) R¹⁶, -R¹⁵-N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tOR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tR¹⁶(Where t is 0 ~ 2), and -R¹⁵-S (O)_tN (R¹⁴)₂(Here, t is 1 to 2) (In the formula, each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵Are independently directly bonded, or linear or branched alkylene or alkenylene chains; each R¹⁶Is an alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where the substituents are not substituted, respectively). It means that the aryl radical substituted with one or more substituents is also selected.

"Aralkill" is the formula: -R_aR_{b b}(In the formula, R_aIs an alkyl radical as defined above, R_{b b}Refers to one or more radicals (which are aryl radicals as defined above), and examples thereof include benzyl, diphenylmethyl and the like. Aryl radicals (including plurals) are optionally substituted, as described above.

"Aryloxy" is the formula: -OR_{b b}(In the formula, R_{b b}Refers to a radical (which is an aryl group as defined above). The aryl portion of the aryloxy radical may be optionally substituted, as defined above.

"Aralkenil" is the formula: -R_cR_{b b}(In the formula, R_cIs an alkenyl radical as defined above, R_{b b}Refers to one or more radicals (which are aryl radicals as defined above), which may optionally be substituted, as described above. The aryl portion of the aralkyl radical may be optionally substituted with respect to the aryl group, as described above. The alkenyl portion of the aralkenyl radical may optionally be substituted with respect to the alkenyl group as defined above.

"Aralkyloxy" is the formula: -OR_{b b}(In the formula, R_{b b}Refers to a radical (which is an aralkyl group as defined above). The aralkyl portion of the aralkyl oxy radical may be optionally substituted, as defined above.

"Cycloalkyl" refers to stable non-aromatic monocyclic or polycyclic hydrocarbon radicals composed only of carbon and hydrogen atoms, with 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms. It may contain a fused or crosslinked ring structure with atoms, which is saturated or unsaturated and binds to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of polycyclic radicals include adamantyl, norbornyl, decalynyl, 7,7-dimethyl-bicyclo [2.2.1] heptanyl and the like. Unless otherwise specified herein, the term "cycloalkyl" is optionally referred to as alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, as required. Heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R¹⁵-OR¹⁴, -R¹⁵-OC (O) -R¹⁴, -R¹⁵-N (R)¹⁴)₂, -R¹⁵-C (O) R¹⁴, -R¹⁵-C (O) OR¹⁴, -R¹⁵-C (O) N (R)¹⁴)₂, -R¹⁵-N (R)¹⁴) C (O) OR¹⁶, -R¹⁵-N (R)¹⁴) C (O) R¹⁶, -R¹⁵-N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tOR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tR¹⁶(Where t is 0 ~ 2), and -R¹⁵-S (O)_tN (R¹⁴)₂(Here, t is 1 to 2) (In the formula, each R¹⁴Are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵Are independently directly bonded, or linear or branched alkylene or alkenylene chains; each R¹⁶Is an alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where the above radicals are not substituted, respectively). It means that it contains a cycloalkyl radical substituted by one or more substituents selected in the above.

"Cycloalkylalkyl" is expressed by the formula: -R_aR_d(In the formula, R_aIs an alkyl radical as defined above, R_dRefers to radicals (which are cycloalkyl radicals as defined above). Alkyl radicals and cycloalkyl radicals may optionally be substituted as defined above.

"Halo" refers to bromo, chloro, fluoro or iodine.

"Haloalkyl" refers to an alkyl radical as defined above, substituted with one or more of the halo radicals as defined above, eg, trifluoromethyl, difluoromethyl, trichloromethyl, etc. Examples thereof include 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like. The alkyl moiety of the haloalkyl radical may optionally be substituted with respect to the alkyl group as defined above.

A "heterocyclyl" is a stable 3- to 18-membered non-aromatic ring radical composed of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Say. Unless otherwise specified herein, the heterocyclyl radical may include a fused or crosslinked ring structure, may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring structure; in the heterocyclyl radical. Nitrogen, carbon or sulfur atoms may be oxidized, if desired; nitrogen atoms may be quaternized, if desired; and heterocyclyl radicals are partially or completely saturated. May be good. Examples of such heterocyclyl radicals are dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroiso. Indrill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolydinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl , Thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl, but not limited to these. Unless otherwise specified herein, the term "heterocyclyl" is optionally referred to as alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl. , Heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R¹⁵-OR¹⁴, -R¹⁵-OC (O) -R¹⁴, -R¹⁵-N (R)¹⁴)₂, -R¹⁵-C (O) R¹⁴, -R¹⁵-C (O) OR¹⁴, -R¹⁵-C (O) N (R)¹⁴)₂, -R¹⁵-N (R)¹⁴) C (O) OR¹⁶, -R¹⁵-N (R)¹⁴) C (O) R¹⁶, -R¹⁵-N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tOR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tR¹⁶(Where t is 0 ~ 2), and -R¹⁵-S (O)_tN (R¹⁴)₂(Here, t is 1 to 2) (In the formula, each R¹⁴Are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵Are independently directly bonded, or linear or branched alkylene or alkenylene chains; each R¹⁶Is an alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, wherein the above radicals are not substituted, respectively). It is meant to contain the heterocyclyl radicals as defined above, which have been substituted with one or more substituents of choice.

"Heterocyclylalkyl" is expressed by the formula: -R_aR_e(In the formula, R_aIs an alkyl radical as defined above, R_eIs a heterocyclyl radical as defined above), and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to an alkyl radical at a nitrogen atom. The alkyl moiety of the heterocyclyl alkyl radical may optionally be substituted with respect to the alkyl group as defined above. The heterocyclyl moiety of the heterocyclyl alkyl radical may be optionally substituted with respect to the heterocyclyl group as defined above.

"Heteroaryl" refers to a 5-18 membered ring aromatic ring radical composed of 1 to 17 carbon atoms and a heteroatom selected from the group consisting of 1 to 10 nitrogen, oxygen and sulfur. .. For the purposes of the present invention, the heteroaryl radical may include a fused or crosslinked ring structure, may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring structure; the nitrogen, carbon, of the heteroaryl radical. Or the sulfur atom is oxidized as needed; the nitrogen atom is quaternized as needed. Examples include azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindrill, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, 1,4- Benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6] ] Imidazo [1, 2-a] pyridinyl, carbazolyl, synnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indozolyl, indyl, indazolyl, isoindrill, indolinyl, isoindolinyl, isoquinolyl, indridinyl, isoxazolyl, naphthyl, naphthylidyl, oxadiyl 2-Oxazepinyl, oxazolyl, oxylanyl, 1-phenyl-1H-pyrrolill, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, prynyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, , Isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (eg, thienyl), but are not limited thereto. Unless otherwise specified herein, the term "heteroaryl" is optionally referred to as alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkyl. Alkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R¹⁵-OR¹⁴, -R¹⁵-OC (O) -R¹⁴, -R¹⁵-N (R)¹⁴)₂, -R¹⁵-C (O) R¹⁴, -R¹⁵-C (O) OR¹⁴, -R¹⁵-C (O) N (R)¹⁴)₂, -R¹⁵-N (R)¹⁴) C (O) OR¹⁶, -R¹⁵-N (R)¹⁴) C (O) R¹⁶, -R¹⁵-N (R)¹⁴) S (O)_tR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tOR¹⁶(Here t is 1-2), -R¹⁵-S (O)_tR¹⁶(Where t is 0 ~ 2), and -R¹⁵-S (O)_tN (R¹⁴)₂(Here, t is 1 to 2) (In the formula, each R¹⁴Are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵Are independently directly bonded, or linear or branched alkylene or alkenylene chains; each R¹⁶Is an alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, wherein the above radicals are not substituted, respectively). It means that it contains a heteroaryl radical as defined above, which is substituted with one or more substituents of choice.

"Heteroarylalkyl" is expressed by the formula: -R_aR_f(In the formula, R_aIs an alkyl radical as defined above, R_fRefers to radicals (which are heteroaryl radicals as defined above). The heteroaryl moiety of the heteroarylalkyl radical may be optionally substituted with respect to the heteroaryl group as defined above. The alkyl moiety of the heteroarylalkyl radical may optionally be substituted with respect to the alkyl group as defined above.

"Heteroarylalkenyl" is expressed by the formula: -R_{b b}R_f(In the formula, R_{b b}Is an alkenyl radical as defined above, R_fIs a heteroaryl radical as defined above). The heteroaryl moiety of the heteroarylalkenyl radical may be optionally substituted with respect to the heteroaryl group as defined above. The alkenyl portion of the heteroarylalkenyl radical may be optionally substituted with respect to the alkenyl group as defined above.

"Trihaloalkyl" refers to an alkyl radical as defined above, which is substituted with three previously defined halo radicals, such as trifluoromethyl. The alkyl moiety of the trihaloalkyl radical may optionally be substituted with respect to the alkyl group as defined above.

"Trihaloalkoxy" is expressed by the formula: -OR_g(In the formula, R_gRefers to a radical (which is a trihaloalkyl as defined above). The trihaloalkyl moiety of the trihaloalkoxy group may optionally be substituted with respect to the trihaloalkyl group, as specified above.

"Painless" refers to the absence of pain in response to stimuli that are normally painful.

"Allodynia" refers to a condition in which normally harmless sensations such as pressure and light contact are perceived as severe pain.

By "prodrug" is meant to indicate a compound that may be converted to a physiologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. The prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to the active compound of the invention. Prodrugs usually convert rapidly in vivo, for example by hydrolysis in the blood to give the parent compound of the invention. Prodrug compounds often offer advantages such as solubility, histocompatibility or delayed release in the body of mammals (Bundgard, H., Design of Prodrugs (1985), 7-9, 21- See page 24 (Elsevier, Amsterdam)). For the study of prodrugs, see Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol.14, and Bioreversible Carriers in Drug. Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both incorporated herein by reference).

Also, the term "prodrug" means to include any carrier that is conjugated, and when such a prodrug is administered to a mammalian subject, it will bring the active compound of the invention in vivo. discharge. Prodrugs of the compounds of the invention may be prepared by routine manipulation or by modifying the functional groups present in the compounds of the invention so that the modifications are cleaved in vivo to become the parent compound of the invention. .. As a prodrug, when a hydroxy, amino or mercapto group is administered to a mammalian subject, the prodrug of the compound of the invention is cleaved into any group that becomes a free hydroxy, free amino or free mercapto group, respectively. Includes bound compounds of the invention. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or amide derivatives of amine functional groups in the compounds of the invention.

The present invention also disclosed herein is isotopically labeled by having one or more atoms replaced by atoms having different atomic masses or mass numbers, pharmaceutically the formula (I). Means to include all acceptable compounds. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example.²H,³H,¹¹C,¹³C,¹⁴C,¹³N,¹⁵N,¹⁵O,¹⁷O,¹⁸O,³¹P,³²P,³⁵S,¹⁸F,³⁶Cl,¹²³I and¹²⁵There is I. These radiolabeled compounds determine the efficacy of a compound by characterizing the site or mode of action on the sodium channel or by binding an affinity to a pharmaceutically important site of the manner on the sodium channel. Or it can be useful to help with the measurement. Certain isotope-labeled compounds of formula (I), such as compounds incorporating radioisotopes, are useful in drug and / or substrate tissue distribution studies. Radioisotope, tritium, ie³H and carbon-14, ie¹⁴C is particularly useful for this purpose because it is an easy introduction and quick detection tool.

That is,²Substitution with heavy isotope hydrogens such as H provides certain therapeutic benefits due to greater metabolic stability, eg, increased half-life in vivo or reduced dose requirement criteria, and therefore in certain situations. Below is preferred.

¹¹C,¹⁸F,¹⁵O and¹³Substitution with positron-releasing isotopes such as N can be useful in positron-emitting tomography (PET) studies to test substrate receptor occupancy. Isotopically labeled compounds of formula (I) are generally suitable isotopics by conventional techniques known to those of skill in the art or in place of previously used unlabeled reagents. The reagent labeled with can be produced by a method similar to that described in Examples and Production Examples described below.

The inventions described herein also include in vivo metabolites of the disclosed compounds. Such products are, for example, the result of oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily by enzymatic processes. Accordingly, the invention includes compounds produced by methods comprising contacting the compounds of the invention with mammals for a time sufficient to obtain their metabolic products. Such products typically administer the radiolabeled compounds of the invention in detectable doses to animals such as rats, mice, guinea pigs, monkeys or humans and leave them for sufficient time for metabolism to occur. The conversion product is identified by isolation from urine, blood or other biological samples.

"Stable compound" and "stable structure" indicate a compound that is robust enough to be isolated from the reaction mixture to a beneficial degree of accuracy and to withstand dispensing into an effective therapeutic agent. ..

"Mammals" include humans, livestock, such as laboratory animals and pets (eg, cats, dogs, pigs, cows, sheep, goats, cows, rabbits) and non-livestock animals, such as wildlife.

"As needed" or "as needed" means that the situational events described below may or may not occur, which may or may not occur. Means to include cases. For example, "aryls substituted as needed" means that the aryl radicals may or may not be substituted, and the description includes both substituted aryl radicals and unsubstituted aryl radicals. ..

"Pharmaceutically acceptable carriers, diluents or excipients" include any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes / colorants, seasonings, surfactants. Contains unlimited amounts of activators, wetting agents, disintegrants, suspending agents, stabilizers, isotonics, solvents, emulsifiers, etc., certified by the US Food and Drug Administration as available for human or livestock use. It is what has been done.

"Pharmaceutically acceptable salts" include both acid and base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to salts that retain biological effects and free base properties and are not biological or other unwanted, these are inorganic acids, limited to these. Not limited to, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid, and organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, arginic acid, ascorbic acid, asparagine. Acids, benzenesulfonic acid, benzoic acid, 4-acetamide benzoic acid, camphoric acid, campha-10-sulfonic acid, capric acid, caproic acid, capricic acid, carbonic acid, silicic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane -1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactalic acid, gentisic acid, glucoheptanoic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutar Acids, glycerophosphates, glycolic acids, horse uric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, Naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotoic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, proglutamic acid, pyruvate, salicylic acid, 4-aminosalicylic acid, It is formed with sebacic acid, stearic acid, succinic acid, tartaric acid, thiosian acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylene acid and the like.

"Pharmaceutically acceptable base addition salt" refers to a salt that retains its biological effect and free acid properties and is biological or other undesired. These salts produce free acids from adducts of inorganic or organic bases. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine and trimethylamine. , Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, prokine, hydrabamine, choline, betaine, venetamine, benzatin , Ethylenediamine, glucosamine, methylglucamine, theobolomine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and other salts, but are not limited thereto. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, chlorin and caffeine.

Crystallization often produces solvates of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention having one or more molecules of solvent. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates containing monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and also. , May be present in the form of the corresponding solvate. The compounds of the present invention may be true solvates, while in other cases the compounds of the present invention may simply retain foreign water or may be a mixture of water and some foreign solvent. ..

"Pharmaceutical composition" refers to the preparation of a compound of the invention with a commonly accepted vehicle in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers, diluents, or excipients for them.

A "therapeutically effective amount", when administered to a mammal, preferably a human, is sufficiently effective to treat a sodium channel-mediated disease or condition in the mammal, preferably a human, as defined below. The amount of the compound of the present invention. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, condition and severity thereof, method of administration and age of the mammal to be treated, but those skilled in the art knowledge of this field and this disclosure. Can be generally determined by

As used herein, "treating" or "treatment" covers the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest. (i) Preventing a disease or condition in a mammal, especially if such mammal has a predisposition to the condition but has not yet been determined to suffer from it; (ii) Suppressing the disease or condition, i.e. stopping its onset; (iii) Relieving the disease or condition, i.e. causing a recession of the disease or condition; or (iv) Eliminating the symptoms that result from the disease or condition, that is, removing the pain without treating the underlying disease or condition. The terms "disease" and "condition" as used herein may be used interchangeably, or a particular disease or condition does not have a known causative agent (thus the pathogenic factor has yet to be found). Therefore, in any case, it differs in that a particular set of symptoms is recognized by the doctor, but not yet recognized as a disease, but only as an unpleasant condition or symptom. May be good.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus enantiomers, diastereomers and other stereoisomeric forms (these are absolute stereochemistry). In that respect, the amino acids may be defined as (R)-or (S)-or (D)-or (L)-). The present invention includes all such potential isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)-and (S)-or (D)-and (L) -isomers may be prepared using chiral synthons or chiral reagents. Alternatively, it may be split using conventional techniques, such as chromatographs and preparative crystallization methods. As a conventional technique for producing / isolating individual enantiomers, chiral synthesis from a suitable optical pure precursor, or, for example, a racemate (or salt or derivative racemic) using a chiral high pressure liquid (HPLC). The division of the body) can be mentioned. Unless otherwise specified, the compounds described herein contain an olefin double bond or other center of geometric asymmetry, and the compound comprises both E and Z geometric isomers. Similarly, all tautomers are included.

A "character isomer" is a compound that is made up of the same atoms and the same bonds, but has different three-dimensional structures and cannot be exchanged with each other. The present invention is intended to use various character isomers and mixtures thereof, and also includes "enantiomers" which refer to two character isomers which are mirror images of molecules that do not overlap with another.

"Tautomer" refers to a proton shifted from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the above compounds.

Also, the intermediate compounds of formula (I) and the species described above and the polymorphs of their crystal habits are all within the scope of the present specification.

The chemical name protocol and structural formulas used herein are modifications of the IUPAC nomenclature system using the ACD / Name version 9.07 software program, and the compounds of the present invention have a central core structure, i.e. 2-oxy. It is named as a derivative of the indole structure. With respect to the complex chemical names used herein, the substituents are named before the group attached to it. For example, cyclopropyl ethyl includes an ethyl skeleton with a cyclopropyl substituent. In the chemical structural formula, all bonds are specified except for some carbon atoms, and it is presumed that the carbon atoms have sufficient hydrogen atom bonds to complete the valence.

So, for example, equation (I) (in equation, j is 0, k is 1, Q is -O-, R¹Is a pentyl and R^2aIs 3,5-dichlorophenyl and R^2b, R^2cAnd R^2dAre each hydrogen and R^3aAnd R^3dAre each hydrogen and R^3bAnd R^3cIs a compound represented by (to form a condensed dioxolyl ring together with the carbocyclic atoms to which they are attached), that is, the following formula:

<chemistry num="7"><img file="JP5118627B2_D0002.tif" /></chemistry>In the present specification, 4'-(3,5-dichlorophenyl) -1'-pentyl spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole]- 2'(1'H)-Named on. Embodiment of the present invention Among the various aspects of the invention described above in the outline of the invention, certain embodiments are preferred.

One embodiment of the present invention is a compound of formula (I) described above in the outline of the present invention. During the ceremony At least one of j and k is 1 and the other is 0 or 1; Q is -O-; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups are, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, halo, respectively. Alkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; and Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, halo or alkyl; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3cIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, halo or alkyl; R^3aAnd R^3dAre both hydrogen; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R^{5 is}Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, halo or alkyl; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Each R⁴And R⁵Is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵However, if they are bound to the same nitrogen atom, R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, -R⁸-OR⁵, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, halo or alkyl; R^3aAnd R^3dAre both hydrogen; R^3bAnd R^3cTogether with the carbon ring atoms to which they are directly attached, form a fused heterocyclyl ring, which is optionally substituted, or a condensed cycloalkyl ring, which is optionally substituted; Each R⁴And R⁵Is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony R¹Is aryl, heteroaryl or heterocyclyl; R^2a, R^2b, R^2cAnd R^2dAre each hydrogen; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused dioxolyl ring.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1 and the rest are 0 or 1; Q is -O-; R¹Is hydrogen, alkyl, -R⁸-C (O) OR⁵Or -R⁸-C (O) N (R)⁴) R⁵Is; R^2aHydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2aCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups are optionally alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy. , Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) is substituted with one or more substituents selected from the group; R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3a, R^3b, R^3cAnd R^3dAre independently selected from hydrogen or halo; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1, or j is 1 and k is 0; Q is -O-; R¹Is hydrogen or alkyl; R^2aAlkyl, haloalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heteroaryl, -R⁸-C (O) N (R)⁴) R⁵And -R⁸-N (R)⁴) R⁵Selected from the group consisting of; R^2aEach of the aryl, aralkyl, aralkenyl, heterocyclyl and heteroaryl groups with respect to alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, as required. Alkoxyyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) is substituted with one or more substituents selected from the group; R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3a, R^3b, R^3cAnd R^3dAre independently selected from hydrogen or halo; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused dioxolyl ring or, optionally substituted, a fused tetrahydrofuranyl ring, and R.^3aAnd R^3dIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1 and the rest are 0 or 1; Q is -O-; R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; and R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵, -R⁹-N (R)⁴) R⁵, Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵, -R⁹-N (R)⁴) R⁵, Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre each hydrogen; R^3aAnd R^3dAre each hydrogen; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; and R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵Or -R⁹-N (R)⁴) R⁵Is; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Each aryl, aralkyl, heterocyclyl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl are substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; and R⁷Are aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵However, if they are bound to the same nitrogen atom, R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1, the other is 0 or 1; Q is -O-; R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) is substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, alkyl or halo; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre independently selected from hydrogen, alkyl or halo; R^3a, R^3b, R^3cAnd R^3dAre independent of hydrogen, halo and -R⁸-OR⁵Selected from the group consisting of; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, dioxolyl, tetrahydrofuranyl and heteroaryl, and R^3aAnd R^3dAre each selected from hydrogen; Each R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1, the other is 0 or 1; Q is -O-; R¹Is -R⁹-N (R)¹⁰) R¹¹, -R⁹-N (R)¹²) C (O) R¹¹Or -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dEach cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups are optionally alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, halo. Alkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl , and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Is^、Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵Are each bound to the same nitrogen atom, R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -R⁹-N (R)¹⁰) R¹¹, -R⁹-N (R)¹²) C (O) R¹¹Or -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here: Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R⁴And R^{5 is}Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -R⁹-N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵Are each bound to the same nitrogen atom, R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -R⁹-N (R)¹²) C (O) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1, the other is 0 or 1; Q is -O-; R¹Is a heterocyclylalkyl or a heteroarylalkyl, and the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl, Heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is a heterocyclylalkyl or a heteroarylalkyl, and the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl, Heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, halo, alkyl or -R⁸-OR⁵Selected from; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, halo, alkyl or -R⁸-OR⁵Selected from; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dAre each hydrogen; Each R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1; Q is -O-; R¹Is a heterocyclylalkyl or a heteroarylalkyl, and the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl, Heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, halo, alkyl or -R⁸-OR⁵Selected from; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, halo, alkyl or -R⁸-OR⁵Selected from; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from dioxolyl or tetrahydrofuranyl, and R^3aAnd R^3dAre each hydrogen; Each R⁵Is^、Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1 and the other is 0 or 1; Q is -O-; R¹Is a heterocyclylalkyl or a heteroarylalkyl, and the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl, Heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; R^3aAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3bAnd R^3cMay form a fused ring selected from dioxolyl or tetrahydrofuranyl together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Each R⁴And R^{5 is}Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony At least one of j and k is 1 and the other is 0 or 1; Q is -O-; R¹Is a heterocyclylalkyl or a heteroarylalkyl, wherein the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -O-; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre each hydrogen; R^3aAnd R^3dAre each hydrogen; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (R)^1a) H-, -C (O)-, -CF₂-, -C (O) O- or -N (R)⁵) C (O)-is; R^1aIs hydrogen or -OR⁵Is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; Or R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; and R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵, -R⁹-N (R)⁴) R⁵, Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; Or R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; Or R¹Is -R⁹-N (R)¹⁰) R¹¹, -R⁹-N (R)¹²) C (O) R¹¹Or -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; Or R¹Is a heterocyclylalkyl or a heteroarylalkyl, wherein the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; And R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (R)^1a) H-is; R^1aIs hydrogen or -OR⁵Is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN-R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (R^1a) H-is; R^1aIs hydrogen or -OR⁵Is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (R^1a) H-is; R^1aIs hydrogen or -OR⁵Is; R¹Is a pentyl; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁵Is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (O)-, -CF₂-, -C (O) O- or -N (R)⁵) C (O)-is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; Or R¹Is -C (O) N (R)⁶) R⁷Aralkill replaced by, where R⁶Is hydrogen, alkyl, aryl, or aralkyl; and R⁷Is hydrogen, alkyl, haloalkyl, -R⁹-CN, -R⁹-OR⁵, -R⁹-N (R)⁴) R⁵, Aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; Or R⁶And R⁷Form heterocyclyls or heteroaryls together with the nitrogen they bind to; R⁶And R⁷Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl group with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, -R, as required.⁸-CN, -R⁸-OR⁵, Heterocyclyl and heteroaryl are substituted with one or more substituents selected from the group; Or R¹-R, if necessary⁸-OR⁵, -C (O) OR⁵, Halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl substituted with one or more substituents selected from the group; Or R¹Is -R⁹-N (R)¹⁰) R¹¹, -R⁹-N (R)¹²) C (O) R¹¹Or -R⁹-N (R)¹⁰) C (O) N (R)¹⁰) R¹¹And here, Each R¹⁰Is hydrogen, alkyl, aryl, aralkyl or heteroaryl; Each R¹¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁹-OC (O) R⁵, -R⁹-C (O) OR⁵, -R⁹-C (O) N (R)⁴) R⁵, -R⁹-C (O) R⁵, -R⁹-N (R)⁴) R⁵, -R⁹-OR⁵Or -R⁹-CN; R¹²Is hydrogen, alkyl, aryl, aralkyl or -C (O) R⁵Is; R¹⁰And R¹¹Each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups with respect to alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, -R, as required.⁸-CN, -R⁸-OR⁵, -R⁸-C (O) R⁵, Heterocyclyl and heteroaryl may be substituted with one or more substituents selected from the group; Or R¹Is a heterocyclylalkyl or a heteroarylalkyl, wherein the heterocyclylalkyl or heteroarylalkyl group is optionally oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-OR⁵, -R⁸-C (O) OR⁵, -R⁸-N (R)⁴) R⁵, -R⁸-C (O) N (R)⁴) R⁵, -R⁸-N (R)⁵) C (O) R⁴, -R⁸-S (O)_mR⁴(Where m is 0, 1 or 2), -R⁸-CN or -R⁸-NO₂Substituents are substituted with one or more substituents selected from the group consisting of; R^2a, R^2b, R^2cAnd R^2dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (= N-CN) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; R^2a, R^2b, R^2cAnd R^2dCycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups, respectively, as required, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, Haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -S (O)_mR⁴, -R⁸-S (O)_nN (R⁴) R⁵, -R⁸-C (O) R⁴, -R⁸-C (O) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴And -N (R)⁵) S (O)_nR⁴(Where each m is independently 0, 1 or 2, and each n is independently 1 or 2) may be substituted with one or more substituents selected from the group; Or R^2aAnd R^2bMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2cAnd R^2dIs as specified above; Or R^2bAnd R^2cMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2dIs as specified above; Or R^2cAnd R^2dMay form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^2aAnd R^2bIs as specified above; R^3a, R^3b, R^3cAnd R^3dAre independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl. Alkoxy, -R⁸-CN, -R⁸-NO₂, -R⁸-OR⁵, -R⁸-N (R)⁴) R⁵, -N = C (R)⁴) R⁵, -S (O)_mR⁴, -OS (O)₂CF₃, -R⁸-C (O) R⁴, -C (S) R⁴, -C (R)⁴)₂C (O) R⁵, -R⁸-C (O) OR⁴, -C (S) OR⁴, -R⁸-C (O) N (R)⁴) R⁵, -C (S) N (R)⁴) R⁵, -N (R)⁵) C (O) R⁴, -N (R)⁵) C (S) R⁴, -N (R)⁵) C (O) OR⁴, -N (R)⁵) C (S) OR⁴, -N (R)⁵) C (O) N (R)⁴) R⁵, -N (R)⁵) C (S) N (R)⁴) R⁵, -N (R)⁵) S (O)_nR⁴, -N (R)⁵) S (O)_nN (R⁴) R⁵, -R⁸-S (O)_nN (R⁴) R⁵, -N (R)⁵) C (= NR⁵) N (R)⁴) R⁵And -N (R)⁵) C (N = C (R)⁴) R⁵) N (R)⁴) R⁵(Where each m is independently 0, 1 or 2 and each n is independently 1 or 2) selected from the group consisting; Or R^3aAnd R^3bTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^3cAnd R^3dIs as specified above; Or R^3bAnd R^3cMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3dIs as specified above; Or R^3cAnd R^3dMay form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, together with the carbocyclic atoms to which they are directly attached, and R^3aAnd R^3bIs as specified above; Each R⁴And R⁵Are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; Or R⁴And R⁵If each bond to the same nitrogen atom, then R⁴And R⁵May form heterocyclyls or heteroaryls together with the nitrogen atoms they bind to; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (O)-, -CF₂-, -C (O) O- or -N (R)⁵) C (O)-is; R¹Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, -R⁸-C (O) R⁵, -R⁸-C (O) OR⁵, -R⁸-C (O) N (R)⁴) R⁵, -S (O)₂-R⁵, -R⁹-S (O)_m-R⁵(Where m is 0, 1 or 2), -R⁸-OR⁵, -R⁸-CN, -R⁹-P (O) (OR⁵)₂Or -R⁹-OR⁹-OR⁵Is; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they are directly attached, form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R⁵Is^、Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl; Each R⁸Is a direct bond, linear or branched alkylene chain, linear or branched alkenylene chain, or linear or branched alkynylene chain; Each R⁹Is a linear or branched alkylene chain, a linear or branched alkenylene chain, or a linear or branched alkynylene chain.

Another embodiment of the present invention is a compound of formula (I) previously described in the outline of the present invention. During the ceremony j is 0 and k is 1 or 2; Q is -C (O)-, -CF₂-, -C (O) O- or -N (R)⁵) C (O)-is; R¹Is a pentyl; R^2a, R^2b, R^2cAnd R^2dAre hydrogen, respectively; R^3aAnd R^3dAre hydrogen, respectively; R^3bAnd R^3cTogether with the carbocyclic atoms to which they directly bond to form a fused dioxolyl ring; Each R⁵Is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl.

Specific embodiments of formula (I) will be described in more detail in the following production examples of the compounds of the present invention. Usefulness and testing of compounds of the invention The present invention relates to compounds, pharmaceutical compositions and methods using the compounds, and central nervous system conditions such as sodium channel-mediated disorders, preferably pain-related disorders, epilepsy, anxiety, depression and bipolar disorders; arrhythmias, atrial appendages. Cardiovascular conditions such as cell and ventricular fibrillation; neuromuscular conditions such as lower extremity restlessness syndrome and muscle paralysis or atrophy; neuroprotection against stroke, neurological trauma and multiple sclerosis; and muscle erythema and family The present invention relates to a pharmaceutical composition for treating a channel disease such as sex rectal pain syndrome by administering an effective amount of a sodium channel blocking regulator, particularly an inhibitor, to a patient in need of such treatment.

In general, the invention is a method of treating a patient's sodium channel-mediated disease, especially pain, or preventing the patient from developing a sodium channel-mediated disease, especially pain, such as mammals in need thereof. The compound regulates the activity of one or more potential-dependent sodium channels, including administering to animals, especially human patients, a compound of the invention or a pharmaceutical composition comprising a compound of the invention in a therapeutically effective amount. Provide a way to do it.

General values for the amount of compounds of the invention in intervention, especially inhibition, of sodium channel ion outflow can be measured using the assays described in the Biological Assays section below. Alternatively, general values of compounds that treat conditions and diseases have been established in industry standard animal models to demonstrate the efficiency of compounds in the treatment of pain. Animal models of human neuropathic pain conditions have been developed and have become reproducible sensory disorders (allodynia, hyperalgesia and spontaneous pain) for a duration that can be assessed by sensory testing. By defining the current degree of mechanical, chemical and temperature-mediated allodynia and hyperalgesia, it is possible to model some of the physiological pathological conditions observed in humans and evaluate drug treatment.

In a rat model of peripheral nerve injury, ectopic activity in the injured nerve corresponds to a motion sign of pain. In these models, intravenous administration of sodium channel blocker and local anesthetic lidocaine reverses tactile allodynia at concentrations that suppress ectopic activity and do not adversely affect general movement and motor function. Can be done (Mao, J. and Chen, LL, Pain (2000), 87: 7-17). Shift effective dose alimetric scaling in these rat models to doses similar to those shown to be effective in humans (Tanelian, DL and Brose, WG, Anesthesiology (1991), 74 (5): 949-951). In addition, lidocaine, applied in the form of a skin patch, is the FDA-approved treatment for postherpetic neuralgia (Devers, A. and Glaler, BS, Clin. J. Pain (Devers, A. and Glaler, BS, Clin. J. Pain). 2000), 16 (3): 205-8).

Sodium channel blockers have clinical uses in addition to pain. Epilepsy and cardiac arrhythmias are often targets for sodium channel blockers. Recent evidence from animal models suggests that sodium channel blockers are also useful for neuroprotection under ischemic conditions caused by stroke or neurological trauma, and in patients with multiple sclerosis (MS). Is suggested (Clare, JJ et al., Supra and Anger, T. et al., Supra).

The compounds of the present invention regulate, preferably suppress, ion outflow through voltage-gated sodium channels in mammals, especially humans. Such arbitrary adjustments are referred to herein as "blockers" and such compounds are referred to as "blockers", regardless of whether suppression or prevention of ion outflow is partial or complete. In general, the compounds of the invention regulate the activity of downward sodium channels, suppress the voltage-dependent activity of sodium channels, and / or squeeze cell membranes by preventing sodium channel activity such as ion outflow. Reduce or prevent mediated sodium ion outflow.

The compounds of the present invention are sodium channel blockers and may therefore be the result of abnormal voltage-gated sodium channel biological activity or may be ameliorated by regulation of voltage-gated sodium channel biological activity. It is useful for treating diseases and conditions in humans and other organisms, including no human diseases and conditions.

As defined herein, a sodium channel-mediated disease or condition refers to a disease or condition that improves when the sodium channel is regulated, such as pain, epilepsy, anxiety, depression and bipolar disease; arrhythmias. Cardiovascular conditions such as atrial cells and ventricular fibrillation; neuromuscular conditions such as lower extremity restlessness syndrome and muscle paralysis or atrophy; neuroprotection against stroke, neurological trauma and multiple sclerosis; and muscle erythema And channel diseases such as familial rectal pain pain syndrome, but are not limited to these.

In addition, sodium channel-mediated diseases or conditions include HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuropathy, lingual neuropathy, neuropathy secondary to metastatic invasion, painful lipomatosis, thorax lesions, etc. Hypertension, autoimmune disease, asthma, drug dependence (eg opiate, benzodiazepine, amphetamine, cocaine, alcohol, butane, absorption), Alzheimer's disease, dementia, age-related memory loss, Koffsakov syndrome, recurrent stenosis, bladder dysfunction , Incontinence, Parkinson's disease, cerebrovascular ischemia, neurosis, gastrointestinal disease, sickle blood cell anemia, transplant rejection, heart failure, myocardial infarction, reperfusion injury, intermittent lameness, angina, spasm, respiratory distress, cerebral Or myocardial ischemia, QT prolongation syndrome, catecholeminergic polyplastic ventricular ataxia, eye disease, constriction, spastic antiparalysis, myopathy, myasthenia, congenital myotension, hyperpotassium blood. Periodic limb palsy, low potassium potassium blood periodic limb palsy, ataxia, anxiety disorder, neuropathic disorder, sickness, paranoia, seasonal emotional disorder, panic disorder, obsession disorder (OCD), fear, self Closure, Asperger's Syndrome, Let's Syndrome, Disruptive Disorder, Attention Defect Disorder, Aggression, Impulsive Control Disorder, Thrombosis, Prenatal Disease, Congestive Cardiac Paralysis, Cardiac Stop, Friedrich Ataxia, Spinal Cerebral Ataxia, Bone Marrow Disorders, radiculopathy, generalized erythema, granulomatous disease, olive bridge cerebral ataxia, spinal cerebral ataxia, transient ataxia, fibrous muscle spasm, progressive paleosphere atrophy, progression Supranuclear paralysis and ataxia, traumatic brain injury, cerebral edema, hydrocephalus injury, spinal cord injury, ataxia, hyperphagia, Praderwilli syndrome, obesity, optic neuritis, cataract, retinal hemorrhage, ischemic retinopathy, retinal pigment Degeneration, acute and chronic glaucoma, ataxia, retinal artery occlusion, butoh disease, Huntington chord disease, cerebral edema, rectal inflammation, post-herpes nerve pain, acute pain, heat hypersensitivity, sarcomatosis, hypersensitivity bowel syndrome, toe Pain, muscle associated with Let's Syndrome, Resh-Naihan Syndrome, Bulgada Syndrome, Riddle Syndrome, Crohn's Disease, Multiple Sclerosis and Multiple Sclerosis (MS)Atrophic lateral sclerosis (ALS), scattered sclerosis, diabetic neuropathy, peripheral neuropathy, Charcoe-Marie Tooth syndrome, arthritis, rheumatoid arthritis, degenerative arthritis, chondricular calcification, atherosclerosis, Paroxysmal tension abnormalities, my asthenia syndrome, myotension, muscle tonic dystrophy, myodystrophies, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, intellectual disability, hypothyroidism, bipolar Depression, anxiety, schizophrenia, sodium channel toxin-related illness, familial limb erythema, primary limb erythema, rectal pain, cancer, epilepsy, partial and general tonic seizures, febrile seizures, absence seizures (Small seizures), myokronus seizures, flaccid seizures, interstitial seizures, Lenox-gastosis, West syndrome (pediatric seizures), multiresistant seizures, seizure prevention (anti-seizure drugs), familial Mediterranean fever syndrome, gout, lower extremities There are general or local anesthesia conditions, including restlessness syndrome, arrhythmia, fibromyalgia, ischemic neuroprotective conditions caused by stroke or neurological trauma, acute arrhythmia, atrial cells and ventricular fibrillation. ..There is a condition of general or local anesthesia, including ventricular fibrillation.There is a condition of general or local anesthesia, including ventricular fibrillation.

As used herein, the term "pain" refers to all categories of pain, including neuropathy pain, inflammatory pain, noxious pain, idiopathic pain, neuropathic pain, facial pain, and burning. Pain, Oral Burning Syndrome, Physical Pain, Visceral Pain, Facial Muscle Pain, Tooth Pain, Cancer Pain, Chemotherapy Pain, Traumatic Pain, Surgical Pain, Post-Surgery Pain, Childbirth Pain, Delivery Pain, Reflex Sympathetic dystrophy, arm plexus detachment wounds, neuropathic bladder disorders, acute pain (eg, musculoskeletal pain and postoperative pain), chronic pain, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, piece Headache, familial hemiplegic eccentric headache, condition associated with headache, sinus sinus headache, tension headache, illusionary limb pain, peripheral nerve injury, post-stroke pain, thorax lesions, HIV pain, post-herpes pain, It is understood to include, but is not limited to, non-cardiac chest pain, irritable bowel syndrome, pain associated with visceral disorders and indigestion and combinations thereof.

The compounds identified herein suppress ion outflow through voltage-gated sodium channels. The compound is preferably a state- or frequency-dependent regulator of sodium channels, having a low affinity for the rest / or closed state and a high affinity for the inactive state. These compounds are likely to interact with overlapping sites located within the inner cavity of sodium through the pores of the channel, similar to those described for other state-dependent sodium channel blockers (Cestele). , S. et al., Supra). These compounds also interact with the outer sites of the inner cavity and are likely to have an allosteric effect on sodium ion conduction through the channel pores.

These causal relationships ultimately contribute to the overall therapeutic benefits provided by these compounds.

The present invention readily provides many different methods for identifying sodium channel modifiers that are useful as therapeutic agents. Identification of sodium channel regulators includes, for example, measuring current, measuring membrane potential, measuring ion outflow (eg, sodium or guanidium), measuring sodium concentration, measuring second messenger and transcription levels. Can be evaluated using various in vitro and in vivo assays, such as, and using, for example, potential sensitive dyes, radiotracers and patch clamp electrophysiology.

One such protocol is to screen for chemical agents capable of regulating the activity of sodium channels and identify them as regulators.

In the conventional assays described in Bean et al., J. General Physiology (1983), 83: 613-642 and Leuwer, M., et al., Br. J. Pharmacol (2004), 141 (1): 47-54, Use patch clamp technology to inspect channel behavior. The technique is known to those of skill in the art and will develop into low or moderate throughput assays using current techniques to evaluate compounds capable of regulating sodium channel behavior.

Competitive binding assays with known sodium channel toxins such as tetrodotoxin, α-scorpion venom, aconitine, BTX, etc. may be suitable for identifying potential therapeutic agents with high selectivity for specific sodium channels. unknown. The use of BTX in such binding assays is well known, McNeal, ET et al., J Med. Chem. (1985), 28 (3): 381-8; and Creveling, CR et al., Methods in. Neuroscience, Vol.8: Neurotoxins (Conn PM Ed) (1992), p25-37, Academic Press, New York.

These assays can be performed in cells, or cells, tissue extracts and express channels of interest in a natural endogenous or recombinant environment. As an assay that can be used¹⁴Plate assays that measure Na + influx with surrogate markers such as C-guanidine influx, or cell depolarization using fluorescent dyes such as the FRET system, and other fluorescent assays or radiolabeled aconitin, Radiolabeled binding assays using BTX, TTX or STX can be mentioned. More direct measurements can be made manually or in an automated electrophysiological system. The guanidine influx assay is described in more detail in the Biological Assays section below.

The processing power of the test compound is an important consideration when choosing a screening assay to use. Low processing capacity means are not desirable in methods where a large number of compounds must be tested. However, on the other hand, low processing power may be sufficient to identify significant differences between a limited number of compounds. It is often necessary to combine assay types that identify specific sodium channels that tune compounds.

Electrophysiological assays using the patch clamp technique have been accepted as criteria for detailed analysis of sodium channel compound interactions and are described in Bean et al., Supra and Leuwer, M. et al., Supra. Manual Low Processing Capacity Screening (LTS) Method, which can compare 2 to 10 compounds per day; Automatic Medium Processing Capacity Screening (MTS) of 20 to 50 patches (ie, compounds) per day, Recently developed system; There is a technology of Molecular Devices (Sunnyvale, CA) that enables automatic high processing power screening (HTS) of 1000-3000 patches (ie compounds) per day.

One of the automatic patch clamp systems utilizes flat electrode technology to accelerate drug discovery. Flat electrode achieves high resistance, cell adhesion seal, and then enables stable low noise pre-cell recording comparable to conventional recording. A suitable facility is the PatchXpress 7000A (Axon Instruments, Union City, CA). Culture techniques involving various cell lines and adherent cells and cells that grow naturally in suspension are ranked for seal success rate and stability. Immortalized cells (eg, HEK and CHO) that stably express relevant sodium ion channels at high concentrations can be applied to high density suspension cultures.

Other assays identify compounds that block certain states of the channel, such as open, closed or dormant, or block the transition from open to closed, closed to dormant, or dormant to open. It can be selected by a researcher who is allowed to do so. Those of skill in the art are generally familiar with such assays.

Binding assays are also available, but they have limited functional value and information. Designs include traditional radioactive filter-based binding assays or confocal-based fluorescence systems (both HTS) available from Evotech OAI Group companies (Hamburg, Germany).

Radioactive flow assay can also be used. In this assay, channels are stimulated to open with veratridine or aconitine to maintain a toxin-stabilized open state, and channel blockers are identified by their prophylactic influx capacity. The assay is radioactive²²[Na] and¹⁴[C] Guanidium ions can be used as tracers. Flash Plate &amp; Cytostar-T plates in living cells avoid separation steps and are stable with respect to HTS. Scintillation plate technology has also increased the HTS adaptability of this method. Due to the functional aspects of the assay, the amount of information is reasonably good.

Yet another format measures membrane potential redistribution using the FLIPR System Membrane Potential Kit (HTS) available from Molecular Dynamics (Amersham Biosciences Division, Piscataway, NJ). This method is limited to slow changes in membrane potential. Several problems arise due to the fluorescent background of the compound. In addition, the test compound directly affects the fluidity of the cell membrane, increasing the intracellular dye concentration. Due to the functional aspects of the assay, the amount of information is reasonably good.

Sodium dyes can be used to measure the rate and amount of sodium ion influx through the channel. This type of assay provides a very high amount of information on potential channel blockers. The assay is functional and directly measures Na + influx. CoroNa Red, SBFI and / or sodium green (Molecular Probe, Eugene OR) can be used to measure Na influx, all of which are Na responsive dyes. These can be used in combination with FLIPR devices. The use of these dyes in screens has never been described in the literature. Calcium dyes also have potential in this format.

In another assay, a FRET-based voltage sensor is used to measure the ability of the test compound to block Na influx directly. Commercially available HTS systems include the VIPR II FRET system (a division of Aurora Biosciences, San Diego, CA, Vertex Pharmaceuticals), which is available from Aurora Biosciences. May be used in combination with possible FRET dyes. This assay measures the response of subseconds to changes in potential. There is no need for regulators of channel function. The assay measures depolarization and hyperpolarization and provides ratiometric output for quantification. The somewhat cheaper MTS version of this assay uses FLEXstation (Molecular Devices) in combination with the Aurora Biosciences FRET dye. Also, other methods of testing the compounds disclosed herein are readily known and available to those of skill in the art.

These results provide the basis for the analysis of structure-activity relationships (SAR) between compounds and sodium channels. Substituents with a core structure of the test compound tend to provide stronger inhibitory compounds. SAR analysis is now one of the tools used by those skilled in the art to identify preferred embodiments of compounds of the invention for use as therapeutic agents.

The regulators so identified are then tested in a variety of in vivo models to determine whether pain, especially chronic pain and other conditions, such as arrhythmias and epilepsy, are alleviated with minimal adverse events. The assays described in the Biological Assays section below are useful for assessing the biological activity of the compounds of the invention.

Generally, the therapeutic agents of the present invention that have been effective satisfy some or all of the following criteria. Oral availability should be at least 20%. Animal model efficacy ranges from less than about 0.1 μg to about 100 mg / Kg body weight, with target human doses between 0.1 μg and about 100 mg / Kg body weight, but doses outside this range are acceptable. ("Mg / Kg" means milligrams of the compound per kilogram of body mass of the subject to whom the compound is administered.) The therapeutic index (or the ratio of the toxic dose to the therapeutic dose) should be greater than 100. .. Titer (IC₅₀(Displayed as a value) should be less than 10 μM, preferably less than 1 μM, most preferably less than 50 nM. I c₅₀(Suppression Concentration-50%) is a measure of the amount of compound required to suppress 50% of ion outflow through sodium channels at a particular time in the assay of the invention. The compounds of the present invention demonstrated IC-50s in the range of less than nanomoles to 10 micromoles in a guanidine influx assay.

In other uses of the invention, the compounds of the invention are used in vivo or as representative agents for comparative purposes to discover other compounds useful in treating or preventing the various diseases disclosed herein. It can be used for in vivo studies.

Another aspect of the invention is a biological sample or Na in a patient._V1.1, Na_V1.2, Na_V1.3, Na_V1.4, Na_V1.5, Na_V1.6, Na_V1.7, Na_V1.8 or Na_V1.9 With respect to suppression of activity, the method involves administering to the patient a compound of formula (I) or a composition comprising the compound, or contacting a biological sample with the compound of formula (I) or a composition comprising the compound. Including letting. As used herein, the term "biological sample" refers to cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or Other body fluids and their extracts include, but are not limited to.

Na in biological samples_V1.1, Na_V1.2, Na_V1.3, Na_V1.4, Na_V1.5, Na_V1.6, Na_V1.7, Na_V1.8 or Na_V1.9 Suppression of activity is useful for a variety of purposes known to those of skill in the art. Examples of such objectives include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena, and the comparative evaluation of new sodium ion channel inhibitors. Pharmaceutical composition and administration of the present invention The present invention also relates to a pharmaceutical composition containing the compound of the present invention disclosed herein. In one embodiment, the invention causes ion outflow through voltage-gated sodium channels when the compounds of the invention are administered to an animal, preferably a mammal, most preferably a human patient, in a pharmaceutically acceptable carrier. It relates to a composition comprising an amount effective for adjusting, preferably suppressing, and treating a sodium channel-mediated disease such as pain.

Also, the pharmaceutical compositions useful herein include a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which is itself to the individual receiving the composition. Any drug that does not induce the production of harmful antibodies can be mentioned and is administered without undue toxicity. Examples of the pharmaceutically acceptable carrier include, but are not limited to, water, saline solution, liquids such as glycerol and ethanol. Pharmaceutically acceptable carriers, diluents and other excipients have been thoroughly investigated in REMINGTON'S PHARMACEUTICAL SCIENCES (Mac Publishing, NJ latest edition).

One of ordinary skill in the art knows how to determine the appropriate dose of compound used to treat the diseases and conditions considered herein. Therapeutic doses are generally specified by doses in the range tested in humans, based on preliminary evidence obtained from animal studies. The dose should be sufficient to result in the desired therapeutic benefit without causing unwanted side effects to the patient.

Typical regimens for the treatment of sodium channel-mediated disease include or may include administration of effective doses over a period of 1 day to several days to 1 week to about 6 months. The doses of the diagnostic / pharmaceutical compounds or compositions of the invention administered in vivo or in vitro are the age, sex, health status and weight of the recipient, the severity of symptoms, the type of concomitant treatment (if any). ), The frequency of treatment, the individual response, and the nature of the desired diagnostic / pharmaceutical effect are understood to vary. The range of effective doses provided herein is not limited, but merely indicates a preferred dose range. However, the most preferred doses are tailored to the individual subject as understood and determined by those skilled in the art (eg, Berkowet et al., Editing, The Merck Manual, Vol. 16, Merck &amp; Co., Ltd., Rahway, NJ, 1992; Goodman etna., Editing, Goodman and Cilman's The Pharmacological Basis of Therapeutics, Volume 10, Pergamon Press, Elmsford, NY, (2001); Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, Volume 3, ADIS Press, Williams and Wilkins, Baltimore, MD. (1987) ), Ebadi, Pharmacology, Little, Brown, Boston, (1985); edited by Osolci et al., Remington's Pharmaceutical Sciences, Volume 18, Mac Publishing, Easton, PA (1990); Katzung, Basic and Clinical Pharmacology, Appleton and Lange , Norwalk, CT (1992)).

The total dose required for each treatment can be administered in multiple doses per day or at one time, if desired. In general, treatment begins with a small dose, less than the optimal dose of the compound. Then, the dose is gradually increased until the optimum effect is obtained under the conditions. Diagnostic pharmaceutical compounds or compositions are administered alone or with other diagnostic agents and / or medications that indicate a condition or for another symptom of the condition. Effective amounts of the diagnostic pharmaceutical compounds or compositions of the invention are about 0.1 μg to about 100 mg / Kg body weight administered at 4 to 72 hour intervals for 2 hours to 1 year and / or 0.0001 to 0.001, Arbitrary amounts of 0.001 to 0.01, 0.01 to 0.1, 0.1 to 1.0, 1.0 to 10, 5 to 10, 10 to 20, 20 to 50 and 50 to 100 mg / Kg, 1 to 4, 4 to 10, 10 to 16 , 16-24, 24-36, 24-36, 36-48, 48-72 hours at arbitrary intervals, 1-14, 14-28, 30-44 days, or any period of 1-24 weeks It may be administered in any range or amount thereof. The compound and / or composition of the present invention may be administered to any vertebrate, such as a mammal. Among the mammals, primate mammals (including humans, apes and monkeys), cloven-hoofed animals (including horses, goats, cows, sheep and pigs), rodents (mouses, rats, rabbits and hamsters) are preferred. And meats (including cats and dogs). Among birds, turkeys, chickens and other birds of the same type are preferred. The most preferred recipient is a human.

For topical administration, it is preferable to administer an effective amount of the pharmaceutical composition according to the present invention to a target region adjacent to peripheral nerve cells to be treated, for example, on the surface of the skin or mucous membrane. The amount in this case is generally in the range of about 0.0001 mg to about 1 g of the compounds of the invention in a single application, the area to be treated, its use is diagnostic, prophylactic or preventive. It depends on the treatment or the severity of the symptoms and the nature of the topical excipient used. A preferred topical formulation is an ointment, in which about 0.001 to about 50 mg of active ingredient per cc of ointment substrate is used. The pharmaceutical composition can be dispensed as a transdermal composition or a transdermal delivery device (patch). Such compositions include, for example, backing, reservoirs of active compounds, control membranes, liners and contact adhesives. Such transdermal patches may be used to provide continuous pulsed administration, or on-demand delivery, of the desired compounds of the invention.

The composition may be intended for transrectal administration, for example, in the form of a suppository that dissolves in the rectum and releases the drug. Typical suppository preparations are generally composed of active ingredients and binders and / or lubricants such as gelatin, cocoa butter or other cold soluble vegetable or synthetic fats and oils.

Typical preparations for intramuscular or intrathecal administration consist of active ingredient suspensions or solutions in oils, or active ingredient solutions in oils such as peanut oil or sesame oil. A typical preparation for intramuscular or intrathecal administration consists of a sterile isotonic aqueous solution containing an active ingredient and a dextrose, sodium chloride, or a mixture of dextrose and sodium chloride.

The compositions of the present invention can be dispensed quickly, sustainably or with a delay in the release of the active ingredient after being administered to a patient using methods known in the art. Controlled release drug delivery systems include osmotic pump systems and dissolution systems that include polymer coated reservoirs or drug-polymer matrix preparations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770 and 4,326,525, and PJ Kuzma et al., Regional Anesthesia 22 (6): 543-551 (1997), all of which are by reference. Incorporated into the specification.

The compositions of the present invention can also be delivered by a nasal drug delivery system for topical, systemic and nasal to brain pharmaceutical treatment. Controlled Particle Dispersion (CPD) technology, conventional nasal spray bottles, inhalers or nebulizers that provide effective topical and systemic delivery of drugs by targeting the olfactory and sinuses. It is known to the trader.

The invention also relates to an intravaginal shell or core drug delivery device suitable for administration to human or animal females. The device is composed of active pharmaceutical ingredients in a sheathed polymer matrix and is similar to the device used to administer testosterone as described in WO 98/50016 on a daily basis. So, the compound can be released in a substantially zero order pattern.

Current methods for ocular administration include topical (topical), subconjunctival injections, periocular injections, intravitreal injections, surgical implants and ionoelectric injections (using small amounts of current, ionized agents). (Delivery within and through body tissue). Those skilled in the art will combine safe and effective compounds for intraocular administration with the most compatible excipients.

The most appropriate route depends on the nature and severity of the condition to be treated. Those skilled in the art will appreciate the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients and other substances associated with delivering the compound to the subject in need thereof. I am also familiar with the decision. Combination therapy The compounds of the present invention may be conveniently combined with one or more other compounds of the invention, one or more other therapeutic agents, or any mixture thereof in the treatment of sodium channel-mediated diseases and conditions. For example, the compounds of formula (I) may be administered simultaneously, sequentially or in isolation, in combination with the following other therapeutic agents: Other therapeutic agents include, but are not limited to: Opiate analgesics, such as morpholin, heroin, cocaine, oxymorpholin, revolver, levallorphan, oxycodone, codeine, dihydrocodein, propoxyphene, nalmephen, fentanyl, hydrocodone, hydromorphone, melipidin, metadon, nalorphine, naloxone, naltrexone, buprenorphine. Butorphanol, nalbuphine and pentazocine; Non-opiate analgesics, such as as acetomenifene, salicylic acid esters (eg, aspirin); Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, phenoprofen, ketoprofen, selecoxib, diclofenac, diflucinal, etdrac, fenbufen, phenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, Ketoprofen, ketoprofen, meclophenamic acid, mefanamic acid, meroxycam, nebumeton, naproxen, nimeslide, nitroflurbiprofen, orsalazine, oxaprodine, phenylbutazone, pyroxicum, sulfasalazine, slindac, tolmethin and zomepyrac; Anticonvulsants such as carbamazepine, oxacarbazepine, lamotrigine, valproate, topiramate, gabapentin and pregabalin; Antidepressants such as tricyclic antidepressants, such as amitriptyline, clomipramine, despramine, imipramine and nortriptyline; COX-2 selectivity inhibitors such as celecoxib, rofecoxib, parecoxib, valdecoxib, delacoxib, etoricoxib and bumilacoxib; Α-adrenergic agonists such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetamidine, modafinil and 4-amino-6,7-dimethoxy2- (5-methanesufhonamide-1,2,3,4- Tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline; Barbituric analgesics such as amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metalbital, methexital, pentobarbital, phenobarbital, secobarbital, tarbutal, teamiral and thiopental; Tachykinin (NK) antagonists, especially NK-3, NK-2 or NK-1 antagonists, such as (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl)]-8,9 , 10,11-Tetrahydro-9-methyl-5 (4-methylphenyl) -7H- [1,4] diazosino [2,1-g] [1,7] -naphthylidine-6-13-dione (TAK637) , 5-[[2R, 3S) -2-[(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4fluorophenyl) -4-morpholinyl] -methyl]- 1,2-dihydro-3H-1,2,4-triazol-3-one (MK869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5 (trifluoromethoxy) phenyl] -methylamino]- 2-Phenylpiperidin (2S, 3S); Coal tar analgesics, especially paracetamol; -Serotonin reuptake inhibitors, such as paroxetine, sertraline, norfluoxetine (fluoxetine desmethylmethabolite), metabolite demethylcertraline, '3 fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d, l- Fenflulamin, femoxetine, ifoxetine, cyanodotiepine, lithoxetine, dapoxetine, nephazodon, sericlamine, trazodon and fluoxetine; Noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, miltazepine, oxaprotyrin, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensin and viloxazine (Vivalan®) , In particular, selective noradrenaline reuptake inhibitors such as reboxetine, especially (S, S) -reboxetine and venlafaxine duloxetine neuroleptics, analgesics / antidepressants; Dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylbenlafaxine, clomipramine, clomipramine metabolite desmethylchromipramine, duloxetine, milnacipran and imipramine; Acetylcholinesterase inhibitors such as donepezil; 5-HT3 antagonists such as ondansetron; Metabotropic glutamate receptor (mGluR) antagonist; Local anesthetics such as mexiletine and lidocaine; Corticosteroids such as dexamethasone; -Antiarrhythmic agents such as mexiletine and phenytoin; -Muscarinic antagonists such as tolterodine, propevilin, tropsium t chloride, darifenacin, solifenacin, temiverine and ipratropium; Cannabinoids; Vanilloid receptor agonist (eg, resiniferatoxin) or antagonist (eg, capsazepine); Sedatives such as glutethimide, meprobamate, methaqualone and dichloral phenazone; Anxiolytics such as benzodiazepines; Antidepressants like mirtazapine; Topical drugs (eg lidocaine, capsaicin and leciniferotoxin); -Muscle relaxants such as benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzapirin, methocarbamol and orfrenazine; -Antihistamines or H1 antagonists; NMDA receptor antagonist; 5-HT receptor agonist / antagonist; PDEV inhibitor; Tramadol®; Cholinergic (nicotinic) analgesics; Α-2-Delta ligand; Prostaglandin E2 subtype antagonist; Leukotriene B4 antagonist; -5-lipoxygenase inhibitor; and 5-HT3 antagonist Sodium channel-mediated disorders and conditions that may be treated and / or prevented using such combinations include pain, painful central and peripheral mediated, acute, chronic, neuropathic and other disorders, and Other central neuropathy such as epilepsy, anxiety, depression and bipolar disease; cardiovascular disorders such as arrhythmia, atrial cells and ventricular fibrillation; neuromuscular disorders such as lower extremity restlessness syndrome and muscle paralysis or atrophy; Neuroprotection against stroke, neurological trauma and multiple sclerosis; and channel diseases such as, but not limited to, muscular erythema and familial rectal pain syndrome.

As used herein, "combination" refers to any mixture or substitutions of one or more compounds of the invention and one or more compounds other than the present invention or one or more additional therapeutic agents. To tell. Unless otherwise stated, the "combination" may include simultaneous or sequential delivery of a compound of the invention with one or more therapeutic agents. Unless otherwise stated, the "combination" may include dosage forms of the compounds of the invention with other therapeutic agents. Unless otherwise stated, the "combination" may include routes of administration of the compounds of the invention to other therapeutic agents. Unless otherwise stated, the "combination" may include preparations of the compounds of the invention with other therapeutic agents. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein. Kit parts The present invention also provides a kit containing a pharmaceutical composition containing at least one compound represented by the above formula. The kit also includes instructions describing the use of pharmaceutical compositions that regulate the activity of ion channels for the treatment of pain and other usefulness described herein. Commercially available packages preferably contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient to prepare an intravenous injection. It will be apparent to those skilled in the art that special packaging and / or dispensing is required for light and / or air sensitive compounds. For example, the package may be transparent to light in color and / or out of contact with the surrounding air and / or may be dispensed with a suitable coating or excipient. .. Production of the compound of the present invention The following reaction schemes are the compounds of the invention, ie, compounds of formula (I) as stereoisomers, enantiomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts, solvents thereof. The method for producing a Japanese product or a prodrug is shown.

<chemistry num="8"><img file="JP5118627B2_D0003.tif" /></chemistry>(In the formula, k, j, Q, R¹, R^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cAnd R^3dIs as specified herein. ) In the following description, it should be understood that combinations of substituents and / or variables in the above formulas are only allowed if such contributions give rise to stable compounds.

It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds need to be protected by appropriate protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acids. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guadinino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C (O) -R'' (where R'' is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters.

Protecting groups may be added and removed according to standard techniques known to those of skill in the art and described herein.

The use of protecting groups is described in detail in Green, TW and PGM Nuts, Protective Groups In Organic Synthesis (1999), Volume 3, Wiley. Further, the protecting group may be a polymer resin such as Wong resin or 2-chlorotrityl chloride resin.

Also, such protected derivatives of the present invention may not have pharmacological activity in their own right, but they are metabolized in the body after being administered to mammals and are pharmacologically active according to the present invention. It will be appreciated by those skilled in the art that the compounds of may be formed. Therefore, such derivatives are referred to as "prodrugs". All prodrugs of the compounds of the invention are included within the scope of the invention.

The following reaction scheme describes a method for producing the compounds of the present invention. It will be appreciated that those skilled in the art can produce these compounds by similar methods or by methods known to those of skill in the art. In addition, the methods described below for other compounds of formula (I) not specifically described below by those skilled in the art, by using appropriate starting compounds and modifying the synthetic parameters as necessary. It is also understood that it can be produced in a similar manner to. In general, starting compounds may be obtained from sources such as Sigma-Aldrich, Lancascar Synthesis, Maybridge, Matrix Synthesis, TCI and Fluorochem USA, or sources known to those of skill in the art (eg, eg). May be synthesized according to Smith, MB and J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)) or manufactured as described herein. You may.

In the following reaction scheme, R¹, R^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cAnd R^3dIs as specified herein, unless otherwise stated. X is Cl or Br. R¹¹Is an alkyl group.

In general, compounds of formula (I) of the invention (where Q is -O-, j is 0 and k is 1) are described in the general procedure described in Reaction Scheme 1 below. Can be synthesized with. As described below, the isatin compound of formula (101) is alkylated with a chloro or bromo compound of formula (102) to give the product of formula (103). The phenolic compound of formula (104) is treated with the Grignard reagent of formula (105) at low temperature (0 ° C) to form a phenoxymagnesium halide intermediate, which is of methylene chloride or toluene (but not limited to). In such a solvent, the isatin compound of formula (103) is reacted with the keto-carbonyl group to obtain an oxyindole of formula (106). The compound of formula (106) is treated with a silane such as triethylsilane to remove the hydroxyl group at the C-3 position of the oxyindole, and then the compound of formula (107) is obtained. Further, the compound of the formula (107) is a SOCl of the compound of the formula (106).₂/ NEt₃It can also be obtained by treating with, and then reducing with Zn flour. The compound of formula (107) is treated with a silyl compound such as, but not limited to, trimethylsilyl chloride to produce a silyl ether intermediate, treated with ytterbium (III) trifluoromethanesulfonate and formaldehyde, of formula (108). Obtain the compound. Alternatively, the compound of formula (108) bases the compound of formula (107), for example LiOH, iPr.₂It can be obtained by treating with NH, LDA (but not limited to these) and then reacting with formaldehyde. Intramolecular cyclization is carried out by the Mitsunobu reaction to obtain a compound of the formula (I) of the present invention (in the formula, Q is -O-, j is 0 and k is 1).

<chemistry num="9"><img file="JP5118627B2_D0004.tif" /></chemistry> The following reaction scheme 1.1 shows the schematic synthesis of amides and heterocyclic compounds as compounds of formula (I). R¹Compounds such as compounds of formula (109) (where A is alkyl or aralkyl in the formula) constitute, for example, in a mixed solvent of tetrahydrofuran or methanol and water (but not limited to these). In, the compound of formula (109) is converted to the corresponding carboxylic acid compound of formula (110) by treating with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide (but not limited to these). be able to. The acid compound of formula (110) can be treated with an isobutylchloroformate in the presence of a base such as N-methylmorpholine (but not limited to) to a mixed anhydride, or a solvent such as toluene, dichloromethane or It can be converted to the corresponding acid chloride by treatment with oxalyl chloride in chloroform (but not limited to) in the presence of a catalytic amount of N, N-dimethylformamide. The mixed anhydrides or acid chlorides react with amines, primary amines, or secondary amines in the presence of bases such as, but not limited to, triethylamine or diisopropylethylamine, and compounds of formula (I). To form the amide compound of formula (111). The acid compound of formula (110) reacts with, for example, in toluene (but not limited to) an aromatic diamine compound to form the benzimidazole compound of formula (111.1) as the compound of formula (I).

<chemistry num="10"><img file="JP5118627B2_D0005.tif" /></chemistry> The following reaction scheme 1.2 shows the schematic synthesis of amine compounds as compounds of formula (I). After removing the protecting group (PG), such as phthalimide or tert-butyloxycarbonyl, but not limited to these, the first or second amino compound of formula (113) can be formed from compound (112). .. By reaction of the amino compound of formula (113) with acyl chloride in the presence of a base such as triethylamine or diisopropylethylamine (but not limited to) in a solvent such as toluene, dichloromethane or chloroform (but not limited to these). As the compound of (I), the amide compound of the formula (114) is obtained. By treating the amino compound of formula (113) with isocyanate in the presence of a base such as triethylamine or diisopropylethylamine (but not limited to) in a solvent such as dichloromethane or chloroform (but not limited to these), formula (I). ), The urea compound of the formula (115) will be formed. The primary or secondary amino compound of formula (113) is placed in a solvent such as, but not limited to, dichloromethane in the presence of a reducing agent, such as sodium cyanoborohydride or sodiumtriacetoxyborohydride. When treated with aldehydes or ketones, higher functionalized amines (116) are produced as compounds of formula (I).

<chemistry num="11"><img file="JP5118627B2_D0006.tif" /></chemistry> The following reaction scheme 1.3 shows the schematic synthesis of amine compounds as compounds of formula (I). The protecting group of the compound of formula (117) is removed and the alcohol compound of formula (118) is oxidized by using an oxidizing agent such as, for example, pyridinium dichromate or Dess-Martin reagent (119, but not limited to them). ) Can be an aldehyde compound. By reducing and aminizing the aldehyde compound of formula (119) with a primary or secondary amine, similar to the conversion of a compound of formula (113) to a compound of formula (116) as shown in reaction scheme 1.2. , The amine compound of the formula (120) can be obtained as the compound of the formula (I).

<chemistry num="12"><img file="JP5118627B2_D0007.tif" /></chemistry> The following reaction scheme 1.4 is R¹The alternative synthesis of the compound of formula (I) into which a variant has been introduced is shown. Compounds of formula (121), where PG is a protecting group, eg, diphenylmethyl (but not limited to), can be synthesized in the order shown in Reaction Scheme 1. The protecting group can be removed under high pressure of hydrogen such as 60 psi to form the oxindole compound of formula (122). The formation of the compound of formula (I) involves subjecting the compound of formula (122) to a base such as, but not limited to, N, N-dimethylformamide, tetrahydrofuran, acetone or acetonitrile in a solvent such as sodium hydroxide, sodium bis. XR, a halide reagent, in the presence of (trimethylsilyl) amide and lithium hydroxide (but not limited to these)¹This can be achieved by alkylating with (where X is chloro, bromo or iodine in the formula). Alternatively, the reaction of the compound of formula (122) with an alcohol under Mitsunobu reaction conditions in a solvent such as tetrahydrofuran, ethyl acetate or dichloromethane, such as, but not limited to, a phosphine reagent such as triphenylphosphine, tributylphosphine or trimethyl. The compound of formula (I) is obtained by carrying out in the presence of phosphine and azadicarboxylates (but not limited to) of diethyl, diisopropyl or di-tert-butyl. Alternatively, the compound of formula (122) is treated with a base such as, but not limited to, sodium hydroxide or lithium hydroxide, followed by an acyl chloride or anhydride, or a sulfonyl chloride reagent of formula (I). , Corresponding acyl or sulfonyl (R)¹) Obtain the compound.

<chemistry num="13"><img file="JP5118627B2_D0008.tif" /></chemistry> R of the compound of formula (I)^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3dHowever, in the case of bromo or trifluoromethylsulfonyloxy groups, additional derivatives can be synthesized as shown in Reaction Scheme 1.5 and Reaction Scheme 1.6 below. The triflate compound can be obtained by treating the bromo compound with diborane in the presence of a palladium catalyst, followed by sequential oxidation with hydrogen peroxide / sodium hydroxide and reduction with trifluoromethanesulfonyl anhydride. Equation (123) or (129) (R^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3dAs a compound of bromo or trifluoromethylsulfonyloxy group) in a solvent such as N, N-dimethylformamide or acetonitrile (but not limited to), a palladium catalyst such as palladium acetate or tris (dibenzylideneacetone) di Palladium (0) (but not limited to) and ligands such as tri (o-tolyl) phosphine, 1,1'-bis (diphenylphosphino) ferrocene or 2- (di-tert-butylphosphino) biphenyl (to these). In the presence of, but not limited to, zinc cyanide or tributyltin cyanide and potassium cyanide can be reacted to give the cyano compound of formula (124) or formula (130) as the compound of formula (I) (Marcantonio, KM). Et al., Org. Lett. (2004), 6: 3723-5 and Yang, C. et al., Org. Lett. (2004), 6: 2837-40). Palladium catalysts such as palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) di under carbon monoxide pressure in a solvent such as N, N-dimethylformamide or acetonitrile. In the presence of palladium (0), but not limited to, Eq. (123) or Eq. (129) (R)^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3d(Having a bromo or trifluoromethylsulfonyloxy group) is reacted with a primary or secondary amine to form an amide compound of formula (125) or formula (131) as a compound of formula (I). (See Takahashi, T. et al., Tetrahedron Lett. (1999), 40: 7843-6 and Schnyder, A. et al., J. Org. Chem. (2001), 66: 4311-5). Under typical Ulmann coupling reaction conditions, Eq. (123) or Eq. (129) (R)^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3dAs a compound of bromo or trifluoromethylsulfonyloxy group, in a solvent such as dimethyl sulfoxide, dioxane or acetonitrile (not limited to these), a copper reagent such as copper iodide or copper bromide (not limited to these). ), Bases such as cesium carbonate, potassium carbonate (but not limited to), amino acids such as N, N-dimethylglycine (but not limited to), and the compound of formula (I) by reacting with a phenolic compound. The diaryl ether compounds of formula (126) or formula (132) can be formed as (Sawyer, JS Etrahedron (2000), 56: 5045-65 and Ma, D. et al., Org. Lett. (2003), 5). (21): See 3799-802). Equation (123) or Equation (129) (R^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3dCompounds of (with, but not limited to, bromo or trifluoromethylsulfonyloxy groups) are mixed in a solvent such as dimethoxyethane, dioxane or tetrahydrofuran, such as triphenylphosphine, tri (o-tolyl) phosphine, 1 , 1'-bis (diphenylphosphine) ferrocene or 2- (di-tert-butylphosphine) biphenyl (but not limited to), with bases such as sodium carbonate, cesium carbonate or sodium hydrogencarbonate (but not limited to these) React with arylboronic acid in the presence or absence of a palladium catalyst such as palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0). , Coupling products of formula (127) or formula (133) can be obtained as compounds of formula (I) (Kotha, S. et al., Tetrakisron (2002), 58: 9633 and Miyaura, N. et al., See Chem. Rev. (1995), 95: 2457). Equation (123) or Equation (129) (R^2a, R^2b, R^2c, R^2d, R^3a, R^3b, R^3cOr R^3dAs a compound of bromo or trifluoromethylsulfonyloxy group) in a solvent such as dioxane or tetrahydrofuran (but not limited to these), a ligand such as triphenylphosphine, tri (o-tolyl) phosphine, 1,1'. -Palladium catalysts, such as with or without bis (diphenylphosphine) ferrocene or 2- (di-tert-butylphosphine) biphenyl (but not limited to), bases such as sodium carbonate, cesium carbonate or sodium tert-butoxide. In the presence of tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0), it is reacted with a primary or secondary amine to give the compound of formula (I), formula (128). Alternatively, an amino compound of formula (134) can be obtained (see Muci, AR et al., Topics in Current Chemistry (2002), 219: 131).

<chemistry num="14"><img file="JP5118627B2_D0009.tif" /></chemistry>

<chemistry num="15"><img file="JP5118627B2_D0010.tif" /></chemistry> Alternatively, the compounds of formula (I) of the present invention (where Q is -O and k is 1) can be synthesized according to the general procedure described in Reaction Scheme 2 below. it can. As described below, the compound of formula (201) is treated at a low temperature with a lithium reagent of formula (202) such as n-BuLi (but not limited to) and then a solvent such as THF (to which). In (but not limited to), the oxyindole of formula (203) is obtained by reacting with the keto-carbonyl group of the isatin compound of formula (103). The compound of formula (204) is obtained after removing the hydroxyl group at the C-3 position of the oxyindole by treating the compound of formula (203) with a silane such as triethylsilane. Further, the compound of the formula (204) is a SOCl of the compound of the formula (203).₂/ NEt₃It is obtained by treating with, and then reducing with Zn powder. The compound of formula (204) was treated with a silyl compound such as, but not limited to, trimethylsilyl chloride to produce a silyl ether intermediate, which was treated with ytterbium (III) trifluoromethanesulfonate and formaldehyde to formulate (205). To obtain the compound of. Alternatively, the compound of formula (205) is a compound of formula (204) with a base such as LiOH, iPr.₂It can be obtained by treating with NH or LDA (but not limited to these) and subsequently reacting with formaldehyde. Intramolecular cyclization by the Mitsunobu reaction gives the compound of the present invention of formula (I) (where Q is -O- and k is 1).

<chemistry num="16"><img file="JP5118627B2_D0011.tif" /></chemistry> Alternatively, the compounds of formula (I) (where Q is -O- or -S- and k is 0) of the present invention are synthesized according to the general procedure described in Reaction Scheme 3 below. Here, by intramolecular cyclization of the compound of formula (203) by the Mitsunobu reaction, formula (I) (where Q is -O- or -S- and k is 0). To obtain the compound of the present invention.

<chemistry num="17"><img file="JP5118627B2_D0012.tif" /></chemistry> Alternatively, equation (I) (in equation, Q is -C (O)-,-(CH)₂)-Or-(CF₂The compounds of the present invention ()-and j is 0) can be synthesized according to the general procedure described in Reaction Scheme 4 below. As described below, the Grignard reagent of formula (401) is reacted with the keto-carbonyl group of the isatin compound of formula (103) in a solvent such as, but not limited to, methylene chloride or toluene, and the formula ( Obtain the Oxindole of 402). The compound of formula (403) is obtained after removing the hydroxyl group at the C-3 position of oxyindole by treating the compound of formula (402) with a silane such as triethylsilane. Further, the compound of the formula (403) is a SOCl of the compound of the formula (402).₂/ NEt₃It can also be obtained by treating with, and then reducing with Zn flour. The compound of formula (403) is alkylated at the C-3 position of its oxindole ring with the compound of formula (404) to obtain the compound of formula (405), which is saponified to obtain the carboxylic acid of formula (406). Produces acid. The carboxylic acid is then converted to the acid chloride of formula (407) after procedures known to those of skill in the art. Due to intramolecular cyclization in the presence of Lewis acid, eg tin (IV) chloride, but not limited to, formula (I) (where Q is -C (O)-and j is 0. The compound of the present invention is obtained. By removing the carbonyl group of the compound of formula (I) using a silane such as triethylsilane, or a reagent known to those of skill in the art, formula (I) (wherein Q is -CH).₂-And j is 0) to obtain the compound of the present invention. The reaction of the carbonyl group of compound (408) of formula (I) with a fluorinating reagent, such as bis (2-methoxyethyl) aminosulfur trifluoride, results in formula (I) (where Q is -CF).₂-And j is 0) to form the difluoro compound of the invention. By reducing the carbonyl group of compound (408) of formula (I) with a reducing agent, such as, but not limited to, sodium borohydride, formula (I) (where Q is -CH (OH)-". , J is 0) to obtain the hydroxy compound of the present invention. Further, by alkylating the hydroxy compound of the formula (I) by a method known to those skilled in the art, the formula (I) (in the formula, Q is -CH (OR).⁵)-And j is 0) to obtain the alkylated compound of the present invention.

<chemistry num="18"><img file="JP5118627B2_D0013.tif" /></chemistry>

<chemistry num="19"><img file="JP5118627B2_D0014.tif" /></chemistry> Alternatively, the compound of the present invention of formula (I) (where Q is -O-, j is 0 and k is 1) is synthesized according to the procedure described in Reaction Scheme 5 below. be able to. As described below, the phenolic compound of formula (104) was treated with the Grignard reagent of formula (105) at low temperature (0 ° C) to form a phenoxymagnesium halide intermediate, which was used as a solvent. For example, in tetrahydrofuran, methylene chloride or toluene (but not limited to these), the reaction is carried out with the keto-carbonyl group of the Isatin compound of formula (101) to obtain the heterocyclic compound of formula (501). The compound of formula (502) can be obtained after removing the hydroxyl group of the heterocyclic compound by treating the compound of formula (501) with a silane such as triethylsilane. Further, the compound of the formula (502) is a SOCl of the compound of the formula (501).₂/ NEt₃It can also be obtained by treating with, and then reducing with Zn flour. The compound of formula (502) is treated with a silyl compound such as, but not limited to, trimethylsilyl chloride to produce a silyl ether intermediate, which is treated with ytterbium (III) trifluoromethanesulfonate and formaldehyde to form the formula (502). Obtain the compound of 503). Alternatively, the compound of formula (503) bases the compound of formula (502), for example LiOH, iPr.₂It can be obtained by treating with NH or LDA (but not limited to these) and subsequently reacting with formaldehyde. Intramolecular cyclization by the Mitsunobu reaction gives the compound of formula (504), which is alkylated with the chloro or bromo compound of formula (102) to give formula (I) (where Q is -O-). , J is 0 and k is 1).

<chemistry num="20"><img file="JP5118627B2_D0015.tif" /></chemistry> Alternatively, the compound of the present invention of formula (I) (where Q is -NHC (O)-and j is 0) can be synthesized according to the procedure described in Reaction Scheme 6 below. it can. Formula (I) by treating the ketone compound (408) with an azide, eg, sodium azide (but not limited to), in an acid such as, but not limited to, trifluoroacetic acid, as described below. (In the formula, Q is -NHC (O)-and j is 0) to obtain the Schmidt-reactive organism of the present invention.

<chemistry num="21"><img file="JP5118627B2_D0016.tif" /></chemistry> Alternatively, the compound of the present invention of formula (I) (where Q is -C (O) O- and j is 0) should be synthesized according to the procedure described in Reaction Scheme 7 below. Can be done. As described below, the compound of formula (701), which can be obtained by following a procedure similar to the synthesis of the compound of formula (405) described in Reaction Scheme 4, is a mixed solvent such as tetrahydrofuran or methanol and water. In (but not limited to), treated with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide (but not limited to) in formula (I) (wherein Q is -C (O) O). -And j is 0) to form the lactone product of the present invention.

<chemistry num="22"><img file="JP5118627B2_D0017.tif" /></chemistry> In the production examples of intermediates used in the production of the compound of the following formula (I) and the examples of the compound of the following formula (I), the compound numbers assigned therein correspond to the compound numbers in the reaction scheme. do not do.

Manufacturing example 1 4-Bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Synthetic Synthesis of A.4-Bromo-1-pentyl-1H-indole 4-Bromoindole (10.0 g, 51.0 mmol) at 0 ° C in a mixture of sodium hydroxide (2.54 g, 66.3 mmol, 60% dispersion in mineral oil) in anhydrous N, N-dimethylformamide (50.0 mL). ) Was added. The reaction mixture was stirred for 0.5 hours, then 1-bromopentane (9.25 g, 61.2 mmol) was added at 0 ° C. The reaction mixture was stirred at ambient temperature for 6 hours and quenched with brine solution (20.0 mL). The reaction mixture was diluted with water (100 mL) and extracted with ether (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with hexane (100%) to give the title compound (13.3 g, 98%) as a yellow oil.¹1 H NMR (300MHz, CDCl₃) δ7.30-7.27 (m, 2H), 7.14 (t, 1H), 6.88 (t, 1H), 6.55 (d, 1H), 4.08 (t, 2H), 1.87-1.77 (m, 2H), 1.39 -1.22 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ136.3,129.2,128.4,122.2,122.1,114.9,108.7,101.3,46.8,29.9,29.1,22.3,13.9.

Synthesis of B.4-Bromo-1-pentyl-1H-indole-2,3-dione N-Bromosuccinimide (50.2 g, 282 mmol) was added little by little to a solution of 4-bromo-1-pentyl-1H-indole (25.0 g, 93.9 mmol) in anhydrous dimethyl sulfoxide (350 mL) over 30 minutes. The reaction mixture was heated at 60 ° C for 3 hours, at which time the internal temperature rose to 120 ° C. After cooling to ambient temperature, the reaction mixture was poured into ethyl acetate / water (1/1, 600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (3 x 500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and dried to give the title compound (25.7 g, 92%) as a yellow solid.¹1 H NMR (300MHz, CDCl₃) δ7.38 (t, 1H), 7.21 (t, 1H), 6.82 (d, 1H), 3.68 (t, 2H), 1.72-1.59 (m, 2H), 1.39-1.25 (m, 4H), 0.86 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ180.9,157.2,152.6,138.4,128.3,121.7,116.3,108.9,40.4,28.9,26.9,22.3,13.9.

Synthesis of C.4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one A solution of isopropylmagnesium chloride (50.7 mL, 101 mmol, 2.0 M in ethanol) was added to a solution of 1,3-benzodioxole-5-ol (12.8 g, 92.9 mmol) in tetrahydrofuran (200 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 0.5 hours, at which time colorless precipitates were formed. After removing the solvent under reduced pressure, the residue was dissolved in methylene chloride (100 mL) and cannulated at 0 ° C for 10 minutes to 4-bromo-1-pentyl-1H-indole-2,3-dione (25.0). g, 84.5 mmol) was added to a solution of dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride solution (100 mL) to separate the organic layer. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate hexane to give the title compound (34.9 g, 97%) as a brown gum-like material.¹1 H NMR (300MHz, DMSO-d₆) δ8.95 (s, 1H), 7.29-7.21 (m, 2H), 6.88-6.81 (m, 1H), 6.55, (s, 1H), 6.14 (s, 1H), 5.86 (dd, 2H), 4.24 (s, 1H), 3.70-3.52 (m, 2H), 1.69-1.55 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, 3H);¹³C NMR (75MHz, DMSO-d₆) δ177.6,152.6,149.1,144.8,141.2,131.7,127.7,127.6,121.0,113.8,108.3,106.7,101.7,101.4,80.540.5,28.8,26.722.2,13.9.

Synthesis of D.4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one 4-Bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one (34.9 g,) To a solution of 80.4 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (18.7 g, 161 mmol) and triethylsilane (18.3 g, 161 mmol). The brown solution was stirred at ambient temperature for 3 hours and concentrated to dryness under reduced pressure. The residue was diluted with dichloromethane (200 mL), washed with saturated aqueous ammonia chloride solution (50.0 mL) and brine (3 x 50.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was crystallized from ether to give the title compound (16.5 g, 49%) as a brown solid.¹1 H NMR (300MHz, CDCl₃) δ7.29-7.21 (m, 2H), 7.14 (dd, 1H), 6.58 (s, 1H), 6.10 (s, 1H), 5.85 (dd, 2H), 5.01 (s, 1H), 3.75-3.55 (m, 2H), 1.69-1.56 (m, 2H), 1.35-1.21 (m, 4H), 0.86 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.9,150.9,147.6,145.4,141.6,130.3127.1126.8,120.8,113.3108.0,106.7,101.5,101.2,59.9,48.6,40.7,28.9,26.9,22.313.9; MS (ES +) m / z 418.3 (M +) 1), 420.3 (M + 1).

E.4-Bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2- On synthesis 4-Bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one (7.50 g, 17.9 mmol) Triethylamine (10.9 g, 108 mmol) and chlorotrimethylsilane (7.80 g, 71.8 mmol) were added to a dry dichloromethane (150 mL) solution at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours and diluted with dichloromethane (100 mL). The mixture was washed with water (3 x 50.0 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in THF (150 mL), then formaldehyde solution (4.90 mL, 179 mmol, 37 wt% in water) and itterbium (III) trifluoromethanesulfonate (1.11 g, 1.79 mmol) were added. The resulting mixture was stirred at ambient temperature for 36 hours. After removing the solvent under reduced pressure, the residue was diluted with dichloromethane (200 mL) and washed with saturated sodium hydrogen carbonate (50.0 mL), saturated ammonia chloride (50.0 mL) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo to give the title compound (6.32 g, 79%) as a fluffy solid.¹1 H NMR (300MHz, CDCl₃) δ8.28 (s, 1H), 7.10 (t, 1H), 7.00 (dd, 1H), 6.89 (dd, 1H), 6.83 (s, 1H), 6.27 (s, 1H), 6.85 (dd, 2H) ), 4.52-4.41 (m, 2H), 3.90 (dd, 1H), 3.70-3.65 (m, 2H), 1.68-1.57 (m, 2H), 1.36-1.29 (m, 4H), 0.83 (t, 3H) );¹³C NMR (75MHz, CDCl₃) δ178.1,150.3,147.2,147.2,140.5,129.6,129.2,125.6,118.4,114.8,109.2,106.9,101.0,98.2,62.6,57.6,39.9,28.9,26.7,22.2,13.5.

Manufacturing example 2 1- (2-Cyclopropylethyl) -3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2- On synthesis Synthesis of A.1- (2-Cyclopropylethyl) -1H-indole-2,3-dione Isatin (6.17 g, 41.9 mmol) was added to a solution of sodium hydroxide (1.61 g, 41.9 mmol, 60% dispersion in mineral oil) in anhydrous N, N-dimethylformamide (25.0 mL) at 0 ° C. The reaction mixture was stirred for 0.5 hours, then (2-bromoethyl) cyclopropane (Maercker, A. et al., Justus Liebigs Ann. Chem. (1972), 759: 132-157) (9.25 g, 61.2 mmol) was added. .. The resulting mixture was stirred at ambient temperature for 16 hours and quenched with water (50.0 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 x 50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo to give the title compound (6.50 g, 90%) as a viscous rubber.¹1 H NMR (300MHz, CDCl₃) δ7.57-7.51 (m, 2H), 7.05 (t, 1H), 6.88 (d, 1H), 3.79-3.74 (m, 2H), 1.59-1.52 (m, 2H), 0.70-0.61 (m, 1H), 0.44-0.38 (m, 2H), 0.05-0.02 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ183.7,158.2,151.2,138.4,125.4,123.6,117.5,110.3,40.3,32.2,8.6,4.3.

B.1- (2-Cyclopropylethyl) -3-Hydroxy-3- (6-Hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Synthesis of 1,3-Benzodioxole-5-ol (1.25 g, 9.06 mmol) in THF (20.0 mL) solution at 0 ° C for 5 minutes in isopropylmagnesium chloride solution (4.53 mL, 9.06 mmol, 2.0 in THF) M) was added dropwise. The reaction mixture was stirred for 0.5 hour, at which time a colorless precipitate formed. After removing the solvent under reduced pressure, the residue was dissolved in dichloromethane (20.0 mL) and cooled to 0 ° C. A solution of 1- (2-cyclopropylethyl) -1H-indole-2,3-dione (1.77 g, 8.23 mmol) in dichloromethane (20.0 mL) was added to the solution at 0 ° C. The resulting mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride solution (30.0 mL). The organic layer was separated, washed with water (3 x 25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was crystallized from ethyl acetate and ether to give the title compound (2.22 g, 76%) as a colorless solid.¹1 H NMR (300MHz, CDCl₃) δ9.52 (s, 1H), 7.46 (d, 1H), 7.37 (dt, 1H), 7.18 (dt, 1H), 6.90 (d, 1H), 6.56 (s, 1H), 6.23 (s, 1H) ), 5.84 (dd, 2H), 4.55 (s, 1H), 3.87-3.63 (m, 2H), 1.64-1.44 (m, 2H), 0.68-0.55 (m, 1H), 0.41-0.27 (m, 2H) ), -0.02-(-0.07) (m, 2H);¹³C NMR (75MHz, CDCl₃) δ179.1,152.4,148.8,142.7,141.3,130.3,129.1,126.3,123.7,117.3,109.5,106.9,101.9,101.4,79.3,40.6,32.2,8.6,4.3,4.2; MS (ES +) m / z 337.6 ( M-17).

Synthesis of C.1- (2-Cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one 1- (2-Cyclopropylethyl) -3-Hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one (2.22) Trifluoroacetic acid (2.12 g, 18.8 mmol) and triethylsilane (2.14 g, 18.8 mmol) were added to a solution of g, 6.27 mmol) in dichloromethane (30.0 mL). The brown solution was stirred at ambient temperature for 0.5 hours and concentrated to dryness under vacuum. The residue was diluted with dichloromethane (100 mL), washed with water (3 x 50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (20/80) to give the title compound (1.69 g, 80%) as a brown solid.¹1 H NMR (300MHz, CDCl₃) δ9.21-9.10 (br, 1H), 7.38-7.30 (m, 2H), 7.16 (t, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 6.33 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.87-3.72 (m, 2H), 1.66-1.46 (m, 2H), 0.69-0.59 (m, 1H), 0.43-0.30 (m, 2H), 0.09 -0.06 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.8,151.3,147.6,144.1,141.5,128.7,126.2,123.1,115.2,109.5,109.4,106.5,101.5,101.2,47.4,40.5,32.2,8.6,4.3,4.2; MS (ES +) m / z 338.3 ( M + 1).

D.1- (2-Cyclopropylethyl) -3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole- 2-on synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Modification to replace on with 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one To obtain the title compound (53%). R_f= 0.28 (EtOAc / Hexane, 1/1) Manufacturing example 3 Ethyl [3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthetic A. Synthesis of ethyl (2,3-dioxo-2,3-dihydro-1H-indole-1-yl) acetate Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with ethyl bromoacetate to give the title compound as a pale yellow powder (79%).¹1 H NMR (300MHz, CDCl₃) δ7.64-7.54 (m, 2H), 7.16-7.11 (m, 1H), 6.77 (d, 1H), 4.47 (s, 2H), 4.22 (q, 2H), 1.26 (t, 3H); MS (ES +) m / z 256.2 (M + 23).

B. Synthesis of Ethyl [3-Hydroxy-3- (6-Hydroxy-1,3-Benzodioxole-5-yl) -2-oxo-2,3-dihydro-1H-Indol-1-yl] Acetate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione is converted to ethyl (2,3-dioxo-2,3-dihydro-1H-indole-1-). A non-critical modification was made to replace yl) acetate to give the title compound (95%).¹1 H NMR (300MHz, DMSO-d₆) δ9.08 (s, 1H), 7.21-7.13 (m, 2H), 6.93-6.86 (m, 3H), 6.57 (s, 1H), 6.19 (s, 1H), 5.88 (m, 2H), 4.47 (m, 2H), 4.13 (q, 2H), 1.19 (t, 3H); MS (ES-) m / z 370.2 (M-1).

Synthesis of C. Ethyl [3- (6-Hydroxy-1,3-benzodioxole-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one is ethyl [3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indol-1- A non-critical modification was made to replace the indole acetate to give the title compound as a white powder (84%).¹1 H NMR (300MHz, DMSO-d₆) δ9.37 (s, 1H), 7.19 (m, 1H), 7.01-6.90 (m, 3H), 6.43 (s, 2H), 5.84 (m, 2H), 4.86 (s, 1H), 4.56 (s , 2H), 4.13 (q, 2H), 1.18 (t, 3H); MS (ES +) m / z 378.2 (M + 23).

D. Ethyl [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Acetate synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Non-critical to replace on with ethyl [3- (6-hydroxy-1,3-benzodioxole-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Modifications were made to give the title compound as a white powder.¹1 H NMR (300MHz, DMSO-d₆) δ9.03 (s, 1H), 7.17-6.85 (m, 5H), 6.22 (s, 1H), 5.83 (s, 2H), 5.04 (t, 1H), 4.56-4.08 (m, 5H), 3.69 (m, 1H), 1.18 (t, 3H); MS (ES +) m / z 408.1 (M + 23).

Manufacturing example 4 Methyl 3-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl ] Methyl} benzoate synthesis A. Synthesis of methyl 3-[(2,3-dioxo-2,3-dihydro-1H-indole-1-yl) methyl] benzoate Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with methyl 3- (bromomethyl) benzoate to give the title compound as an orange solid (84%).¹1 H NMR (300MHz, CDCl₃) δ7.99-7.95 (m, 2H), 7.60 (d, 1H), 7.53-7.47 (m, 2H), 7.43 (d, 1H), 7.09 (t, 1H), 6.43 (d, 1H), 4.95 (s, 2H), 3.89 (s, 3H).

B. Methyl 3-{[3-Hydroxy-3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Synthesis of methyl} benzoate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was methyl 3-[(2,3-dioxo-2,3-dihydro1H-indole-). Subcritical modifications were made to replace 1-yl) methyl] benzoate to give the title compound (96%).¹1 H NMR (300MHz, CDCl₃) δ8.65 (s, 1H), 7.92 (s, 1H), 7.85 (d, 1H), 7.41-7.38 (m, 1H), 7.32-7.24 (m, 2H), 7.19-7.13 (m, 1H) , 7.04-6.9 (m, 1H), 6.63 (d, 1H), 6.44 (s, 1H), 6.39 (s, 1H), 5.79 (s, 2H), 5.05 (s, 1H), 4.83 (dd, 2H) ), 3.80 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ178.7,167.0,151.0,148.5,142.1,141.1,135.7,131.6,130.5,130.1,129.1,129.0,128.4,125.5,123.9,116.7,109.7,106.5,101.3,100.5,78.6,60.6,52.4,43.6; MS (ES +) m / z 456.1 (M + 23).

C. Methyl 3-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] methyl} benzoate Synthetic Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indole-2-one is methyl 3-{[3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H A non-critical modification was made to replace -indole-1-yl] methyl} benzoate to give the title compound (98%). MS (ES +) m / z 418.2 (M + 1).

D. Methyl 3-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1 -Indole] Methyl} benzoate synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On methyl 3-{[3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] methyl} benzoate A non-critical modification was made to replace the title compound as a white powder (81%). MS (ES +) m / z 470.3 (M + 23), 448.3 (M + 1).

Manufacturing example 5 Methyl 4-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl) ] Methyl} benzoate synthesis A. Synthesis of methyl 4-[(2,3-dioxo-2,3-dihydro-1H-indole-1-yl) methyl] benzoate Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with methyl 4- (bromomethyl) benzoate to give the title compound as an orange solid (84%).¹H-NMR (300MHz, CDCl₃) δ8.00 (d, 2H), 7.61 (d, 1H), 7.46 (t, 1H), 7.38 (d, 2H), 7.09 (t, 1H), 6.69 (d, 1H), 4.96 (s, 2H) ), 3.88 (s, 3H); MS (ES +) m / z 296.1 (M + 1).

B. Methyl 4-{[3-Hydroxy-3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Synthesis of methyl} benzoate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was methyl 4-[(2,3-dioxo-2,3-dihydro-1H-indole). Subcritical modifications were made to replace -1-yl) methyl] benzoate to give the title compound (79%). MS (ES +) m / z 416.1 (M-17).

C. Methyl 4-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] methyl} benzoate Synthetic Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indole-2-one is methyl 4-{[3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H Modifications were made to replace -indole-1-yl] methyl} benzoate to give the title compound as a solid (98%). MS (ES +) m / z 418.1 (M + 1).

D. Methyl 4-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1 -Indole] Methyl} benzoate synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -On methyl 4-{[3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] methyl} benzoate A non-critical modification was made to replace with the title compound (81%). MS (ES +) m / z 448.1 (M + 1).

Manufacturing example 6 2- {3- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1- Il] propyl} -1H-isoindole 1,3 (2H) -dione synthesis A.1- [3- (1,3-Dioxo-1,3-dihydroisoindole 2-yl) -propyl] -1H-synthesis of indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione. Compounds obtained (92%):¹1 H NMR (300MHz, CDCl₃) δ7.80-7.79 (m, 4H), 7.61-7.56 (m, 1H), 7.49-7.46 (m, 1H), 7.18-7.16 (m, 1H), 7.07-7.05 (m, 1H), 3.72- 3.60 (m, 4H), 1.97-1.92 (m, 2H).

B.2-{3- [3-Hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro1H-indole-1-yl] Propyl} -1H-isoindole 1,3 (2H) -dione synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1- [3- (1,3-dioxo-1,3-dihydroisoindole 2). -Il) -propyl] -1H-indole-2,3-Dione was replaced with a non-critical modification to give the title compound (96%).¹1 H NMR (300MHz, CDCl₃) δ7.86-7.78 (m, 4H), 7.21-7.13 (m, 2H), 7.00-6.97 (m, 1H), 6.87-6.85 (m, 2H), 6.15 (s, 1H), 5.86-5.84 ( m, 2H), 3.69-3.65 (m, 4H), 2.46-2.45 (m, 1H), 1.94-1.87 (m, 2H); MS (ES +) m / z 473.4 (M-17).

C.2-{3- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro1H-indole-1-yl] propyl} -1H -Isoindole 1,3 (2H)-Synthesis of Zeon Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one 2-{3- [3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H- Indole-1-yl] propyl} -1H-isoindole-1,3 (2H) -dione was replaced with a non-critical modification to give the title compound (94%).¹1 H NMR (300MHz, CDCl₃,) δ7.81-7.78 (m, 2H), 7.70-7.67 (m, 2H), 7.32-7.27 (m, 2H), 7.12-7.07 (m, 1H), 6.90-6.87 (m, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.86 (dd, 2H), 4.82 (s, 1H), 3.96-3.66 (m, 4H), 2.17-2.04 (m, 2H); MS (ES +) m / z 457.0 (M + 1).

D.2- {3- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole- 1-Il] propyl} -1H-isoindole-1,3 (2H) -dione synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On 2-{3- [3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] propyl} Subcritical modifications were made to replace -1H-isoindole-1,3 (2H) -dione to give the title compound as a foamy solid (94%).¹1 H NMR (300MHz, CDCl₃) δ9.20 (s, 1H), 7.81-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.35-7.25 (m, 2H), 7.16-7.14 (m, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 5.86 (dd, 2H), 4.64 (d, 1H), 3.67-4.13 (m, 5H), 2.18-2.05-(m, 2H);¹³C NMR (75MHz, CDCl₃) δ 180.6,168.6,151.2,147.8,143.2,141.2,134.2,134.2,131.9,130.0,128.7,125.1,123.2,113.9,108.7,108.3,101.3,100.6,64.9,58.0,37.6,36.1,26.5; MS (ES + ) m / z 487.3 (M + 1).

Manufacturing example 7 2- {2- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1- Indole} -1H-isoindole 1,3 (2H) -dione synthesis A.1- [2- (1,3-Dioxo-1,3-dihydro-isoindole-2-yl) -ethyl] -1H-synthesis of indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with 2- (2-bromoethyl) -1H-isoindole-1,3 (2H) -dione, and the title compound. Obtained (75%)¹1 H NMR (300MHz, CDCl₃) δ7.85-7.78 (m, 4H), 7.65 (td, 1H), 7.55 (dd, 1H), 7.25 (d, 1H), 7.12 (t, 1H), 4.00-3.80 (m, 4H); MS (ES +) m / z 321 (M + 1), 343 (M + 23).

B.2-{2- [3-Hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl) ] Ethyl} -1H-isoindole-1,3 (2H) -dione synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1- [2- (1,3-dioxo-1,3-dihydro-isoindole). A non-critical modification was made to replace -2-yl) -ethyl] -1H-indole-2,3-dione to give the title compound (99%).¹1 H NMR (300MHz, CD₃OD) δ7.85-7.68 (m, 4H), 7.29 (td, 1H), 7.18-6.96 (m, 3H), 6.88 (s, 1H), 6.16 (s, 1H), 5.85 (s, 1H), 5.82 (s, 1H), 3.81-4.01 (m, 4H); MS (ES +) m / z 441 (M-17), 458 (M + 23).

C.2- {2- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro1H-indole-1-yl] ethyl} -1H -Isoindole-1,3 (2H) -Synthesis of Zeon Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one 2-{2- [3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H- Indole-1-yl] ethyl} -1H-isoindole 1,3 (2H) -dione was replaced with a non-critical modification to give the title compound as a white solid (90%).¹1 H NMR (300MHz, CD₃OD) δ10.15-10.05 (br, 1H), 8.66-8.58 (m, 4H), 8.07-7.70 (m, 4H), 7.12 (s, 1H), 7.18 (s, 1H), 6.70 (s, 1H) ), 6.69 (s, 1H), 5.50 (s, 1H), 4.91-4.56 (m, 4H); MS (ES +) m / z 443 (M + 1).

D.2- {2- [3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole- 1-Il] Ethyl} -1H-Isoindole 1,3 (2H) -Dione Synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On 2-{2- [3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] ethyl} A modification was made to replace -1H-isoindole-1,3 (2H) -dione to give the title compound (56%).¹1 H NMR ( 300MHz, CD₃OD) δ9.97 (s, 1H), 8.72-8.62 (m, 4H), 8.07-7.67 (m, 5H), 7.01 (s, 1H), 6.71 (s, 1H), 6.70 (s, 1H), 5.79 (t, 1H), 4.88-4.50 (m, 6H); MS (ES +) m / z 455 (M-17), 473 (M + 1), 495 (M + 23).

Manufacturing example 8 Synthesis of 1- (diphenylmethyl) -3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Synthesis of A.1- (diphenylmethyl) -1H-indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with 1,1'-(bromomethylene) dibenzene to give the title compound as an orange solid (68%). ). MS (ES +) m / z 336.4 (M + 23).

Synthesis of B.1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Subcritical to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 1- (diphenylmethyl) -1H-indole-2,3-dione according to the procedure described in Production Example 2B. The title compound was obtained as an off-white powder (99%). MS (ES +) m / z 474.5 (M + 23).

Synthesis of C.1- (diphenylmethyl) -3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one 1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole Modifications were made to replace with -2-on to give the title compound as an off-white solid (84%). MS (ES +) m / z 458.4 (M + 23).

D.1- (Diphenylmethyl) -3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Synthesis of Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Replace on with 1- (diphenylmethyl) -3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one Subcritical changes were made to give the title compound (56%). MS (ES +) m / z 488.3 (M + 23).

Manufacturing example 9 1- [3- (benzyloxy) propyl] -3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole- 2-on synthesis A.1-Synthesis of 1- [3- (benzyloxy) propyl] -1H-indole-2,3-dione Following the procedure described in Production Example 1A, subcritical modifications were made to replace 4-bromoindole with isatin and 1-bromopentane with benzyl3-bromopropyl ether to give the title compound as a pale yellow syrup (95). %).¹1 H NMR (300MHz, CDCl₃) δ7.57-6.92 (m, 9H), 4.50 (s, 2H), 3.84 (t, 2H), 3.54 (t, 2H), 2.03-1.94 (m, 2H); MS (ES)⁺) m / z 296.3 (M + 1), 318.3 (M + 23).

B.1- [3- (benzyloxy) propyl] -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indol-2 -On synthesis Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1- [3- (benzyloxy) propyl] -1H-indole-2,3-dione. Substitute non-critical changes were made to give the title compound (70%).¹1 H NMR (300MHz, CDCl₃) δ9.42 (s, 1H), 7.32-7.16 (m, 8H), 6.96 (d,), 6.61 (s, 1H), 6.23 (s, 1H), 5.86-5.83 (m, 2H), 4.44 ( s, 2H), 3.88-3.73 (m, 2H), 3.46 (t, 2H), 2.06-1.85 (m, 2H); MS (ES +) m / z 416.3 (M-17), 456.3 (M + 23) ..

Synthesis of C.1- [3- (benzyloxy) propyl] -3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one 1- [3- (benzyloxy) propyl] -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro- A non-critical modification was made to replace 2H-indole-2-one to give the title compound (92%).¹1 H NMR (300MHz, CDCl₃) δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81 (ABq, 1H), 4.99 (s, 1H), 4.42 (s , 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES +) m / z 418.3 (M + 1).

D.1- [3- (benzyloxy) propyl] -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H- Synthesis of indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -On to 1- [3- (benzyloxy) propyl] -3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Substitute non-critical changes were made to give the title compound (93%). MS (ES +) m / z 448.2 (M + 1).

Manufacturing example 10 Methyl 2-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl ] Methyl} benzoate synthesis A. Synthesis of methyl 2-[(2,3-dioxo-2,3-dihydro-1H-indole-1-yl) methyl] benzoate Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with methyl 2- (bromomethyl) benzoate to give the title compound as a yellow solid (68%).¹1 H NMR (300MHz, CDCl₃) δ8.05 (dd, 1H), 7.64 (dd, 1H), 7.50-7.31 (m, 3H), 7.22 (d, 1H), 7.10 (t, 1H), 6.72 (d, 1H), 5.41 (s , 2H), 3.95 (s, 3H).

B. Methyl 2-{[3-Hydroxy-3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Synthesis of methyl} benzoate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to methyl 2-[(2,3-dioxo-2,3-dihydro-1H-indole). Subcritical modifications were made to replace -1-yl) methyl] benzoate to give the title compound as a colorless individual (97%).¹1 H NMR (300MHz, DMSO-d₆) δ9.29 (s, 1H), 7.97 (dd, 1H), 7.53-7.36 (m, 3H), 7.28 (s, 1H), 7.10 (td, 1H), 6.96-6.83 (m, 2H), 6.59 (d, 2H), 6.25 (s, 1H), 5.95-5.86 (m, 2H), 5.31-5.07 (m, 2H), 3.88 (s, 3H); MS (ES +) m / z 456.1 (M + 23) ).

C. Methyl 2-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indol-1-yl] methyl} benzoate Synthetic Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indole-2-one is methyl 2-{[3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H Subcritical modifications were made to replace -indole-1-yl] methyl} benzoate to give the title compound as a white solid (100%).¹1 H NMR (300MHz, DMSO-d₆) δ9.32 (s, 1H), 7.94 (dd, 1H), 7.50-7.34 (m, 2H), 7.26 (d, 1H), 7.08 (t, 1H), 7.00-6.86 (m, 2H), 6.76 (s, 1H), 6.64 (d, 1H), 6.38 (s, 1H), 5.93-5.86 (m, 2H), 5.34-5.12 (m, 2H), 4.83 (s, 1H), 3.87 (s, 3H) ); MS (ES +) m / z 418.2 (M + 1).

D. Methyl 2-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1 -Indole] Methyl} benzoate synthesis Methyl 2-{[3- (6-Hydroxy-1,3-benzodioxol-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] methyl} benzoate (17.1 g) , 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500 mL) solution was degassed by bubbling argon for 2 hours. Lithium diisopropylamide solution (45.1 mL, 2M solution, 90.0 mmol) was slowly added to this solution at -78 ° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonia chloride solution. The mixture was concentrated in vacuo to remove THF and then ethyl acetate (500 mL) was added. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was recrystallized from ethyl acetate / hexane to give the title compound (13.7 g, 75%).¹1 H NMR (300MHz, DMSO-d₆) δ9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H), 7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93 -5.86 (m, 2H), 5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H); MS (ES +) m / z 448.3 (M + 1).

Production example 11 [3- (1,3-Benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] Synthesis of acetic acid A.1-Synthesis of Pentyl-1H-Indole-2,3-Zeon Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with 1-bromopentane to give the title compound as an orange solid (85%).¹1 H NMR (300MHz, CDCl₃) δ7.60-7.52 (m, 2H), 7.08 (td, 1H), 6.87 (d, 1H), 3.69 (t, 2H), 1.74-1.61 (m, 2H), 1.40-1.28 (m, 4H) , 0.88 (t, 3H).

Synthesis of B.3- (1,3-benzodioxole-5-yl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one 1-Pentyl-1H-Indole-2,3-dione (2.80 g, 12.8 mmol) in THF (50.0 mL) solution at -78 ° C, 3,4- (methylenedioxy) phenylmagnesium bromide (14.0 mL, 14.0 mL, 1 M THF solution, 14.0 mmol) was added slowly. The mixture was stirred at 0 ° C. for 1 hour and quenched with ammonium chloride solution. The mixture was poured into water (150 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (3.10 g, 71%) as an orange oil.¹1 H NMR (300MHz, CDCl₃) δ7.34-7.23 (m, 2H), 7.05 (t, 1H), 6.91-6.85 (m, 2H), 6.83-6.78 (m, 1H), 6.71 (d, 1H), 5.92-5.89 (m, 2H), 3.82-3.55 (m, 2H), 3.40 (br, 1H), 1.76-1.61 (m, 2H), 1.39-1.28 (m, 4H), 0.87 (t, 3H).

Synthesis of C.3- (1,3-benzodioxole-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro Non-replacement of -2H-indole-2-one with 3- (1,3-benzodioxole-5-yl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Critical changes were made to give the title compound as an oil (90%).¹1 H NMR (300MHz, CDCl₃) δ7.30 (td, 1H), 7.14 (d, 1H), 7.03 (td, 1H), 6.89 (d, 1H), 6.75 (d, 1H), 6.67 (dd, 1H), 6.57 (d, 1H) ), 5.90 (s, 2H), 4.50 (s, 1H), 3.81-3.62 (m, 2H), 1.76-1.62 (m, 2H), 1.41-1.28 (m, 4H), 0.88 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.8,148.1,147.2,143.5,130.0,129.4,128.4,125.1,122.9,122.0,108.7,108.6,101.1,51.9,40.4,29.0,27.1,22.3,14.0.

Synthesis of D. Methyl [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] acetate 3- (1,3-Benzodioxole-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one (1.00 g, 3.10 mmol) and methyl bromoacetate (0.44 mL, 4.60) It was degassed by bubbling argon gas into a solution of mmol) in THF (20.0 mL) for 1 hour. Sodium hydroxide (0.19 g, 4.60 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and quenched with ammonium chloride solution. The mixture was poured into water (150 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.94 g, 76%) as a colorless oil.¹1 H NMR (300MHz, CDCl₃) δ7.30 (td, 1H), 7.25 (dd, 1H), 7.06 (td, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 6.74-6.65 (m, 2H), 5.90-5.87 (m, 2H), 3.71-3.64 (m, 2H), 3.45 (d, 1H), 3.41 (s, 3H), 3.18 (d, 1H), 1.74-1.60 (m, 2H), 1.39-1.22 (m) , 4H), 0.85 (t, 3H);¹³C NMR (75MHz, CDCl₃,) δ177.8,170.0,147.9,147.0,143.9,133.1,131.3,128.6,124.6,122.3,119.9,108.7,108.1,107.4,101.2,52.8,51.6,41.8,40.4,29.0,26.8,22.3,14.0; MS ( ES +) m / z 418.1 (M + 23), 396.1 (M + 1).

E. [3- (1,3-Benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] Synthesis of acetic acid Methyl [3- (1,3-benzodioxol-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] acetate (5.90 g, 15.0 mmol) Lithium hydroxide monohydrate (1.26 g, 28.0 mmol) was added to a solution of THF / water (2 / 1v / v, 120 mL). The mixture was stirred at ambient temperature overnight. Under vacuum, most of the THF was removed and water (150 mL) was added. The solution was extracted with ethyl acetate / hexane (1 / 3v / v, 50.0 mL). The aqueous layer was acidified with 1N HCl until the pH value reached 2, and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give the title compound (5.00 g, 88%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.29 (td, 1H), 7.21 (dd, 1H), 7.05 (td, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.72-6.64 (m, 2H), 5.90-5.86 (m, 2H), 3.65 (t, 2H), 3.43 (d, 1H), 3.11 (d, 1H), 1.70-1.55 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H) );¹³C NMR (75MHz, CDCl₃) δ178.2,174.0,148.0,147.1,143.4,132.6,131.4,128.7,124.4,122.7,119.8,108.9,108.2,107.2,101.2,52.6,41.5,40.4,29.0,26.6,22.3,14.0; MS (ES +) m / z 404.0 (M + 23), 382.0 (M + 1).

Manufacturing example 12 Synthesis of 3- [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] propanoic acid A. Synthesis of methyl 3- [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] propanoate Following the procedure described in Production Example 11D, a non-critical modification was made to replace methyl bromoacetate with methyl 3-bromopropionate to give the title compound as a colorless oil (76%).¹1 H NMR (300MHz, CDCl₃) δ7.28 (td, 1H), 7.17 (dd, 1H), 7.06 (td, 1H), 6.89 (d, 1H), 6.84 (d, 1H), 6.77 (dd, 1H), 6.68 (d, 1H) ), 5.89-5.84 (m, 2H), 3.67 (t, 2H), 3.53 (s, 3H), 2.69-2.56 (m, 1H), 2.54-2.41 (m, 1H), 2.21-2.08 (m, 1H) ), 1.99-1.86 (m, 1H), 1.72-1.59 (m, 2H), 1.38-1.24 (m, 4H), 0.85 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,173.1,147.9,146.9,143.2,133.5,131.6,128.5,124.9,122.6,120.1,108.7,108.1,107.6,101.1,55.2,51.6,40.2,32.4,29.5,29.1,27.1,22.3,14.0; MS (ES +) m / z 410.1 (M + 1), 432.0 (M + 23).

B.3- [3- (1,3-Benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] Synthesis of propanoic acid Following the procedure described in Production Example 11E, methyl [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl ] Acetate is replaced with methyl 3- [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] propanoate. A critical modification was made to give the title compound as a colorless solid (92%). MS (ES-) m / z 394.2 (M-1).

Production example 13 Synthesis of 3- (4,5-difluoro2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (4,5-difluoro2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-. A non-critical modification was made to replace benzodioxole-5-ol with 3,4-difluorophenol to give the title compound (31%).¹1 H NMR (300MHz, CDCl₃) δ9.69-9.65 (br, 1H), 7.51-7.41 (m, 2H), 7.26-7.21 (m, 1H), 6.99-6.57 (m, 3H), 4.18-4.14 (br, 1H), 3.78- 3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 330 (M-17), 370 (M +) twenty three).

Synthesis of B.3- (4,5-difluoro2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro Non-critical modification to replace -2H-indole-2-one with 3- (4,5-difluoro2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one To obtain the title compound (98%).¹1 H NMR (300MHz, CDCl₃) δ7.46-7.19 (m, 3H), 7.03-6.68 (m, 3H), 5.03 (s, 1H), 3.76-3.67 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 ( m, 4H), 0.87 (t, 3H); MS (ES +) m / z 332 (M + 1).

Synthesis of C.3- (4,5-difluoro2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 Subcritical modifications were made to replace -one with 3- (4,5-difluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound ( 96%). MS (ES +) m / z 344 (M-17), 384 (M + 23).

Production example 14 Synthesis of 3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 4-fluorophenol to give the title compound (53%).¹1 H NMR (300MHz, CDCl₃) δ9.42-9.14 (br, 1H), 7.53-6.86 (m, 6H), 6.56-6.48 (m, 1H), 4.58-4.28 (br, 1H), 3.79-3.58 (m, 2H), 1.77- 1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 312 (M-17), 352 (M + 23).

Synthesis of B.3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Tri (5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one (2.42 g, 7.35 mmol) in dichloromethane (10.0 mL) solution Fluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) were added at ambient temperature. The reaction mixture was stirred at 40 ° C. for 15 hours and concentrated to dryness in vacuo. The residue was triturated with ether to give the title compound (2.10 g, 91%) as a solid. MS (ES +) m / z 314 (M + 1).

Synthesis of C.3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Paraformaldehyde (1.76) in a solution of 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one (2.10 g, 6.70 mmol) in THF (20.0 mL). g, 58.8 mmol) and lithium diisopropylamine (7.35 mL, 2.0 M in THF, 14.7 mmol) were added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours and ammonium chloride solution (10.0 mL) and ethyl acetate (100 mL) were added. Wash the organic layer with water and saline and Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum to give the title compound.¹1 H NMR (300MHz, CDCl₃) δ9.55-9.10 (br, 1H), 7.53-6.86 (m, 6H), 6.57-6.49 (m, 1H), 4.74-4.30 (br, 1H), 4.18-4.07 (m, 2H), 3.79- 3.60 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 326 (M-17), 366 (M +) twenty three).

Production example 15 Synthesis of 3- (5-Bromo-2-hydroxyphenyl) -3- (Hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 4-bromophenol to give the title compound (41%).¹1 H NMR (300MHz, CDCl₃) δ9.46-9.25 (br, 1H), 7.51-6.80 (m, 7H), 4.73-4.51 (br, 1H), 3.79-3.56 (m, 2H), 1.76-1.60 (m, 2H), 1.41- 1.22 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 377 (M-17), 379 (M-17), 412 (M + 23), 414 (M + 23).

Synthesis of B.3- (5-Bromo-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one In a solution of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one (2.22 g, 5.64 mmol) in dichloromethane (10.0 mL), Trifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) were added at ambient temperature. The reaction mixture was stirred at 50 ° C. for 15 hours and concentrated to dryness under vacuum to give the title compound. MS (ES +) m / z 374 (M + 1), 376 (M + 1).

Synthesis of C.3- (5-Bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 14C, 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one was added to 3- (5-bromo-2-one). Subcritical modifications were made to replace hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound. MS (ES +) m / z 386 (M-17), 388 (M-17), 426 (M + 23), 428 (M + 23).

Manufacturing example 16 Synthesis of 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 4-chloro-3-fluorophenol to give the title compound (33%).¹1 H NMR (300MHz, CDCl₃) δ9.80 (s, 1H), 7.52-7.41 (m, 2H), 7.23 (t, 1H), 6.96 (d, 1H), 6.84 (d, 1H), 6.80 (d, 1H), 4.15 (s , 1H), 3.79-3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 346 (M-17) ), 386 (M + 23).

Synthesis of B.3- (5-chloro-4-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Follow the procedure described in Production Example 15B to add 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to 3- (5-). Subcritical changes were made to replace chloro-4-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound (99%). ).¹1 H NMR (300MHz, CDCl₃) δ10.0-9.70 (br, 1H), 7.45-7.18 (m, 3H), 6.98 (d, 1H), 6.90-6.82 (m, 2H), 5.01 (s, 1H), 3.75-3.66 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES +) m / z 348 (M + 1).

Synthesis of C.3- (5-chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 Sub-replacement of -one with 3- (5-chloro-4-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one was performed to obtain the title compound. (46%). MS (ES +) m / z 360 (M-17), 400 (M + 23).

Production example 17 Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 3-chloro-4-fluorophenol to give the title compound (14%). MS (ES +) m / z 346 (M-17), 386 (M + 23).

Synthesis of B.3- (4-chloro-5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Follow the procedure described in Production Example 15B to add 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to 3- (4-). Subcritical changes were made to replace chloro-5-fluoro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound. MS (ES +) m / z 348 (M + 1).

Synthesis of C.3- (4-chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical changes were made to replace -one with 3- (4-chloro-5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to obtain the title compound. (50% in 2 steps). MS (ES +) m / z 360 (M-17), 400 (M + 23).

Production example 18 Synthesis of 3- (4,5-dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (4,5-dichloro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 3,4-dichlorophenol to give the title compound (26%).¹1 H NMR (300MHz, CDCl₃) δ9.60 (s, 1H), 7.50-7.40 (m, 2H), 7.22 (td, 1H), 7.11 (s, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 4.31-4.12 (br, 1H), 3.79-3.59 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES +) m / z 363 (M) -17), 403 (M + 23).

Synthesis of B.3- (4,5-dichloro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 15B, 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one was added to 3- (4, 4, A non-critical modification was made to replace 5-dichloro-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound (86%).¹1 H NMR (300MHz, CDCl₃) δ 10.0-9.50 (br, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.22 (td, 1H), 7.09 (s, 1H), 6.95 (d, 1H), 6.93 (s) , 1H), 5.04 (s, 1H), 3.77-3.68 (m, 2H), 1.77-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES +) m / z 348 (M + 1).

Synthesis of C.3- (4,5-dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 Subcritical modifications were made to replace -one with 3- (4,5-dichloro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound. MS (ES +) m / z 376 (M-17), 416 (M + 23).

Manufacturing example 19 Synthesis of 3- (hydroxymethyl) -3- [2-hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3-hydroxy-3- [2-hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioki. A non-critical modification was made to replace sole-5-ol with α, α, α-trifluorocresol to give the title compound (46%).¹1 H NMR (300MHz, CDCl₃) δ9.75 (s, 1H), 7.50-7.39 (m, 3H), 7.21 (td, 1H), 7.10-7.02 (m, 2H), 6.96 (d, 1H), 4.26 (s, 1H), 3.82 -3.59 (m, 2H), 1.77-1.63 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES +) m / z 362 (M-17), 402 (M) +23).

Synthesis of B.3- [2-Hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 15B, 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one was added to 3-hydroxy-3. -[2-Hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indol-2-one was replaced with a non-critical modification to give the title compound (78%). ).¹1 H NMR (300MHz, CDCl₃) δ8.20-8.00 (br, 1H), 7.43-7.14 (m, 5H), 7.02 (d, 1H), 6.95 (d, 1H), 5.11 (s, 1H), 3.82-3.72 (m, 2H) , 1.79-1.66 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES +) m / z 364 (M + 1).

Synthesis of C.3- (Hydroxymethyl) -3- [2-Hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Sub-replacement of -one with 3- [2-hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H-indole-2-one was performed to obtain the title compound. It was. MS (ES +) m / z 376 (M-17), 416 (M + 23).

Production example 20 Synthesis of 3- (2-Hydroxy-4-methoxyphenyl) -3- (Hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Synthesis of A.3- (5-Bromo-2-hydroxy-4-methoxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 4-bromo-3-methoxyphenol to give the title compound (48%).¹1 H NMR (300MHz, CDCl₃) δ9.85 (s, 1H), 7.52-7.38 (m, 2H), 7.22 (td, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.13-4.03 (br, 1H), 3.86 (s, 3H), 3.80-3.57 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.88 (t, 3H); MS (ES + ) m / z 402 (M-17), 404 (M-17), 442 (M + 23), 444 (M + 23).

Synthesis of B.3- (2-Hydroxy-4-methoxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 15B, 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one was added to 3- (5-). Subcritical modifications were made to replace bromo-2-hydroxy-4-methoxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound (83%). ).¹1 H NMR (300MHz, CDCl₃) δ9.78-9.20 (br, 1H), 7.43-7.31 (m, 2H), 7.19 (t, 1H), 6.97 (d, 1H), 6.79 (d, 1H), 6.70-6.64 (m, 1H) , 6.38 (dd, 1H), 5.02 (s, 1H), 3.77 (s, 3H), 3.70 (t, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t) , 3H); MS (ES +) m / z 326 (M + 1).

Synthesis of C.3- (2-Hydroxy-4-methoxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical modifications were made to replace -one with 3- (2-hydroxy-4-methoxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound (41%). ).¹1 H NMR (300MHz, CDCl₃) δ10.79 (s, 1H), 7.51-7.37 (m, 2H), 7.26 (td, 1H), 6.99 (d, 1H), 6.95 (d, 1H), 6.59 (d, 1H), 6.34 (dd) , 1H), 4.67 (d, 1H), 4.14 (d, 1H), 3.76 (s, 3H), 3.78-3.69 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H) ), 0.87 (t, 3H); MS (ES +) m / z 338 (M-17), 378 (M + 23).

Production example 21 Ethyl [3- (6-Hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthesis of A. Ethyl [3-Hydroxy-3- (6-Hydroxy-2,3-dihydro-1H-Inden-5-yl) -2-oxo-2,3-Dihydro-1H-Indole-1-yl] Acetate Synthetic Ethyl 4-bromo-1-pentyl-1H-indole-2,3-dione (2,3-dioxo-2,3-dihydro-1H-indole-1-yl) according to the procedure described in Production Example 1C. Non-critical modifications were made to acetate and to replace 1,3-benzodioxole-5-ol with 5-indanol to give the title compound (84%).¹1 H NMR (300MHz, CDCl₃) δ8.76 (s, 1H), 7.55 (d, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.9 (s, 1H), 6.80 (d, 1H), 6.65 (s, 1H) ), 4.45 (ABq, 2H), 4.32-4.25 (br, 1H), 4.20 (q, 2H), 2.83 (t, 2H), 2.74-2.65 (m, 2H), 2.06-1.94 (m, 2H), 1.27 (t, 3H); MS (ES +) m / z 350 (M-17), 390 (M + 23).

Synthesis of B. Ethyl [3- (6-Hydroxy-2,3-dihydro-1H-inden-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 15B, 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one is ethyl [3-hydroxy. -3- (6-Hydroxy-2,3-dihydro-1H-indene-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Make a non-critical change to replace with acetate , The title compound was obtained.¹1 H NMR (300MHz, CDCl₃) δ8.50-7.90 (br, 1H), 7.40-7.32 (m, 2H), 7.38 (td, 1H), 6.94 (s, 1H), 6.84 (d, 1H), 6.75 (s, 1H), 5.16 (s, 1H), 4.48 (ABq, 2H), 4.21 (q, 2H), 2.85 (t, 2H), 2.81-2.61 (m, 2H), 2.09-1.92 (m, 2H), 1.25 (t, 3H) ); MS (ES +) m / z 352 (M + 1).

C. Ethyl [3- (6-Hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl ] Acetate synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 Non-critical to replace -one with ethyl [3- (6-hydroxy-2,3-dihydro-1H-inden-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate The title compound was obtained. MS (ES +) m / z 364 (M-17), 404 (M + 23).

Production example 22 Ethyl [3- (Hydroxymethyl) -3- (3-Hydroxy-5,6,7,8-Tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-Indol-1-yl] Acetate synthesis A. Ethyl [3-Hydroxy-3- (3-Hydroxy-5,6,7,8-Tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-Indol-1-yl] acetate Synthesis of Ethyl 4-bromo-1-pentyl-1H-indole-2,3-dione (2,3-dioxo-2,3-dihydro-1H-indole-1-yl) according to the procedure described in Production Example 1C. Subcritical modifications were made to acetate and to replace 1,3-benzodioxole-5-ol with 5,6,7,8-tetrahydronaphthalene-2-ol to give the title compound (81%).¹1 H NMR (300MHz, CDCl₃) δ8.61 (s, 1H), 7.54 (dd, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H), 6.50 (s, 1H) ), 4.45 (ABq, 2H), 4.21 (q, 2H), 4.18-4.14 (br, 1H), 2.73-2.47 (m, 4H), 1.77-1.63 (m, 4H), 1.24 (t, 3H); MS (ES +) m / z 364 (M-17), 404 (M + 23) Synthesis of B. Ethyl [3- (3-Hydroxy-5,6,7,8-Tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 15B, 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one is ethyl [3-hydroxy. -3- (3-Hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] Subcritical changes to replace acetate And the title compound was obtained.¹1 H NMR (300MHz, CDCl₃) δ7.42-7.32 (m, 2H), 7.20 (t, 1H), 6.84 (d, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 5.12 (s, 1H), 4.47 (ABq) , 2H), 4.21 (q, 2H), 2.76-2.44 (m, 4H), 1.78-1.64 (m, 4H), 1.24 (t, 3H); MS (ES +) m / z 366 (M + 1).

C. Ethyl [3- (Hydroxymethyl) -3- (3-Hydroxy-5,6,7,8-Tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-Indole-1- Indole] Acetate synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On is replaced with ethyl [3- (3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate. A critical modification was made to give the title compound. MS (ES +) m / z 378 (M-17), 418 (M + 23).

Production example 23 Synthesis of ethyl [4-bromo-3- (4,5-difluoro2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate A. Synthesis of ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-indole-1-yl) acetate Following the procedure described in Production Example 2A, subcritical modifications were made to replace isatin with 4-bromoisatin and (2-bromoethyl) cyclopropane with ethylbromoacetate to give the title compound as a yellow solid (68%). ).¹1 H NMR (300MHz, CDCl₃) δ7.39 (t, 1H), 7.27 (dd, 1H), 6.71 (dd, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES +) m / z 312 (M + 1), 314 (M + 1), 334 (M + 23), 336 (M + 23).

Synthesis of B. Ethyl [4-Bromo-3- (4,5-difluoro2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione is converted to ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-). Subcritical modifications were made to indole-1-yl) acetate and to replace 1,3-benzodioxole-5-ol with 3,4-difluorophenol to give the title compound as a white solid (42%). .. MS (ES +) m / z 424 (M-17), 426 (M-17), 464 (M + 23), 466 (M + 23).

Synthesis of C. Ethyl [4-Bromo-3- (4,5-difluoro2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Ethyl [4-bromo-3- (4,5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indole-1-yl] acetate (0.90 g, 2.00 mmol) ), Triethylsilane (2.00 mL, 12.2 mmol) and trifluoroacetic acid (0.94 mL, 12.2 mmol) were heated at 90 ° C. for 2 days. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to a column chromatograph (ethyl acetate / hexane, 1/3) to give the title compound (0.37 g, 43%).¹1 H NMR (300MHz, CDCl₃) δ7.35-7.22 (m, 3H), 6.82-6.71 (m, 2H), 6.52 (t, 1H), 5.10 (s, 1H), 4.45 (s, 2H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES +) m / z 426.4 (M + 1), 428.4 (M + 1).

D. Ethyl [4-bromo-3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthetic Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical changes to replace -one with ethyl [4-bromo-3- (4,5-difluoro-2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate And the title compound was obtained (83%). MS (ES +) m / z 456.3 (M + 1), 458.3 (M + 1).

Production example 24 Ethyl [4-bromo-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro -1H-Indole-1-yl] Acetate Synthesis Synthesis of A.6- (benzyloxy) -2,2-dimethylbenzofuran-3 (2H) -one DMF (50.0 mL) of 6- (benzyloxy) benzofuran-3 (2H) -one (Adams, JL et al., J Med. Chem. (1996), 39 (26): 5035-46) (1.60 g, 6.67 mmol) ) Sodium hydroxide (0.59 g, 14.7 mmol) and iodomethane (1.46 mL, 23.3 mmol) were added to the solution at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride (50.0 mL). The aqueous mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/10) to give the title compound (0.85 g, 47%).¹1 H NMR (300MHz, CDCl₃) δ7.55 (d, 1H), 7.44-7.30 (m, 5H), 6.69 (dd, 1H), 6.54 (d, 1H), 5.10 (s, 2H), 1.43 (s, 6H); MS (ES + ) m / z 269.5 (M + 1).

B. Synthesis of 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol Palladium hydroxide (0.22 g, 20 wt%, loading, 0.32 mmol) in a solution of 6- (benzyloxy) -2,2-dimethylbenzofuran-3 (2H) -one (0.85 g, 3.20 mmol) in methanol (100 mL). ) Was added. The resulting mixture was hydrogenated under 60 psi hydrogen for 16 hours. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (0.46 g, 88%).¹1 H NMR (300MHz, CDCl₃) δ6.92 (d, 1H), 6.30-6.21 (m, 2H), 4.77 (s, 1H), 2.90 (s, 2H), 1.44 (s, 6H).

C. Ethyl [4-Bromo-3-hydroxy-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro- 1H-Indole-1-yl] Acetate Synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione is converted to ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-). Indole-1-yl) acetate and with non-critical modifications replacing 1,3-benzodioxole-5-ol with 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol, the title compound Got MS (ES +) m / z 498.5 (M + 23), 500.5 (M + 23).

D. Ethyl [4-bromo-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole- 1-Indole] Acetate synthesis Ethyl [4-Bromo-3-hydroxy-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H- A mixture of indole-1-yl] acetate (1.32 g, 2.80 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluoroacetic acid (0.94 mL, 12.2 mmol) in dichloromethane (50.0 mL) at 35 ° C. 3 Stirred for hours. The mixture was diluted with dichloromethane (100 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/3) to give the title compound (1.04 g, 81%).¹1 H NMR (300MHz, CDCl₃) δ7.32-7.15 (m, 2H), 6.74 (d, 1H), 6.50-6.36 (br, 2H), 5.04 (s, 1H), 4.51-4.34 (m, 2H), 4.25-4.14 (m, 2H), 2.92-2.69 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H), 1.23 (t, 3H); MS (ES +) m / z 460.5 (M + 1), 462.5 (M) +1).

E. Ethyl [4-bromo-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3 -Dihydro-1H-Indole-1-yl] Acetate Synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On is ethyl [4-bromo-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole A non-critical modification was made to replace -1-yl] acetate to give the title compound (25%). MS (ES +) m / z 490.5 (M + 1), 492.5 (M + 1).

Production example 25 Synthesis of 3,3-dimethyl 2,3-dihydro-1-benzofuran-6-ol A. Synthesis of 4- (benzyloxy) -1-bromo-2- (2-methylallyloxy) benzene Potassium carbonate (4.46 g, 32.2 mmol) in a solution of 5- (benzyloxy) -2-bromophenol (Simas, ABC et al., Synthesis, (1999): 1017-21) (8.15 g, 29.3 mmol) in DMF (150 mL). ) Was added slowly at 0 ° C. The mixture was stirred at ambient temperature for half an hour, then 3-bromo-2-methylpropene (3.35 mL, 32.2 mmol) was added at 0 ° C. for half an hour. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonia chloride (50 mL). The aqueous mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/20) to give the title compound (10.0 g, 94%).¹1 H NMR (300MHz, CDCl₃) δ7.43-7.29 (m, 5H), 6.53 (d, 1H), 6.45 (dd, 1H), 5.15-4.94 (m, 4H), 4.43 (s, 2H), 1.82 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ159.1,155.6,140.1,136.5,133.1,128.6,128.1,127.5,112.9,107.2,103.3,102.0,72.4,70.3,19.3.

Synthesis of B.6- (benzyloxy) -3,3-dimethyl-2,3-dihydrobenzofuran Tributyltin hydride (7.42 mL, 27.2 mmol) and benzoyl peroxide (7.42 mL, 27.2 mmol) in a benzene (400 mL) solution of 4- (benzyloxy) -1-bromo-2- (2-methylallyloxy) benzene (5.00 g, 15.1 mmol). 0.70 g, 2.90 mmol) was added at 0 ° C. The resulting mixture was refluxed at 100 ° C. overnight. After cooling to ambient temperature, the mixture was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/20) to give the title compound (3.48 g, 91%). MS (ES +) m / z 255.6 (M + 1).

Synthesis of C.3,3-dimethyl-2,3-dihydro-1-benzofuran-6-ol Pd / C (1.45 g) is added to a solution of 6- (benzyloxy) -3,3-dimethyl-2,3-dihydrobenzofuran (3.48 g, 13.7 mmol) in methanol (200 mL), and the mixture is hydrogenated at 40 psi. Hydrogenated overnight. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/7) to give the title compound (1.66 g, 74%). MS (ES +) m / z 165.4 (M + 1).

Production example 26 1- (Diphenylmethyl) -3- (5-Hydroxy-2,3-dihydro-1-benzofuran-6-yl) -3- (Hydroxymethyl) -1,3-dihydro-2H-indole-2-one Synthetic Synthesis of A.1- (diphenylmethyl) -3-hydroxy-3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1,3-benzodioxole-5-ol was replaced with 2,3-dihydrobenzofuran-5-ol (Alabaster, RJ et al.; Synthesis (1988), 12: 950-2). And with a non-critical modification to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 1- (diphenylmethyl) -1H-indole-2,3-dione, the title compound Got MS (ES +) m / z 472.2 (M + 23).

Synthesis of B.1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indole-2-one 1- (diphenylmethyl) -3-hydroxy-3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H- A non-critical modification was made to replace indole-2-one to give the title compound. MS (ES +) m / z 434.4 (M + 1).

C.1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2- On synthesis 1- (Diphenylmethyl) -3- (5-Hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2-one (1.01 g, 2.30 mmol) Paraformaldehyde (1.00 g, 30.0 mmol) was added to a solution of THF (50.0 mL). Argon was bubbled into the reaction mixture for 1 hour, then diisopropylamine (1.00 g, 10.0 mmol) was added at 0 ° C. The reaction mixture was stirred at ambient temperature for 20 hours and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2 x 50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give 0.67 g (65%) of the title compound. MS (ES +) m / z 486.4 (M + 23).

Production example 27 3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -4-methoxy-1-{[5- (trifluoromethyl) -2-furyl] methyl} Synthesis of -1.3-dihydro-2H-indole-2-one A. Synthesis of ethyl 2- (2- (tert-butoxycarbonylamino) -6-methoxyphenyl) -2-oxoacetate N-BuLi (0.25 mol, 1.6 M pentane solution) was added to a solution of tert-butyl 3-methoxyphenyl carbamate (25.6 g, 0.11 mol) in THF (300 mL) at -78 ° C. The resulting solution was stirred at 0 ° C for 3 hours, cooled again to -78 ° C, and then diethyl oxalate (20.1 g, 0.14 mol) was added. The mixture was stirred at 78 ° C. for 45 minutes at ambient temperature for 1 hour and quenched with 1N HCl. The mixture was extracted with ether. The organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to give 3.70 g (27% of recovery starting material) of the title compound. MS (ES +) m / z 324.3 (M + 1).

Synthesis of B.4-methoxy-1H-indole-2,3-dione Ethyl 2- (2- (tert-butoxycarbonylamino) -6-methoxyphenyl) -2-oxoacetate (3.70 g, 110 mmol) and 10% H₂SO₄The mixture (100 mL) was heated at 100 ° C. for 10 hours. After cooling to ambient temperature, the reaction mixture was extracted with ether (3 x 100 mL). The combined ether solution was washed with water (2 x 50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to give 0.37 g (19%) of the title compound. MS (ES +) m / z 200.1 (M + 23).

C.4-Methoxy-1-{[5- (trifluoromethyl) -2-furyl] methyl} -1H-synthesis of indole-2,3-dione Following the procedure described in Production Example 1A, 4-bromoindole to 4-methoxy-1H-indole-2,3-dione and 1-bromopentane to 2- (bromomethyl) -5- (trifluoromethyl) furan A non-critical modification was made to replace with the title compound (26%). MS (ES +) m / z 348.2 (M + 23).

D.3-Hydroxy-3- (6-hydroxy-1,3-benzodioxole-5-yl) -4-methoxy-1-{[5- (trifluoromethyl) -2-furyl] methyl}- Synthesis of 1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to 4-methoxy-1-{[5- (trifluoromethyl) -2-furyl]. Subcritical modifications were made to replace methyl} -1H-indole-2,3-dione to give the title compound (56%). MS (ES +) m / z 486.4 (M + 23).

E.3- (6-Hydroxy-1,3-benzodioxol-5-yl) -4-methoxy-1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3- Synthesis of dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indol-2-one 3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -4-methoxy-1-{[5- (trifluoromethyl)- Subcritical modifications were made to replace 2-frill] methyl} -1,3-dihydro-2H-indole-2-one to give the title compound (86%). MS (ES +) m / z 448.4 (M + 1).

F.3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -4-methoxy-1-{[5- (trifluoromethyl) -2-furyl] Synthesis of methyl} -1.3-dihydro-2H-indole-2-one Following the procedure described in Production Example 26C, 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2 -On 3- (6-hydroxy-1,3-benzodioxol-5-yl) -4-methoxy-1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3 A non-critical modification was made to replace -dihydro-2H-indole-2-one to give the title compound (64%). MS (ES +) m / z 500.4 (M + 23).

Production example 28 4,7-Dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2- On synthesis A. Synthesis of 4,7-dichloro-1-pentyl-1H-indole-2,3-dione 4,7-Dichloro-1H-indole-2,3-dione in a mixture of anhydrous N, N-dimethylformamide (5.00 mL) of sodium hydroxide (0.17 g, 6.94 mmol, 60% dispersion in mineral oil) A solution of (1.00 g, 4.60 mmol) of N, N-dimethylformamide (5.00 mL) was added at 0 ° C. The brown reaction mixture was stirred for 0.5 hours, then 1-bromopentane (0.84 g, 5.55 mmol) anhydrous N, N-dimethylformamide (5.00 mL) was added. The reaction mixture was stirred at ambient temperature for 16 hours and poured into wet ethyl ether (30.0 mL). After separating the organic layer, it was washed with water (2 × 20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The rubbery residue was dried under vacuum and the solid was pulverized with ether to give the title compound (0.98 g, 98%). MS (ES +) m / z 286.2 (M + 1).

B.4,7-Dichloro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Synthesis of Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 4,7-dichloro-1-pentyl-1H-indole-2,3-dione. Substituting non-critical modifications were made to give the title compound as a white solid (68%).¹1 H NMR (300MHz, CDCl₃) δ8.61 (s, br, 1H), 7.26 (t, 1H), 7.03 (d, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.86 (dd, 2H), 4.21 (s , br, 1H), 4.01-3.96 (m, 2H), 1.73-1.58 (m, 2H), 1.34-1.21 (m, 4H), 0.84 (t, 3H); MS (ES +) m / z 408.2 (M) -17).

C. Synthesis of 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one with 4,7-dichloro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro- A non-critical modification was made to replace 2H-indole-2-one to give the title compound as a white solid (72%).¹1 H NMR (300MHz, CDCl₃) δ7.27-7.23 (m, 1H), 7.03 (d, 1H), 6.55 (s, 1H), 6.04 (s, 1H), 5.84 (dd, 2H), 5.03 (s, 1H), 4.09-3.99 (m, 2H), 1.72-1.62 (m, 2H), 1.33-1.24 (m, 4H), 0.86 (t, 3H); MS (ES +) m / z 409.2 (M + 1).

D.4,7-Dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole- 2-on synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Replace on with 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one A critical modification was made to give the title compound as a rubbery solid (94%). MS (ES +) m / z 439.3 (M + 1).

Production example 29 Synthesis of ethyl 2- (4-chloro-3- (6-hydroxy-2,3-dihydrobenzofuran-5-yl) -3- (hydroxymethyl) -2-oxoindoline-1-yl) acetate A. Synthesis of ethyl (4-chloro-2,3-dioxo-2,3-dihydro-1H-indole-1-yl) acetate Following the procedure described in Production Example 2A, a non-critical modification was made to replace isatin with 4-chloro-1H-indole-2,3-dione and (2-bromoethyl) cyclopropane with ethylbromoacetate, with the title compound. Was obtained as a colorless solid (95%).¹1 H NMR (300MHz, CDCl₃) δ7.48 (t, 1H), 7.08 (d, 1H), 6.67 (d, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES +) m / z 268.6 (M + 1).

B. Ethyl [4-chloro-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1- Indole] Acetate synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to ethyl (4-chloro-2,3-dioxo-2,3-dihydro-1H-). A non-critical modification was made to replace indole-1-yl) acetate to give the title compound as a white solid (75%).¹1 H NMR (300MHz, CDCl₃) δ8.70 (br, 1H), 7.31 (t, 1H), 7.12 (d, 1H), 6.68 (d, 1H), 6.46 (d, 2H), 4.53-4.46 (m, 2H), 4.18 (q) , 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS (ES +) m / z 387.8 (M-17).

C. Ethyl [4-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthetic Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro Ethyl -2H-indole-2-one [4-chloro-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro A non-critical modification was made to replace -1H-indole-1-yl] acetate to give the title compound as a white solid (75%).¹1 H NMR (300MHz, CDCl₃) δ7.33-7.27 (m, 2H), 7.12 (d, 1H), 6.71 (d, 1H), 6.50-6.48 (m, 1H), 5.10 (s, 1H), 4.54-4.42 (m, 4H) , 4.19 (q, 2H), 3.11-2.90 (m, 2H), 1.23 (t, 3H); MS (ES +) m / z 388.8 (M + 1).

D. Ethyl [4-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole -1-Il] Synthesis of acetate Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On is ethyl [4-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate A non-critical modification was made to obtain the title compound as a rubbery solid (99%). MS (ES +) m / z 418.7 (M + 1).

Production example 30 Synthesis of 3-hydroxy-3- [6- (hydroxymethyl) -1,3-benzodioxole-5-yl] -1-pentyl-1,3-dihydro-2H-indole-2-one THF of (6-bromo-1,3-benzodioxol-5-yl) methanol (Mann, J. et al., J Chem. Soc Perkin Trans 1 (1984): 2081-8) (1.27 g, 5.50 mmol) To the (45.0 mL) solution, n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) was added dropwise at -75 ° C. The reaction mixture was stirred at -75 ° C for 45 minutes, then a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in THF (20.0 mL) was added at -75 ° C. .. The resulting mixture was stirred at ambient temperature for 12 hours and quenched with ammonium chloride solution (5.00 mL). Further, ethyl acetate and water were added and separated. The organic layer was concentrated to dryness in vacuo. The residue was subjected to column chromatography eluting with 50% EtOAc: Hexanes to give the title compound (0.29 g, 25%) as a solid.¹1 H NMR (300MHz, CDCl₃) δ7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H), 6.81 (s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56 (m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,147.4,147.2,142.8,133.5,132.2,131.1,130.1,125.3,123.8,111.4,109.2,108.1,101.5,79.5,64.7,40.4,29.0,26.8,22.3,13.9; MS (ES +) m / z 352.1 (M-17).

Production example 31 Synthesis of Ethyl [1-Hexyl-3- (6-Hydroxy-1,3-benzodioxole-5-yl) -2-oxo-2,3-dihydro-1H-indole-3-yl] acetate A.1-Synthesis of 1-hexyl-1H-indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with n-bromohexane to give the title compound as a viscous rubber (90%).¹1 H NMR (300MHz, CDCl₃) δ7.58-7.51 (m, 2H), 7.08 (t, 1H), 6.87 (d, 1H), 3.68 (t, 2H), 1.71-1.62 (m, 2H), 1.41-1.22 (m, 6H) , 0.85 (t, 3H).

B.1-Synthesis of 1-hexyl-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, a non-critical change to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 1-hexyl-1H-indole-2,3-dione The title compound was obtained as a colorless solid (53%).¹1 H NMR (300MHz, CDCl₃) δ9.44 (br, 1H), 7.47-7.44 (m, 1H), 7.40-7.34 (m, 1H), 7.17 (t, 1H), 6.89 (d, 1H), 6.55 (s, 1H), 6.21 (s, 1H), 5.84-5.82 (m, 2H), 4.58 (br, 1H), 3.71-3.56 (m, 2H), 1.67-1.62 (m, 2H), 1.32-1.21 (m, 6H), 0.84 -0.80 (m, 3H);¹³C NMR (75MHz, CDCl₃) δ179.0,152.3,148.8,142.5,141.3,130.3,129.2,126.1,123.7,117.2,109.5,106.8,101.9,101.4,79.2,40.4,31.3,27.1,26.4,22.4,13.9; MS (ES +) m / z 352.5 (M-17).

Synthesis of C.1-hexyl-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one to 1-hexyl-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indol-2- A non-critical change to replace on gave the title compound as a white solid (98%).¹1 H NMR (300MHz, CDCl₃) δ7.38-7.13 (m, 3H), 6.94 (d, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 5.84 (dd, 2H), 5.02 (s, 1H), 3.74-3.63 (m, 2H), 1.70-1.61 (m, 2H), 1.37-1.19 (m, 6H), 0.83 (t, 3H); MS (ES +) m / z 354.2 (M + 1).

D. Ethyl [1-hexyl-3- (5-6-hydroxy-1,3-benzodioxol-yl) -2-oxo-2,3-dihydrazide mud -1H- indol-3-yl] acetate Synthetic To a solution of diisopropylamine (1.14 g, 11.0 mmol) in THF (10.0 mL) was added n-butyllithium (7.00 mL, 11.0 mmol, 1.6 M hexane solution) at -75 ° C. The resulting mixture was stirred at -75 ° C for half an hour and at -75 ° C 1-hexyl-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro. It was added slowly to a solution of -2H-indole-2-one in THF (20.0 mL). After stirring at -75 ° C for another half hour, ethyl bromoacetate was added. The mixture was stirred at ambient temperature for 18 hours and quenched with saturated ammoniu chloride solution. The organic solvent was removed in vacuo and the aqueous residue was diluted with ethyl acetate (100 mL). The organic layer was washed with saturated ammonia chloride (25.0 mL) and brine (50.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with 40% EtOAc / Hexanes to give the title compound (0.19 g, 8%) as an oil. MS (ES +) m / z 440.5 (M + 1).

Production example 32 Synthesis of 4-bromo-3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one A. Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, a non-critical modification was made to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 4-bromoisatin to make the title compound a beige solid. Obtained (95%).¹1 H NMR (300MHz, DMSO-d₆) δ10.40 (s, 1H), 9.09 (s, 1H), 7.22 (s, 1H), 7.04 (t, 1H), 6.90 (d, 1H), 6.75 (d, 1H), 6.43 (br, 1H) ), 6.21 (s, 1H), 5.88 (d, 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.0,148.7,147.0,145.8,139.5,131.3,130.8,125.4,118.8,118.4,109.4,108.9,101.0,97.4,76.6; MS (ES +) m / z 366.4 (M + 1), 364.5 (M + 1) ).

Synthesis of B.4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Replace indole-2-one with 4-bromo-3 hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indol-2-one Subcritical modifications were made to give the title compound as a cream-colored solid (95%). MS (ES +) m / z 348.5 (M + 1), 346.3 (M + 1).

Synthesis of C.4-bromo-3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Follow the procedure described in Production Example 31D to add 1-hexyl-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one to 4 Non-critical to replace -bromo-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one, and ethylbromoacetate with para-formaldehyde The title compound was obtained as a colorless solid (70%).¹1 H NMR (300MHz, DMSO-d₆) δ9.00 (br, 1H), 7.13-6.95 (m, 3H), 6.84 (d, 1H), 6.16 (d, 1H), 5.90-5.84 (m, 2H), 5.16-4.83 (m, 2H) ;¹³C NMR (75MHz, DMSO-d₆) δ177.8,150.4,147.1,146.8,139.8,130.2,129.3,125.8,117.7,115.8,109.3,107.9,101.2,97.6,63.5,57.4.

Production example 33 4-Bromo-3- (6-hydroxy-2,3-dihydro1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro2H-indole-2-one A. Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione to 4-bromoisatin and 1,3-benzodioxol-5-ol to 2 A non-critical modification was made to replace, 3-dihydrobenzofuran-6-ol to give the title compound as a colorless solid (78%).¹1 H NMR (300MHz, DMSO-d₆) δ10.36 (s, 1H), 9.15 (s, 1H), 7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74 (d, 1H), 6.35 (br, 1H), 5.90 (s, 1H), 4.45 (t, 2H), 3.05 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.4,160.2,154.0,145.7,131.6,130.7,125.5,125.4,118.9,117.7,116.1,108.8,96.8,76.9,71.8,29.1; MS (ES-) m / z 344.4 (M-17), 360.4 ( M-1).

Synthesis of B.4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one 4-bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indol-2-one A non-critical modification was made to replace with the title compound as an individual (62%). MS (ES +) m / z 346.5 (M + 1), 348.5 (M + 1).

Synthesis of C.4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Follow the procedure described in Production Example 31D to add 1-hexyl-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one to 4 -Bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one, and ethylbromoacetate replaced with paraformaldehyde A critical modification was made to obtain the title compound, which was used as is for further reactions.

Production example 34 4-Bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H -Indole-2-on synthesis A. Synthesis of 4-bromo-1- (pyridin-2-ylmethyl) -1H-indole-2,3-dione Sodium hydroxide (3.34 g, 86.9 mmol, 60% dispersion in mineral oil) little by little at 0 ° C in a solution of 4-bromoisatin (8.94 g, 39.5 mmol) in anhydrous N, N-dimethylformamide (100 mL). added. The brown reaction mixture was stirred for 30 minutes and then neutralized with sodium hydroxide (1.52 g, 39.5 mmol, 60% dispersion in mineral oil) at 0 ° C. 2- (bromomethyl) pyridine hydrobromide. A (10.0 g, 39.5 mmol) N, N-dimethylformamide solution was added. The reaction mixture was stirred for 16 hours and quenched with water (100 mL). The reaction mixture was extracted with diethyl ether (3 x 100 mL) and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (5 x 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was milled with ether to give the title compound (10.6 g, 85%) as a brown solid.¹1 H NMR (300MHz, DMSO-d₆) δ8.53 (d, 1H), 7.67 (t, 1H), 7.30 (t, 2H), 7.25-7.19 (m, 2H), 6.94 (d, 1H), 5.04 (s, 2H);¹³C NMR (75MHz, DMSO-d₆) δ180.5,157.3,154.2,152.3,149.5,138.4,137.5,128.6,123.3,122.3,121.5,116.4,110.3,45.8.

B.4-Bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H- Synthesis of indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 4-bromo-1- (pyridin-2-ylmethyl) -1H-indole-2, Subcritical changes were made to 3-dione and to replace 1,3-benzodioxole-5-ol with 2,3-dihydrobenzofuran-6-ol to give the title compound as a colorless solid (91%). .. Melting point:&gt; 225 ° C.¹1 H NMR (300MHz, DMSO-d₆) δ9.29 (s, 1H), 8.54 (d, 1H), 7.70 (dt, 1H), 7.61 (br, 1H), 7.32-7.26 (m, 2H), 7.07 (d, 1H), 7.00 (d) , 1H), 6.72 (d, 1H), 6.60 (br, 1H), 6.02 (s, 1H), 4.91 (ABq, 2H), 4.47 (t, 2H), 3.06 (d, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,160.4,156.3,153.8,149.6,146.1,137.5,130.9,130.8,126.5,125.8,123.1,121.5,118.8,117.3,116.4,108.3,96.7,76.6,71.9,45.7,29.1; MS (ES +) m / z 455.4 (M + 1), 437.4 (M-17).

C.4-Bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H-indole-2- On synthesis 4-Bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H-indole- Triethylamine (1.40 mL, 9.91 mmol) and SOCl in a 2-ion (1.12 g, 2.48 mmol) anhydrous dichloromethane (25.0 mL) solution.₂(0.40 mL, 4.96 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours and quenched with water (30.0 mL). The organic layer was separated, washed with water (3 x 30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give a gum-like substance. The residue was dissolved in acetic acid / tetrahydrofuran (3.00 mL / 22.0 mL), then zinc powder (0.81 g, 12.4 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 16 hours. After filtering the solid, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3 x 30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give the title compound (1.50 g, 77%) as a gum-like substance. MS (ES +) m / z 437.3 (M + 1).

D.4-Bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1,3-dihydro -2H-Indole-2-one synthesis Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -On 4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H-indole-2 -Made a non-critical change to replace on and obtained the title compound (34%). MS (ES +) m / z 468.4 (M + 1).

Manufacturing example 35 5-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} Synthesis of -1,3-dihydro-2H-indole-2-one A. 5-Fluoro-1-{[5- (trifluoromethyl) -2-furyl] methyl} -1H-synthesis of indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace isatin with 5-fluoroisatin and (2-bromoethyl) cyclopropane with 2- (bromomethyl) -5- (trifluoromethyl) furan. , The title compound was obtained as a red solid (59%).¹1 H NMR (300MHz, DMSO-d₆) δ7.54-7.50 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (dd, 1H), 7.14-7.13 (m, 1H), 6.75 (d, 1H), 4.99 (s, 2H) ;¹³C NMR (75MHz, DMSO-d₆) δ 182.4 (d), 160.7, 158.5 (d), 157.5, 153.0 (d), 146.5 (d), 139.9 (q), 124.3, 119.3 (d), 114.5 (d), 112.7 (d), 112.0 (d), 110.5, 36.8.

B.5-Fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl}- Synthesis of 1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to 5-fluoro-1-{[5- (trifluoromethyl) -2-furyl]. Subcritical modifications were made to replace methyl} -1H-indole-2,3-dione to give the title compound as a pale yellow solid (66%).¹1 H NMR (300MHz, DMSO-d₆) δ9.15 (s, 1H), 7.21 (s, 1H), 7.15 (dd, 1H), 7.08-6.95 (m, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.22 (d) , 1H), 5.90 (d, 2H), 4.96 (s, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.7,160.57,157.4,154.0,148.6,147.4,140.1 (m), 139.6 (m), 134.7 (d,²J_CF= 29.4Hz), 121.3,119.5,117.7,115.1 (d,¹J_CF= 92.1Hz), 114.5, 111.8 (d,¹J_CF= 97.5Hz), 109.7,109.6,107.2,101.3,97.8,75.1,36.9; MS (ES +) m / z 450.3 (M + 1) C.5-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3- Synthesis of dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one 5-fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2- Subcritical modifications were made to replace frills] methyl} -1,3-dihydro-2H-indole-2-one to give the title compound as a pale yellow solid (72%).¹1 H NMR (300MHz, DMSO-d₆) δ9.31 (s, 1H), 7.13 (dd, 1H), 7.02 (dd, 2H), 6.82 (d, 1H), 6.59 (d, 2H), 6.39 (s, 1H), 5.87 (d, 2H) ), 5.07-4.96 (m, 2H), 4.84 (s, 1H);¹³C NMR (75MHz, DMSO-d₆) δ176.1,160.5,157.4,153.9,150.5,147.5,140.2,139.6,139.1,132.3 (d,²J_CF= 33.3Hz), 115.3,114.5 (m), 114.2,113.9,111.9 (d,¹J_CF= 98.7Hz), 109.9,109.7 (d,²J_CF= 32.7Hz), 101.3,98.3,48.5,36.8; MS (ES +) m / z 436.2 (M + 1).

D.5-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1-{[5- (trifluoromethyl) -2-furyl] Synthesis of methyl} -1,3-dihydro-2H-indole-2-one 5-Fluoro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3-dihydro- A mixture of 2H-indole-2-one (3.64 g, 8.41 mmol), paraformaldehyde (2.52 g, 84.1 mmol) and lithium hydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL) and water (84.0 mL). In 10.0 mL), the mixture was stirred at 0 ° C for 4 hours. After removing the solvent by vacuum, the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous HCl solution (3 × 25.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (50%) to give the title compound (0.65 g, 59%) as a colorless solid.¹1 H NMR (300MHz, DMSO-d₆) δ9.11 (s, 1H), 7.12 (d, 1H), 6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d , 2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.1,160.5; MS (ES +) m / z 466.2 (M + 1), 448.2 (M-17).

Production example 36 Synthesis of tert-butyl- (2-chloromethyl-5-trifluoromethylthiophene-3-yloxy) dimethylsilane A. Synthesis of methyl 3-tert-butyldimethylsilanyloxy-5-trifluoromethyl-2-thiophenecarboxylate N, N-dimethylformamide (50.0 mL) of methyl 3-hydroxy-5-trifluoromethyl-2-thiophene carboxylate (Karp, GM et al., Syntehsis (2000), 8: 1078-1080) (19.4 g, 85.8 mmol) ) Imidazole (8.77 g, 129 mmol) was added to the solution, and then tert-butyldimethylsilyl chloride (19.4 g, 129 mmol) was added at 0 ° C. The reaction mixture was stirred at ambient temperature overnight. Further, imidazole (7.50 g) and tert-butyldimethylsilyl chloride (10.5 g) were added. The reaction mixture was stirred for an additional 4 hours and quenched with water (100 mL). The reaction mixture was extracted with ether (3 x 500 mL). The combined organic layers were washed with water (3 x 500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (1/9) to give the title compound (26.5 g, 90%) as a yellow oil.¹1 H NMR (300MHz, CDCl₃) δ6.91 (s, 1H), 3.82 (s, 3H), 0.21 (s, 6H), 0.06 (s, 9H);¹³C NMR (75MHz, CDCl₃) δ161.5,155.5,133.7,133.2,123.6 (q,¹J_CF= 14.4Hz), 119.8,51.9,25.4,18.2, -4.6.

B. [3- (tert-Butyldimethylsilanyloxy) -5-trifluoromethylthiophen-2-yl] Synthesis of methanol Methyl 3-tert-butyldimethylsilanyloxy-5-trifluoromethyl-2-thiophene carboxylate (10.0) in a mixture of lithium aluminum hydride (1.67 g, 43.9 mmol) in anhydrous ether (75.0 mL) at 0 ° C. A solution of g, 29.3 mmol) in absolute ethanol (25.0 mL) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and quenched by the slow addition of water (50.0 mL). After separating the aqueous layer, the organic layer was washed with saturated ammonia chloride (3 x 20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (1/9) to give the title compound (6.95 g, 76%) as a yellow oil.¹1 H NMR (300MHz, CDCl₃) δ6.89 (s, 1H), 4.68 (s, 2H), 2.11 (br, 1H), 0.96 (s, 9H), 0.88 (s, 6H);¹³C NMR (75MHz, CDCl₃) δ148.0,127.0,124.0,122.4 (q,¹J_CF= 14.7Hz), 120.5,56.1,25.5,18.1, -4.6.

Synthesis of C.tert-butyl- (2-chloromethyl-5-trifluoromethylthiophene-3-yloxy) dimethylsilane [3- (tert-Butyldimethylsilanyloxy) -5-trifluoromethylthiophen-2-yl] To a solution of methanol in anhydrous dichloromethane (100 mL), triethylamine (4.05 g, 40.0 mmol) was added, and then 0 ° C. Thionyl chloride (2.38 g, 20.0 mmol) was added in. The reaction mixture was stirred for 30 minutes and quenched with water (50.0 mL). After separation, the organic layer was washed with water (3 x 50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with hexane to give the title compound (2.31 g, 70%) as a yellow oil, which was used directly.

Production example 37 1- (Diphenylmethyl) -3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (Hydroxymethyl) -5-methyl-1,3-dihydro-2H-indol-2 -On synthesis Synthesis of A.1- (diphenylmethyl) -5-methyl-1H-indole-2,3-dione Following the procedure described in Production Example 2A, a non-critical modification was made to replace isatin with 5-methylisatin and (2-bromoethyl) cyclopropane with 1,1'-(bromomethylene) dibenzene, and the title compound was bright orange. Obtained as a solid of color (74%).¹1 H NMR (300MHz, CDCl₃) δ7.42-7.26 (m, 11H), 7.09 (d, 1H), 6.95 (s, 1H), 6.37 (d, 1H), 2.24 (s, 3H).

B.1- (Diphenylmethyl) -3-Hydroxy-3- (6-Hydroxy-1,3-benzodioxol-5-yl) -5-Methyl-1,3-dihydro-2H-Indol-2- On synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione is converted to 1- (diphenylmethyl) -5-methyl-1H-indole-2,3-dione. A non-critical modification was made to obtain the title compound as a colorless solid (92%).¹1 H NMR (300MHz, CDCl₃) δ9.23 (br, 1H), 7.40-7.15 (m, 11H), 6.90-6.85 (m, 2H), 6.57 (s, 1H), 6.33 (d, 1H), 6.31 (s, 1H), 5.87 (s, 2H), 4.46 (brs, 1H), 2.28 (s, 3H); MS (ES +) m / z 448.4 (M-17).

Synthesis of C.1- (diphenylmethyl) -3- (6-hydroxy-1,3-benzodioxole-5-yl) -5-methyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one 1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -5-methyl-1,3-dihydro A non-critical modification was made to replace -2H-indole-2-one to give the title compound as a colorless solid (84%).¹1 H NMR (300MHz, CDCl₃) δ7.37-7.25 (m, 9H), 7.22-7.17 (m, 2H), 7.10 (s, 1H), 6.91 (s, 1H), 6.86 (d, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 6.38 (d, 1H), 5.88 (ABq, 2H), 5.07 (s, 1H), 2.23 (s, 3H); MS (ES +) m / z 450.3 (M + 1).

D.1- (Diphenylmethyl) -3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (Hydroxymethyl) -5-methyl-1,3-dihydro-2H-indole -2-On synthesis 1- (Diphenylmethyl) -3- (6-Hydroxy-1,3-benzodioxol-5-yl) -5-methyl-1,3-dihydro-2H-indole-2-one (1.61g, 3.60) Diisopropylamine (7.20 mmol) was added to a solution of (mmol) and paraformaldehyde (0.43 g, 14.6 mmol) in dichloromethane (60.0 mL). After stirring at ambient temperature for 3 hours, the reaction system was quenched with saturated aqueous ammonium chloride solution (60.0 mL). The organic layer was separated, washed with water (3 x 100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (20-60%) to give the title compound (1.07 g, 63%) as a colorless solid.¹1 H NMR (300MHz, CDCl₃) δ10.09 (br, 1H), 7.37-7.16 (m, 12H), 6.99 (s, 1H), 6.87 (d, 1H), 6.62 (s, 1H) 6.54 (s, 1H), 6.37 (d, 1H), 5.87 (d, 2H), 4.45 (ABq, 2H), 2.33 (s, 3H); MS (ES +) m / z 480.4 (M + 1).

Production example 38 Synthesis of 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3-hydroxy-3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-. A non-critical modification was made to replace benzodioxole-5-ol with 2-methyl-1,3-benzothiazole-5-ol to give the title compound as a colorless solid (81%).¹1 H NMR (300MHz, DMSO-d₆) δ9.90 (br, 1H), 9.05 (br, 1H), 7.78 (d, 1H), 7.25 (dd, 1H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H), 3.81 -3.58 (m, 2H), 2.75 (br, 3H), 1.80-1.60 (m, 2H), 1.50-1.31 (m, 4H), 0.90 (t, 3H); MS (ES +) m / z 383.4 (M) +1).

Synthesis of B.3- (5-Hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one 3-Hydroxy-3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one (0.50 g, 1.31 mmol) ) Suspension of hydroiodic acid (10.0 mL) was refluxed for 1.5 days. The reaction mixture was concentrated to dryness under vacuum. The residue was used as is in the next step.

C.3- (Hydroxymethyl) -3- (5-Hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Synthetic Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical changes to replace -one with 3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one And the title compound was obtained. MS (ES +) m / z 367.5 (M + 1).

Production example 39 (5-Chloro-1,3,4-thiadiazole-2-yl) Synthesis of methanol Sodium borohydride (0.30 g, 7.99 mmol) in anhydrous methanol (5.00 mL) solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (0.51 g, 2.60 mmol) at 0 ° C. added. The reaction mixture was stirred at ambient temperature for 16 hours, diluted with acetic acid (3.00 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic matter was washed with saturated aqueous sodium hydrogen carbonate solution (3 × 25.0 mL) and saturated aqueous sodium chloride solution (2 × 25.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give the title compound (0.30 g, 75%) as a pale yellow semi-solid.¹1 H NMR (300MHz, CDCl₃) δ5.04 (s, 2H), 2.80 (br, 1H); MS (ES +) 151.1 (M + 1), 153.1 (M + 1).

Production example 40 1- (Diphenylmethyl) -3- (6-Hydroxy-3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (Hydroxymethyl) -1,3-dihydro-2H- Synthesis of indole-2-one A.1- (Diphenylmethyl) -3-hydroxy-3- (6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole -2-On synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1- (diphenylmethyl) -1H-indole-2,3-dione, and 1 A non-critical modification was made to replace 3-benzodioxol-5-ol with 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-ol to give the title compound. MS (ES +) m / z 478.5 (M + 1).

B.1- (Diphenylmethyl) -3- (6-Hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Synthesis of Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one 1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-3,3-dimethyl-2,3-dihydro1-benzofuran-5-yl) -1,3 A non-critical modification was made to replace -dihydro-2H-indole-2-one to give the title compound (73% in 2 steps).¹1 H NMR (300MHz, CDCl₃) δ7.38-7.20 (m, 12H), 7.11-7.04 (m, 2H), 6.97 (s, 1H), 6.58 (s, 1H), 6.57-6.51 (m, 1H), 6.50 (s, 1H) , 5.08 (s, 1H), 4.19 (s, 2H), 1.25 (s, 3H), 1.18 (s, 3H); MS (ES +) m / z 426.6 (M + 1).

C.1- (Diphenylmethyl) -3- (6-Hydroxy-3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (Hydroxymethyl) -1,3-dihydro- Synthesis of 2H-indole-2-one Following the procedure described in Production Example 26C, 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2 -On 1- (diphenylmethyl) -3- (6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2- A non-critical change to replace on was made to give the title compound. MS (ES +) m / z 492.5 (M + 1) Production example 41 Synthesis of 7-fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one A. Synthesis of 7-fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, a non-critical modification to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 7-fluoro-1H-indole-2,3-dione And the title compound was obtained (80%).¹1 H NMR (300MHz, DMSO-d₆) δ10.66 (s, 1H), 9.11 (s, 1H), 7.18 (s, 1H), 7.07-6.98 (m, 1H), 6.83-6.74 (m, 1H), 6.66 (d, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.92-5.85 (m, 2H); MS (ES +) m / z 304.5 (M + 1).

B. Synthesis of 7-fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro 2H-indole-2-one to 7-fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro-2H-indol-2-one A non-critical modification was made to replace with the title compound (100%).¹1 H NMR (300MHz, DMSO-d₆) δ10.84 (s, 1H), 9.22 (s, 1H), 7.01 (t, 1H), 6.87-6.78 (m, 1H), 6.71 (d, 1H), 6.62 (s, 1H), 6.35 (s) , 1H), 5.90-5.85 (m, 2H), 4.67 (s, 1H); MS (ES +) m / z 288.5 (M + 1).

Production example 42 Ethyl [4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1 -Il] Acetate synthesis A. Ethyl [4-Bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1- Indole] Acetate synthesis Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-). Subcritical modifications were made to indole-1-yl) acetate and to replace 1,3-benzodioxole-5-ol with 2,3-dihydrobenzofuran-6-ol to give the title compound as a white solid. (68%).¹1 H NMR (300MHz, CDCl₃) δ8.66 (br, 1H), 7.31-7.19 (m, 3H), 6.73 (dd, 1H), 6.49-6.45 (m, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H) , 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES +) m / z 432.2 (M-17).

B. Ethyl [4-Bromo-3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthetic Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro Ethyl -2H-indole-2-one [4-bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro Subcritical modifications were made to replace with -1H-indole-1-yl] acetate to give the title compound as a white solid (81%).¹1 H NMR (CDCl_3,300MHz) δ7.31-7.19 (m, 3H), 6.75 (d, 1H), 6.50-6.45 (m, 1H), 5.08 (s, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H) ), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES +) m / z 433.3 (M + 1).

C. Ethyl [4-Bromo-3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (Hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole -1-Il] Synthesis of acetate Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On is ethyl [4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Subcritical changes were made to replace with to give the title compound (99%). MS (ES +) m / z 463.2 (M + 1).

Production example 43 Ethyl [5-chloro-3- (6-hydroxy-2,3-dihydro1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1- Indole] Acetate synthesis Synthesis of A. Ethyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indole-1-yl) acetate Following the procedure described in Production Example 2A, a non-critical modification was made to replace isatin with 5-chloro-1H-indole-2,3-dione and (2-bromoethyl) cyclopropane with ethyl 2-bromoacetate. The title compound was obtained as a solid (98%).¹1 H NMR (300MHz, CDCl₃) δ7.60 (d, 1H), 7.54 (dd, 1H), 6.74 (d, 1H), 4.46 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES +) m / z 268.6 (M + 1).

B. Ethyl [5-chloro-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1- Indole] Acetate synthesis Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was added to ethyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indole-). Subcritical modifications were made to 1-yl) acetate and to replace 1,3-benzodioxole-5-ol with 2,3-dihydrobenzofuran-6-ol to give the title compound as a white solid (85). %).¹1 H NMR (300MHz, CDCl₃) δ8.70 (br, 1H), 7.31-7.24 (m, 2H), 6.92 (d, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.53-4.46 (m, 2H), 5.09 -4.40 (d, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS (ES +) m / z 387.8 (M-17).

C. Ethyl [5-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Synthetic Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Indole-2-one ethyl [5-chloro-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H A non-critical modification was made to replace -indole-1-yl] acetate to give the title compound as a white solid (94%).¹1 H NMR (300MHz, CDCl₃) δ7.30-7.24 (m, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 5.05 (s, 1H), 4.53-4.46 (m, 4H), 4.21 (q, 2H), 3.14-2.94 (m, 2H), 1.25 (t, 3H); MS (ES +) m / z 388.8 (M + 1).

D. Ethyl [5-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole -1-Il] Synthesis of acetate Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 -On is ethyl [5-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate A non-critical modification was made to replace with the title compound (99%). MS (ES +) m / z 418.7 (M + 1).

Production example 44 Synthesis of methyl [3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate A. Synthesis of methyl (2,3-dioxo-2,3-dihydro-1H-indole-1-yl) acetate Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with methylbromoacetate to give the title compound (72%).¹1 H NMR (300MHz, CDCl₃) δ7.64-7.53 (m, 2H), 7.14 (t, 1H), 6.77 (d, 1H), 4.48 (s, 2H), 3.76 (s, 3H); MS (ES +) m / z 220.4 (M) +1).

B. Synthesis of methyl [3- (4-chloro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Methyl 4-bromo-1-pentyl-1H-indole-2,3-dione (2,3-dioxo-2,3-dihydro-1H-indole-1-yl) according to the procedure described in Production Example 1C. Subcritical modifications were made to acetate and to replace 1,3-benzodioxole-5-ol with 3-chlorophenol to give the title compound as a yellow solid (29%).¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 7.48 (d, 1H), 7.38 (t, 1H), 7.19 (t, 1H), 7.01 (br, 1H), 6.80-6.64 (m, 3H), 5.28 (brs) , 1H), 4.51 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS (ES +) m / z 370.5 (M + 23), 372.4 (M + 23).

Synthesis of C. Methyl [3- (4-chloro-2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro Non-replacement of -2H-indole-2-one with methyl [3- (4-chloro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Critical changes were made to give the title compound as a semi-solid (83%).¹1 H NMR (300MHz, CDCl₃) δ7.36 (t, 1H), 7.29 (bd, 1H), 7.18 (t, 1H), 6.95 (br, 1H), 6.86-6.78 (m, 3H), 5.13 (br, 1H), 4.55 (d , 1H), 4.45 (d, 1H), 3.75 (s, 3H); MS (ES +) m / z 332.5 (M + 1), 334.5 (M + 1).

Synthesis of D. Methyl [3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical changes were made to replace -one with methyl [3- (4-chloro-2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate to give the title compound. It was. MS (ES +) m / z 362.5 (M + 1) 364.5 (M + 1).

Production example 45 Synthesis of ethyl [3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate A. Synthesis of ethyl [3- (4,5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione is converted to ethyl (2,3-dioxo-2,3-dihydro-1H-indole-1-). A non-critical modification was made to replace the indole acetate to give the title compound as a brown oil. MS (ES +) m / z 364.3 (M + 1), 348.5 (M-17).

Synthesis of B. Ethyl [3- (4,5-difluoro-2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indol-2-one to ethyl [3- (4,5-difluoro-2-hydroxyphenyl) -3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl] acetate Substituting non-critical modifications were made to give the title compound as a pale yellow oil (83%).¹1 H NMR (300MHz, CDCl₃) δ7.39 (t, 1H), 7.34 (d, 1H), 7.26-7.22 (m, 1H), 6.92-6.82 (m, 2H), 6.73 (dd, 1H), 5.11 (br, 1H), 4.50 (d, 1H), 4.43 (d, 1H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES +) m / z 448.5 (M + 1).

Synthesis of C. Ethyl [3- (4,5-difluoro2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical changes were made to replace -one with methyl [3- (4-chloro-2-hydroxyphenyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate to give the title compound. It was. MS (ES +) m / z 378.3 (M + 1), 361.3 (M-17).

Production example 46 Synthesis of 3- (4-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (4-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1C, 4-bromo-1-pentyl-1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodio. A non-critical modification was made to replace xol-5-ol with 3-bromophenol to give the title compound as a white solid (48%).¹1 H NMR (300MHz, CDCl₃) δ9.66 (br, 1H), 7.50-7.38 (m, 2H), 7.24-7.16 (m, 2H), 6.98-6.86 (m, 2H), 6.64 (d, 1H), 4.15 (br, 1H) , 3.80-3.55 (m, 2H), 1.75-1.62 (m, 2H), 1.40-1.34 (m, 4H), 0.89 (t, 3H); MS (ES +) m / z 391.4 (M + 1), 393.4 (M + 1).

Synthesis of B.3- (4-Bromo-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Made a non-critical change to replace indole-2-one with 3- (4-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one. The title compound was obtained as a white powder (91%).¹1 H NMR (300MHz, CDCl₃) δ7.40 (t, 1H), 7.31 (d, 1H) 7.24-7.23 (m, 2H), 7.01-6.91 (m, 2H), 6.74 (d, 1H), 5.05 (br, 1H), 3.80- 3.65 (m, 2H), 1.75-1.63 (m, 2H), 1.38-1.29 (m, 4H), 0.88 (t, 3H); MS (ES +) m / z 374.4 (M + 1), 376.4 (M +) 1).

Synthesis of C.3- (4-Bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 Subcritical modifications were made to replace -one with 3- (4-bromo-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one to give the title compound. R_f= 0.5 (EtOAc / Hexane, 1/4) Production example 47 Synthesis of 3- (5-Bromo-2-hydroxyphenyl) -3- (Hydroxymethyl) -1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to isatin and 1,3-benzodioxol-5-ol was added to 4-bromophenol. A non-critical modification was made to replace with to give the title compound as a yellowish solid (71%). MS (ES +) m / z 319.4 (M + 1), 321.4 (M + 1).

Synthesis of B.3- (5-Bromo-2-hydroxyphenyl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1D, 4-bromo-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H -Made a non-critical change to replace indole-2-one with 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1,3-dihydro-2H-indole-2-one and make the title compound white Obtained as a powder (98%). MS (ES +) m / z 306.2 (M + 1), 304.2 (M + 1).

Synthesis of C.3- (5-Bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 35D, 5-fluoro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2-furyl) ] Methyl} -1,3-dihydro-2H-indole-2-one is replaced by 3- (5-bromo-2-hydroxyphenyl) -1,3-dihydro-2H-indole-2-one. To obtain the title compound. MS (ES +) m / z 334.2 (M + 1), 336.2 (M + 1).

Production example 48 Synthesis of 1- (diphenylmethyl) -3- (hydroxymethyl) -3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one Synthesis of A.1- (diphenylmethyl) -3-hydroxy-3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1- (diphenylmethyl) -1H-indole-2,3-dione, 1, A non-critical modification was made to replace 3-benzodioxole-5-ol with 3- (trifluoromethoxy) phenol to give the title compound (75%). MS (ES +) m / z 514.5 (M + 23).

Synthesis of B.1- (diphenylmethyl) -3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indol-2-one 1- (diphenylmethyl) -3-hydroxy-3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indol-2-one A non-critical modification was made to replace with the title compound (82%). MS (ES +) m / z 498.4 (M + 23).

Synthesis of C.1- (diphenylmethyl) -3- (hydroxymethyl) -3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2 Make a non-critical change to replace -one with 1- (diphenylmethyl) -3- [2-hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one, title The compound was obtained. MS (ES +) m / z 488 (M-17), 528 (M + 23).

Production example 49 Synthesis of 1- (diphenylmethyl) -3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro2H-indole-2-one Synthesis of A.1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1,3-benzodioxole-5-ol was converted to 2,3-dihydrobenzofuran-6-ol (Foster et al., J Chem.Soc. 1948: 2254-2258). And a non-critical modification to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 1- (diphenylmethyl) -1H-indole-2,3-dione, making the title compound white. Obtained as a solid (68%). MS (ES +) m / z 450.4 (M + 1).

Synthesis of B.1- (diphenylmethyl) -3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-Indole-2-one 1- (diphenylmethyl) -3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H- A non-critical modification was made to replace indole-2-one to give the title compound as a white solid (67%). MS (ES +) m / z 434.3 (M + 1).

C.1- (Diphenylmethyl) -3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl)-(3-Hydroxymethyl) -1,3-dihydro-2H-Indole-2- On synthesis Following the procedure described in Production Example 26C, 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2 -Non-critical to replace 1- (diphenylmethyl) -3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Modifications were made to give the title compound as a white solid (45%). MS (ES +) m / z 464.5 (M + 1).

Production example 50 Synthesis of 4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one A. Synthesis of 4-bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1,3-benzodioxole-5-ol to 2,3-dihydrobenzofuran-6-ol and 1- (2-cyclopropylethyl) -1H-indole- A non-critical modification was made to replace 2,3-dione with 4-bromo-1H-indole-2,3-dione to give the title compound as a white solid (78%).¹1 H NMR (300MHz, DMSO-d₆) δ10.36 (s, 1H), 9.15 (s, 1H), 7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74 (d, 1H), 6.35 (br, 1H), 5.90 (s, 1H), 4.45 (t, 2H), 3.05 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.4,160.2,154.0,145.7,131.6,130.7,125.5,125.4,118.9,117.7,116.1,108.8,96.8,76.9,71.8,29.1; MS (ES-) m / z 344.4 (M-17), 360.4 ( M-1).

Synthesis of B.4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one to 4-bromo-3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indol-2 A non-critical change was made to replace-on to give the title compound as a white solid (62%). MS (ES +) m / z 346.5 (M + 1), 348.5 (M + 1).

Synthesis of C.4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 14C, 3- (5-fluoro-2-hydroxyphenyl) -1-pentyl-1,3-dihydro-2H-indole-2-one was added to 4-bromo-3- (6-). Subcritical modifications were made to replace hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1,3-dihydro-2H-indole-2-one to give the title compound (16%). R_f= 0.21 (EtOAc / Hexane, 7/3) Production example 51 7-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -3- (hydroxymethyl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} Synthesis of -1,3-dihydro-2H-indole-2-one A.7-Fluoro-1-{[5- (trifluoromethyl) -2-furyl] methyl} -1H-synthesis of indole-2,3-dione Following the procedure described in Production Example 1A, a non-critical modification was made to replace 4-bromoindole with 7-fluoroisatin and 1-bromopentane with 2- (bromomethyl) -5- (trifluoromethyl) furan. The title compound was obtained (34%). MS (ES +) m / z 336.2 (M + 23).

B.7-Fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl}- Synthesis of 1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was added to 7-fluoro-1-{[5- (trifluoromethyl) -2-furyl]. Subcritical modifications were made to replace methyl} -1H-indole-2,3-dione to give the title compound (75%). MS (ES +) m / z 474.3 (M + 23).

C.7-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3- Synthesis of dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one 7-fluoro-3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl)- Subcritical modifications were made to replace 2-frill] methyl} -1,3-dihydro-2H-indole-2-one to give the title compound (65%). MS (ES +) m / z 436.4 (M + 1).

D.7-Fluoro-3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (Hydroxymethyl) -1-{[5- (trifluoromethyl) -2-furyl] Synthesis of methyl} -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 26C, 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2- On is 7-fluoro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} -1,3- A non-critical modification was made to replace dihydro-2H-indole-2-one to give the title compound (67%). MS (ES +) m / z 488.4 (M + 23).

Production example 52 Synthesis of 3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A. Synthesis of 3-hydroxy-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1-pentyl-1H-indole-2,3-dione, and 1,3-. A non-critical modification was made to replace benzodioxole-5-ol with 2,3-dihydrobenzofuran-6-ol to give the title compound as a white powder (90%). MS (ES +) m / z 376.3 (M + 23).

Synthesis of B.3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one to 3-hydroxy-3- (6-hydroxy-2,3-dihydro1-benzofuran-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2- A non-critical change was made to replace on and the title compound was obtained (76%). MS (ES +) m / z 338.3 (M + 1).

Synthesis of C.3- (6-Hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Made a non-critical change to replace on with 3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one , The title compound was obtained (46%). MS (ES +) m / z 368.3 (M + 1), 380.4 (M + 23).

Production example 53 Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one A. Synthesis of 3- (5-bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -3-hydroxy-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, 1- (2-cyclopropylethyl) -1H-indole-2,3-dione was converted to 1- (diphenylmethyl) -1H-indole-2,3-dione, and 1 A non-critical modification was made to replace 3-benzodioxole-5-ol with 4-bromophenol to give the title compound as an orange solid (90%). MS (ES +) m / z 486.2 (M + 1), 488.2 (M + 1).

Synthesis of B.3- (5-Bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -1,3-dihydro-2H-indole-2-one Follow the procedure described in Production Example 15B to add 3- (5-bromo-2-hydroxyphenyl) -3-hydroxy-1-pentyl-1,3-dihydro-2H-indole-2-one to 3- (5-). Subcritical modifications were made to replace bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -3-hydroxy-1,3-dihydro-2H-indole-2-one to give the title compound as a white powder (white powder). 99%).¹1 H NMR (300MHz, CDCl₃) δ7.39-7.20 (m, 11H), 7.11-7.06 (m, 4H), 6.82 (d, 1H), 6.57-6.51 (m, 1H), 5.04 (s, 1H); MS (ES +) m / z 471.2 (M + 1), 473.2 (M + 1).

Synthesis of C.3- (5-Bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 26C, 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -1,3-dihydro-2H-indole-2 Subcritical changes were made to replace -one with 3- (5-bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -1,3-dihydro-2H-indole-2-one to give the title compound. .. MS (ES +) m / z 500.4 (M + 1), 502.4 (M + 1).

Production example 54 Synthesis of 3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one A.1-Synthesis of Pentyl-1H-Indole-2,3-Zeon Following the procedure described in Production Example 2A, a non-critical modification was made to replace (2-bromoethyl) cyclopropane with 1-bromopentane to give the title compound as a red solid (72%).¹1 H NMR (300MHz, CDCl₃) δ7.90 (d, 1H), 7.53-7.45 (m, 1H), 7.03-6.97 (m, 1H), 6.82 (d, 1H), 3.64-3.57 (m, 2H), 1.68-1.52 (m, 2H), 1.34-1.21 (m, 4H), 0.79 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ183.6,158.1,151.0,138.4,125.3,123.5,117.5,110.2,40.2,28.9,26.9,22.2,13.9.

B. Synthesis of 3-hydroxy-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2B, a non-critical modification to replace 1- (2-cyclopropylethyl) -1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione The title compound was obtained as a colorless individual (47%).¹1 H NMR (300MHz, CDCl₃) δ9.41 (s, 1H), 7.46 (dd, 1H), 7.37 (dt, 1H), 7.16 (dt, 1H), 6.89 (d, 1H), 6.53 (s, 1H), 6.22 (s, 1H) ), 5.83 (dd, 2H), 4.70 (br, 1H), 3.73-3.54 (m, 2H), 1.69-1.60 (m, 2H), 1.34-1.26 (m, 4H), 0.85 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ178.9,152.2,148.8,142.5,141.3,130.3,129.3,126.1,123.8,117.1,109.5,106.8,101.8,101.4,79.3,40.4,28.9,26.8,22.3,13.9; MS (ES + 1) m / z 355.5 (M + 1).

Synthesis of C.3- (6-Hydroxy-1,3-benzodioxole-5-yl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 2C, 1- (2-cyclopropylethyl) -3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1,3-dihydro -2H-indole-2-one to 3-hydroxy-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2- A non-critical change to replace on gave the title compound as a colorless solid (81%).¹1 H NMR (300MHz, CDCl₃) δ9.67 (br, 1H), 7.39-7.29 (m, 2H), 7.18-7.13 (m, 1H), 6.94 (d, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.71-3.63 (m, 2H), 1.71-1.61 (m, 2H), 1.35-1.27 (m, 4H), 0.86 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ178.8,151.3,147.6,143.9,141.53,128.7,126.4,126.2,123.1,115.3,109.4,106.5,101.5,101.2,47.4,40.5,28.9,26.9,22.3,13.9; MS (ES +) m / z 340 ( M + 1).

Synthesis of D.3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2-one Following the procedure described in Production Example 1E, 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro-2H-indol-2 -Made a non-critical change to replace on with 3- (6-hydroxy-1,3-benzodioxol-5-yl) -1-pentyl-1,3-dihydro2H-indole-2-one, title Compounds were obtained (67%).¹1 H NMR (300MHz, CDCl₃) δ10.85-10.63 (br, 1H), 7.48-7.35 (m, 2H), 7.28-7.19 (m, 1H), 6.96 (d, 1H), 6.52 (d, 2H), 5.82 (dd, 2H) , 4.63 (d, 1H), 4.11 (d, 1H), 3.70 (d, 2H), 2.04-1.74 (br, 1H), 1.65-162 (m, 2H), 1.31-1.24 (m, 4H), 0.84 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ180.3,152.6,148.1,143.2,141.3,129.2,129.1,126.2,123.3,112.4,109.6,108.2,101.9,101.3,64.6,59.8,40.6,28.9,26.9,22.2,13.9; MS (ES +) m / z 370.1 (M + 1).

Example 1 1'-(2-Cyclopropylethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="23"><img file="JP5118627B2_D0018.tif" /></chemistry> 1- (2-Cyclopropylethyl) -3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indol-2- Triphenylphosphine (0.82 g, 3.13 mmol) and diethyl azodicarboxylate (0.55, 3.13 mmol) were added to an anhydrous THF (20.0 mL) solution of on (0.92 g, 2.51 mmol) at -78 ° C. The brown reaction solution was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride (50.0 mL). The organic solvent was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The brown residue was subjected to column chromatography eluting with ethyl acetate / hexane (5% -20%, gradient) to give the title compound (0.63 g, 72%), which was crystallized from ether to give a colorless solid. .. Melting point: 125-127 ° C.¹1 H NMR (300MHz, CDCl₃) δ7.30-7.25 (m, 1H), 7.14 (d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (m , 2H), 4.76 (m, 2H), 3.93-3.74 (m, 2H), 1.65-1.57 (m, 2H), 0.76-0.56 (m, 1H), 0.48-0.41 (m, 2H), 0.08-0.03 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,155.9,148.8,142.6,142.3,132.4,128.8,124.0,123.1,119.5,108.6,103.1,101.5,93.6,80.6,58.2,40.5,32.5,30.8,8.7,4.4; MS (ES +) m / z 350.3 (M + 1).

Example 1.1 1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'-(1'H) -On Synthesis

<chemistry num="24"><img file="JP5118627B2_D0019.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one, 3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3 A non-critical modification using -dihydro-2H-indol-2-one gave the title compound as a white solid (80%). Melting point 85-87 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.28 (t, 1H), 7.15 (d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (dd, 2H) ), 4.77 (ABq, 2H), 3.85-3.62 (m, 2H), 1.76-1.66 (m, 2H), 1.40-1.33 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.3,155.9,148.8,142.4,142.3,132.5,128.9,123.9,119.6,108.6,103.0,101.5,93.6,80.5,58.2,40.4,29.0,27.1,22.3,14.0; MS (ES +) m / z 352 ( M + 1).

Example 1.2 4'-Bromo-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="25"><img file="JP5118627B2_D0020.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Substituted for 3-dihydro-2H-indole-2-one 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl- A non-critical modification using 1,3-dihydro-2H-indole-2-one gave the title compound as a colorless solid.¹1 H NMR (300MHz, CDCl₃) δ7.16 (d, 1H), 7.15 (s, 1H), 6.84 (dd, 1H), 6.45 (s, 1H), 6.06 (s, 1H), 5.86 (dd, 2H), 4.90 (ABq, 2H) ), 3.83-3.60 (m, 2H), 1.74-1.64 (m, 2H), 1.39-1.28 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.1,157.2,149.1,144.6,142.0,130.3,130.1,127.0,120.0,116.5,107.6,102.5,101.5,93.3,77.3,59.6,40.6,29.0,27.0,22.3,14.0; MS (ES +) m / z 430 (M + 1).

Example 1.3 Synthesis of (2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) acetate

<chemistry num="26"><img file="JP5118627B2_D0021.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one ethyl [3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo-2,3 A non-critical modification was made using -dihydro-1H-indole-1-yl] acetate to give the title compound as a white powder in 90% yield.¹1 H NMR (300MHz, DMSO-d₆) δ7.31-7.26 (m, 1H), 7.17-7.00 (m, 3H), 6.67 (s, 1H), 6.18 (s, 1H), 5.90-5.89 (m, 2H), 4.76-4.66 (m, 2H), 4.59 (s, 2H), 4.13 (q, 2H), 1.17 (t, 3H);¹³C NMR (75MHz, DMSO-d₆) δ177.3,168.3,155.6,148.8,142.4,142.1,132.0,129.3,124.1,123.7,120.4,109.6,103.3,101.9,93.8,79.8,61.8,57.8,41.8,14.5; MS (ES +) m / z 390.2 ( M + 23).

Example 1.4 Methyl 2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] benzoate Synthetic

<chemistry num="27"><img file="JP5118627B2_D0022.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-di -methyl replaced by a hydro -2H- indol-2-one 2 - {[3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo A non-critical modification was made using -2,3-dihydro-1H-indol-1-yl] methyl} benzoate to give the title compound as a white powder in a yield of 74%. Melting point: 166 ~ 167 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.05 (m, 1H), 7.44 (m, 1H), 7.34 (t, 1H), 7.22-7.10 (m, 3H), 7.03 (m, 1H), 6.70 (d, 1H), 6.52 (s , 1H), 6.21 (s, 1H), 5.90-5.84 (m, 2H), 5.52-5.33 (m, 2H), 4.99 (d, 1H), 4.72 (d, 1H), 3.95 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,167.5,156.0,148.9,142.4,142.3,137.4,132.8,132.1,131.4,129.0,128.6,127.4,126.5,123.9,123.6,119.4,109.5,103.1,101.5,93.7,80.7,58.4,52.3,42.4 ; MS (ES +) m / z 430.3 (M + 1), 452.3 (M + 23).

Example 1.5 Methyl 3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] benzoate Synthetic

<chemistry num="28"><img file="JP5118627B2_D0023.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Methyl 3-{[3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo replaced with 3-dihydro-2H-indole-2-one A non-critical modification was made using -2,3-dihydro-1H-indol-1-yl] methyl} benzoate to give the title compound as a white powder in a yield of 73%.¹1 H NMR (300MHz, CDCl₃) δ7.97-7.95 (m, 2H), 7.53-7.50 (m, 1H), 7.45-7.40 (m, 1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.73- 6.71 (m, 1H), 6.52 (s, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 5.18 (d, 1H), 4.72 (d, 1H), 4.80 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H);¹³C NMR (75MHz, CDCl₃) δ177.7,166.6,156.0,149.0,142.4,141.7,136.1,132.2,131.7,130.9,129.2,128.1,124.0,123.7,119.4,109.2,103.1,101.6,93.7,80.5,64.3,58.3,52.3,43.7; MS (ES +) m / z 430 (M + 1).

Example 1.6 Methyl 4-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] benzoate Synthetic

<chemistry num="29"><img file="JP5118627B2_D0024.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Methyl 4-{[3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2-oxo replaced with 3-dihydro-2H-indole-2-one A non-critical modification was made using -2,3-dihydro-1H-indol-1-yl] methyl} benzoate to give the title compound as a white powder in a yield of 87%.¹1 H NMR (300MHz, CDCl₃) δ8.01 (d, 2H), 7.38 (d, 2H), 7.18 (t, 2H), 7.02 (t, 1H), 6.72 (d, 1H), 6.52 (s, 1H), 6.12 (s, 1H) ), 5.86 (m, 2H), 5.11 (d, 1H), 4.96 (d, 1H), 4.86 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H);¹³C NMR (75MHz, CDCl₃) δ177.7,166.6,156.0,149.0,142.4,141.8,140.8,132.1,130.3,129.8,129.0127.3,124.1,123.7,119.3,109.2,103.0,102.0,93.7,80.5,58.3,52.2,43.9; MS (ES +) m / z 430.1 (M + 1).

Example 1.7 1'-(Diphenylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="30"><img file="JP5118627B2_D0025.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 1- (diphenylmethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1 A non-critical modification using 3-dihydro-2H-indole-2-one was performed to give the title compound as a white powder in a yield of 26%. MS (ES +) m / z 462.3 (M + 1).

Example 1.8 Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="31"><img file="JP5118627B2_D0026.tif" /></chemistry> 1'-(diphenylmethyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on (2.10 g, 4.70 mmol) ) Was added to a solution of EtOAc (100 mL) and acetic acid (0.10 mL) with palladium (1.00 g) on carbon. The reaction mixture was hydrogenated at an ambient temperature of 60 psi under hydrogen for 5 days and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to give the title compound (0.87 g, 66%) as a white powder. Melting point: 252 ° C (collapse)¹1 H NMR (300MHz, CDCl₃) δ10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s, 1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES +) m / z 282.2 (M + 1).

Example 1.9 2- [3- (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Propyl]- 1H-isoindole 1,3 (2H) -dione synthesis

<chemistry num="32"><img file="JP5118627B2_D0027.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 2-{3- [3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2- Non-critical modifications using oxo-2,3-dihydro-1H-indole-1-yl] propyl} -1H-isoindole-1,3 (2H) -dione to yield the title compound in 45%. Obtained.¹1 H NMR (300MHz, CDCl₃) δ7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H), 7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68- (m, 4H), 2.15-2.10-(m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,168.2,155.9,148.8,142.4,141.9,134.0,132.5,132.0,128.9,124.1,123.4,123.3,119.4,108.4,103.2,101.5,93.6,80.4,58.2,38.0,35.6,26.8; MS (ES + ) m / z 469.3 (M + 1), 491.3 (M + 23).

Example 1.10 2- [2- (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Ethyl]- Synthesis of 1H-isoindole-1,3 (2H) -dione

<chemistry num="33"><img file="JP5118627B2_D0028.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 2-{2- [3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -2- Non-critical modifications using oxo-2,3-dihydro-1H-indole-1-yl] ethyl} -1H-isoindole-1,3 (2H) -dione to yield the title compound in 61%. Obtained.¹1 H NMR (300MHz, CDCl₃) δ7.81-7.73 (m, 2H), 7.71-7.62 (m, 2H), 7.18-7.08 (m, 2H), 6.98 (t, 1H), 6.87 (d, 1H), 6.43 (s, 1H) , 6.29 (s, 1H), 5.91-5.81 (ABq, 2H), 4.79 (d, 1H), 4.58 (d, 1H), 4.18-3.92 (m, 4H), 3.06 (t, 2H), 1.59-1.35 (br, 2H);¹³C NMR (75MHz, CDCl₃) δ178,168.2,156.1,148.7,142.2,141.9,134.1,132.4,131.8,128.7,124.1,123.4,123.3,119.0,107.8,103.7,101.4,93.4,80.9,58.1,39.0,35.6; MS (ES +) m / z 455 (M + 1), 477 (M + 23).

Example 1.11 1'-[3- (benzyloxy) propyl] spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Synthetic

<chemistry num="34"><img file="JP5118627B2_D0029.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 1- [3- (benzyloxy) propyl] -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- ( A non-critical modification was made using hydroxymethyl) -1,3-dihydro-2H-indole-2-one to give the title compound as pale yellow syrup in 98% yield.¹1 H NMR (300MHz, CDCl₃) δ7.38-6.95 (m, 9H), 6.49 (s, 1H), 6.08 (s, 1H), 5.83 (dd, 2H), 5.86 (ABq, 1H), 4.58 (ABq, 1H), 3.96-3.79 (m, 2H), 3.53 (t, 2H), 2.06-2.00 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,155.9,148.8,142.5,142.2,138.1,132.3,128.9,127.9,127.6,123.9,123.1,119.5,108.7,103.0,101.4,93.6,80.4,73.1,67.4,58.1,37.7,27.9; MS (ES + ) m / z 430.3 (M + 1).

Example 1.12 5,6-Difluoro-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="35"><img file="JP5118627B2_D0030.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol- instead of 3-dihydro-2H-indole-2-one A non-critical modification using 2-one was performed to give the title compound in 71% yield. Melting point: 48-50 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.33 (td, 1H), 7.18-7.12 (m, 2H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.51 (dd, 1H), 4.96 (d, 1H), 4.71 (d , 1H), 3.87-3.64 (m, 2H), 1.82-1.65 (m, 2H), 1.46-1.28 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.6,156.8,152.9,149.8,144.2,142.6,131.8,129.4,124.1,123.5,111.7,109.0,100.2,80.9,57.9,40.6,29.1,27.2,22.5,14.1; MS (ES +) m / z 344 ( M + 1).

Example 1.13 5-Fluoro-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="36"><img file="JP5118627B2_D0031.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 3- (5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indole-2- A non-critical modification using on was performed to give the title compound in a yield of 3%.¹1 H NMR (300MHz, CDCl₃) δ7.37-7.28 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.01 (m, 1H), 6.98-6.82 (m, 3H), 6.45-6.37 (m, 1H), 4.95 ( d, 1H), 4.69 (d, 1H), 3.89-3.63 (m, 2H), 1.81-1.65 (m, 2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.7,159.4,156.6,132.2,130.1,129.3,124.1,123.4,116.3,110.8,110.5,108.9,80.4,58.4,40.6,29.2,27.3,22.5,14.1; MS (ES +) m / z 326 (M +) 1).

Example 1.14 5-Bromo-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="37"><img file="JP5118627B2_D0032.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (5-Bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol-2-one replaced by 3-dihydro-2H-indole-2-one A non-critical modification using on was performed to give the title compound in 4% yield.¹1 H NMR (300MHz, CDCl₃) δ7.38-7.23 (m, 2H), 7.17-7.01 (m, 2H), 6.93 (d, 1H), 6.84 (d, 1H), 6.79 (d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64 (m, 2H), 1.81-1.65 (m, 2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.7,160.1,142.6,132.7,132.1,131.4,129.3,126.5,124.1,123.5,113.1,112.2,108.9,80.3,58.0,40.6,29.2,27.3,22.5,14.2; MS (ES +) m / z 386 ( M + 1), 388 (M + 23).

Example 1.15 5-Chloro-6-fluoro-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="38"><img file="JP5118627B2_D0033.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (5-Chloro-4-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-replaced with 3-dihydro-2H-indol-2-one A non-critical modification using Indol-2-one was performed to give the title compound in 80% yield. Melting point: 74-76 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.38-7.27 (m, 1H), 7.18-7.02 (m, 2H), 6.94 (d, 1H), 6.77 (d, 1H), 6.69 (d, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.87-3.64 (m, 2H), 1.82-1.65 (m, 2H), 1.47-1.28 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.5,160.6,157.4,142.6,133.9,131.8,129.5,124.6,124.1,123.5,113.1,109.0,100.0,81.2,57.5,40.6,29.2,27.2,22.5,14.1; MS (ES +) m / z 360 ( M + 1).

Example 1.16 6-Methoxy-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="39"><img file="JP5118627B2_D0034.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (2-Hydroxy-4-methoxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol-2-one replaced with 3-dihydro-2H-indole-2-one A non-critical modification using on gave the title compound in 99% yield.¹1 H NMR (300MHz, CDCl₃) δ7.30 (td, 1H), 7.14 (dd, 1H), 7.03 (t, 1H), 6.91 (d, 1H), 6.58 (d, 1H), 6.52 (d, 1H), 6.36 (dd, 1H) ), 4.93 (d, 1H), 4.69 (d, 1H), 3.91-3.63 (m, 2H), 3.77 (s, 3H), 1.81-1.65 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.4,162.1,161.5,142.5,132.9,128.8,123.9,123.5,123.1,121.0,108.5,107.5,96.6,80.5,57.6,55.6,40.3,29.0,27.1,22.3,14.0; MS (ES +) m / z 338 (M + 1).

Example 1.17 6-Chloro-5-fluoro-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="40"><img file="JP5118627B2_D0035.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (4-Chloro-5-fluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-replaced with 3-dihydro-2H-indole-2-one A non-critical modification using Indol-2-one gave the title compound in a yield of 44%.¹1 H NMR (300MHz, CDCl₃) δ7.34 (td, 1H), 7.14 (dd, 1H), 7.06 (td, 1H), 6.98 (d, 1H), 6.93 (d, 1H), 6.50 (d, 1H), 4.96 (d, 1H) ), 4.70 (d, 1H), 3.87-3.63 (m, 2H), 1.81-1.65 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.2,156,9,154.8,151.6,142.5,131.5,129.4,128.6,123.7,121.7,121.9,111.2,108.9,80.6,57.9,40.5,29.0,27.1,22.3,14.0; MS (ES +) m / z 360 ( M + 1).

Example 1.18 1'-Pentyl-5- (trifluoromethyl) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="41"><img file="JP5118627B2_D0036.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (Hydroxymethyl) -3- [2-Hydroxy-5- (trifluoromethyl) phenyl] -1-pentyl-1,3-dihydro-2H- by replacing 3-dihydro-2H-indol-2-one A non-critical modification using Indol-2-one gave the title compound in 27% yield.¹1 H NMR (300MHz, CDCl₃) δ7.48 (dd, 1H), 7.35 (td, 1H), 7.16-6.90 (m, 5H), 5.02 (d, 1H), 4.76 (d, 1H), 3.91-3.65 (m, 2H), 1.82 -1.67 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.5,163.3,142.6,131.8,129.8,129.3,127.7,124.1,124.0,123.9,123.6,121.0,110.6,108.9,80.5,57.6,40.5,29.0,27.1,22.3,13.9; MS (ES +) m / z 376 (M + 1).

Example 1.19 5,6-Dichloro-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="42"><img file="JP5118627B2_D0037.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (4,5-Dichloro-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol-replaced with 3-dihydro-2H-indole-2-one A non-critical modification using 2-one was performed to give the title compound in a yield of 43%.¹1 H NMR (300MHz, CDCl₃) δ7.35 (td, 1H), 7.17-7.03 (m, 3H), 6.94 (d, 1H), 6.76 (s, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.88-3.65 (m, 2H), 1.82-1.67 (m, 2H), 1.47-1.29 (m, 4H), 0.92 (t, 3H).¹³C NMR (75MHz, CDCl₃) δ176.2,159.9,142.5,133.3,131.5,129.4,124.6,124.5,123.9,123.4,112.4,108.9,80.8,57.5,40.5,29.0,27.1,22.3,14.0; MS (ES +) m / z 376 (M +) 1), 378 (M + 1).

Example 1.20 1'-(diphenylmethyl) -5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1 'H)-On synthesis

<chemistry num="43"><img file="JP5118627B2_D0038.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 1- (diphenylmethyl) -3- (6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 A non-critical modification using-(hydroxymethyl) -1,3-dihydro-2H-indole-2-one was performed to give the title compound. Melting point: 190 ~ 192 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.40-7.26 (m, 10H), 7.19-7.15 (m, 1H), 7.07-6.93 (m, 3H), 6.55-6.51 (m, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 4.98 (d, 1H), 4.71 (d, 1H), 4.17 (s, 2H), 1.17 (s, 3H), 1.14 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ178.1,161.1,161.0,141.8,137.9,137.2,132.8,130.0,128.6,128.5,128.4,128.2,128.0,127.8,123.9,123.1,120.8,116.1,112.1,93.4,85.4,80.4,58.7,57.4,41.3 , 27.7,27.6; MS (ES +) m / z 474.5 (M + 1).

Example 1.21 5,5-Dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="44"><img file="JP5118627B2_D0039.tif" /></chemistry> 1'-(diphenylmethyl) -5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1 Palladium (0.10 g) on carbon was added to a solution of'H) -one (0.23 g, 0.49 mmol) in methanol (50.0 mL). The mixture was hydrogenated overnight at an ambient temperature of 120 psi under hydrogen. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to dryness under vacuum. The residue was subjected to a column chromatograph (ethyl acetate / hexane, 1/2) to give the title compound (0.10 g, 68%). Melting point: 95-100 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.74 (s, 1H), 7.28-7.20 (m, 1H), 7.15 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H), 6.43 (s, 1H), 6.40 (s , 1H), 4.94 (d, 1H), 4.66 (d, 1H), 4.19 (s, 2H), 1.20 (s, 3H), 1.16 (3H);¹³C NMR (75MHz, CDCl₃) δ180.4,161.3,161.0,140.3,133.0,130.1,128.8,124.2,123.4,120.0,116.6,110.1,93.4,85.5,80.6,58.3,41.4,27.7,27.6; MS (ES +) m / z 308.6 (M +) 1).

Example 1.22 4', 7'-Dichloro-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthetic

<chemistry num="45"><img file="JP5118627B2_D0040.tif" /></chemistry> 4,7-Dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol-2- Triphenylphosphine (0.54 g, 2.04 mmol) is added to a solution of on (0.69 g, 1.57 mmol) anhydrous tetrahydrofuran (15.0 mL), followed by diisopropylazodicarboxylate (0.41 g, 2.04 mmol) slowly at 0 ° C. added. The brown reaction mixture was stirred at ambient temperature for 16 hours and quenched with ammonium chloride solution (2.00 mL). The organic solvent was removed under vacuum. The residue was dissolved in ethyl acetate (20.0 mL), washed with 10% aqueous HCl solution (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (35%) to give a solid, which was crystallized from ethyl acetate / ether to give the title compound (0.13 g, 20%) as a colorless solid. Melting point: 106 ~ 108 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.24-7.16 (m, 1H), 6.81 (d, 1H), 6.44 (s, 1H), 6.07 (s, 1H), 5.86 (dd, 2H), 4.87 (dd, 2H), 4.12-4.07 (m, 2H), 1.76-1.66 (m, 2H) 1.36-1.31 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.5,157.0,149.2,142.1,140.0,132.3,131.0,130.2,124.6,116.0,113.8,102.3,101.5,93.3,77.2,58.5,42.1,29.5,28.7,22.3,14.0; MS (ES +) m / z 420.4 (M + 1).

Example 1.23 4'-Bromospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="46"><img file="JP5118627B2_D0041.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, Substituted for 3-dihydro-2H-indole-2-one 4-bromo-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1,3- A non-critical modification using dihydro-2H-indole-2-one gave the title compound as a colorless solid in a yield of 71%.¹1 H NMR (300MHz, DMSO-d₆) δ10.79 (s, 1H), 7.19-7.08 (m, 2H), 6.90 (dd, 1H), 6.58 (s, 1H), 6.25 (s, 1H), 5.90 (d, 2H), 4.74 (ABq) , 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.5,157.0,148.8,144.5,141.9,131.2,130.6,126.1,119.2,117.5,109.8,103.3,101.8,93.3,77.6,59.7; MS (ES-) m / z 360.4 (M-1), 358.4 ( M-1).

Example 1.24 4'-Bromo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="47"><img file="JP5118627B2_D0042.tif" /></chemistry> 4-Bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one (1.80 g, Tributylphosphine (1.26 g, 1.54 mL, 6.24 mmol) was added to a solution of 4.80 mmol) of acetic anhydride in ethyl acetate (50 mL) at 0 ° C under nitrogen. A solution of di-tert-butylazodicarboxylate (1.44 g, 6.24 mmol) in ethyl anhydride (15.0 mL) was added over 10 minutes. The reaction solution was stirred for 2 hours and then quenched with saturated ammonia chloride solution (30.0 mL). After separating the aqueous layer, the organic layer was washed with 10% aqueous HCl (2 x 25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate hexane (70%) to obtain a solid, which was pulverized with diethyl ether to give the title compound (0.64 g, 37%) as a colorless solid.¹1 H NMR (300MHz, DMSO-d₆) δ10.77 (s, 1H), 7.18-7.13 (m, 1H), 7.08 (d, 1H), 6.90 (d, 1H), 6.47 (s, 1H), 6.30 (s, 1H), 4.80 (ABq) , 2H), 4.46 (t, 2H), 2.92 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.7,162.2,161.7,144.5,131.1,131.0,126.1,119.8,119.2,119.1,118.3,109.7,92.4,77.6,72.5,59.2,28.8; MS (ES-) m / z 358.4 (M-1), 356.3 (M-1).

Example 1.25 4'-Bromo-1'-(Pyridine-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-On synthesis

<chemistry num="48"><img file="JP5118627B2_D0043.tif" /></chemistry> 4-Bromo-3- (6-hydroxy-2,3-dihydro1-benzofuran-5-yl) -3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1,3-dihydro-2H- A mixture of indole-2-one (1.81 g, 3.88 mmol), triphenylphosphine (2.04 g, 7.77 mmol) and diisopropylazodicarboxylate (1.57 g, 7.77 mmol) in reflux in anhydrous dioxane (60 mL). Heated for 16 hours. After cooling to ambient temperature, the solvent was evacuated. The gum-like residue was diluted with ethyl acetate (50.0 mL), washed with water (3 x 25.0 mL) and brine (3 x 25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (80%) to give the title compound (0.64 g, 37%) as a colorless solid. Melting point:&gt; 200 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ8.47 (d, 1H), 7.77 (dt, 1H), 7.37 (d, 1H), 7.27 (dt, 1H), 7.19-7.13 (m, 2H), 6.94 (dd, 1H), 6.61 (s) , 1H), 6.33 (s, 1H), 5.08 (d, 1H), 5.03 (d, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.48 (t, J = 8.6Hz, 2H) , 2.96 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ177.4,162.2,161.8,155.3,149.8,145.3,137.6,131.0,130.5,126.8,123.3,122.2,119.9,119.5,119.0,118.1,109.3,92.4,77.5,72.5,58.8,45.3,28.8; MS (ES + ) m / z 451.3 (M + 1).

Example 1.26 5'-Fluoro-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="49"><img file="JP5118627B2_D0044.tif" /></chemistry> 5-Fluoro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-{[5- (trifluoromethyl) -2-furyl] methyl} Tributylphosphine (2.18 g, 2.70 mL, 10.8 mmol) was added to a solution of -1,3-dihydro-2H-indole-2-one (3.34 g, 7.18 mmol) in anhydrous tetrahydrofuran (80.0 mL) under nitrogen. A solution of di-tert-butylazodicarboxylate (2.49 g, 10.8 mmol) in anhydrous tetrahydrofuran (25.0 mL) was added over 10 minutes. The reaction solution was stirred for 1 hour and quenched with saturated ammonia chloride (30.0 mL). The solvent was removed under reduced pressure and the gum-like material was extracted with ethyl acetate (3 x 75.0 mL). The organic layer was washed with 10% aqueous HCl solution (2 x 25.0 mL), saturated aqueous sodium hydrogen carbonate solution (3 x 25.0 mL) and then saline (3 x 25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (30%) to give the title compound (1.10 g, 34%) as a colorless solid. Melting point: 139 ~ 141 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.02-6.96 (m, 1H), 6.93-6.89 (m, 2H), 6.74-6.73 (m, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.09 (s, 1H) , 5.87 (dd, 2H), 4.95 (ABq, 2H), 4.78 (Abq, 2H);¹³C NMR (75MHz, CDCl₃) δ176.9,161.5,158.3,155.9,151.7,149.2,142.6,137.1,137.1,133.7,118.6,115.6,115.3,112.7,112.4,112.0,109.7,109.6,109.4,102.8,101.7,93.8,80.1,58.6,37.1 ; MS (ES +) m / z 448.2 (M + 1).

Example 1.27 1'-(diphenylmethyl) -5'-methylspiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one synthesis Synthesis of

<chemistry num="50"><img file="JP5118627B2_D0045.tif" /></chemistry> 1- (Diphenylmethyl) -3- (6-Hydroxy-1,3-benzodioxole-5-yl) -3- (Hydroxymethyl) -5-methyl-1,3-dihydro-2H-indol-2 -Tributylphosphine (0.82 g, 4.07 mmol) was added to a solution of on (1.31 g, 2.72 mmol) ethyl acetate (50.0 mL). The above reaction mixture was added to a solution of di-tert-butylazodicarboxylate (0.94 g, 4.07 mmol) in ethyl acetate (45.0 mL) over 5 minutes. N₂After mixing underneath for 10 minutes, the reaction system was quenched with saturated aqueous ammonium chloride solution (60.0 mL). The organic layer was separated, washed with 1.0N hydrochloric acid solution (3 x 100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (10-50%) to give the title compound (0.98 g, yield: 78%).¹1 H NMR (300MHz, CDCl₃) δ7.40-7.25 (m, 10H), 7.02, (s, 1H), 6.96 (s, 1H), 6.79 (d, 1H), 6.50 (s, 1H), 6.36 (d, 1H), 6.08 ( s, 1H), 5.86 (d, 2H), 4.82 (ABq, 2H), 2.20 (s, 3H).

Example 1.28 5'-Methylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="51"><img file="JP5118627B2_D0046.tif" /></chemistry> Stainless steel hydrogenated vessels, in order, 1'-(diphenylmethyl) -5'-methylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indol]- It was charged with 2'(1'H) -one (0.90 g, 1.95 mmol), glacial acetic acid (50.0 mL) and palladium hydroxide (0.10 g, 1.35 mmol, 20 wt% on carbon). The container is flushed with nitrogen, sealed, heated to 60 ° C and 120 psi H.₂I put it down. After stirring after 4 days, the reaction mixture was diluted with ethyl acetate and passed through a bed of Celite. The filtrate was washed with water (6 x 100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (40-50%) to give the title compound (0.25 g, 43%). Melting point: 269 ~ 271 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.45 (s, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.76 (d, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 5.87 (d, 2H) ), 4.64 (ABq, 2H), 2.17 (s, 3H); MS (ES +) m / z 296.28 (M + 1).

Example 1.29 5'-Methyl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="52"><img file="JP5118627B2_D0047.tif" /></chemistry> In a suspension of sodium hydroxide (0.03 g, 0.63 mmol, 60% dispersion in mineral oil) in N, N-dimethylformamide (5.00 mL), 5'-methylspiro [flo [2,3-f] [1] , 3] Benzodioxol-7,3'-indole] -2'(1'H) -one (0.10 g, 0.33 mmol) in N, N-dimethylformamide (5.00 mL) slowly at 0 ° C. added. After stirring at 0 ° C. for 15 minutes, a solution of 2- (bromomethyl) -5- (trifluoromethyl) furan (0.11 g, 0.49 mmol) in N, N-dimethylformamide (40.0 mL) was added. The resulting mixture was stirred at ambient temperature for 4 hours and quenched with water (20.0 mL). The mixture was extracted with ethyl acetate (3 x 25.0 mL). The combined organic layers were washed with water (50.0 mL) and brine (2 x 25.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate / hexane (15-50%) to give the title compound (0.11 g, yield: 77%). Melting point: 96-98 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 6.38 (d, 1H), 6.11 (s, 1H) ), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80 (ABq, 2H), 2.29 (s, 3H); MS (ES +) m / z 444.2 (M + 1).

Example 1.30 6-Bromo-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="53"><img file="JP5118627B2_D0048.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3- (4-Bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1-pentyl-1,3-dihydro-2H-indol-2-one replaced by 3-dihydro-2H-indole-2-one A non-critical modification using on gave the title compound as a colorless solid in a yield of 82%.¹1 H NMR (300MHz, CDCl₃) δ7.33 (td, 1H), 7.15-7.14 (m, 2H), 7.04 (dd, 1H), 6.96-6.90 (m, 2H), 6.56 (d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.6,161.6,142.5,132.1,129.1,128.4,124.4,123.9,123.3,122.8,114.1,108.8,80.4,57.6,40.4,29.0,27.1,22.3,14.0; MS (ES +) m / z 386.3 (M +) 1), 388.3 (M + 1).

Example 1.31 5-Bromo-1'-(diphenylmethyl) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="54"><img file="JP5118627B2_D0049.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (5-Bromo-2-hydroxyphenyl) -1- (diphenylmethyl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole replaced by 3-dihydro-2H-indole-2-one A non-critical modification using -2-one gave the title compound as a white solid (72%).¹1 H NMR (300MHz, CDCl₃) δ7.43-7.25 (m, 11H), 7.14-6.93 (m, 4H), 6.83 (d, 1H), 6.71 (d, 1H), 6.52 (d, 1H), 5.0 (d, 1H), 4.73 (d, 1H); MS (ES +) m / z 484.4 (M + 1), 482.4 (M + 1).

Example 1.32 2-Methyl-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzothiazole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="55"><img file="JP5118627B2_D0050.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, Replaced with 3-dihydro-2H-indole-2-one 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1, A non-critical modification using 3-dihydro-2H-indol-2-one gave the title compound as a white solid (50%). Melting point: 105 ~ 107 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.59 (d, 1H), 7.28 (dt, 1H), 7.02-6.92 (m, 2H), 5.02 (d, 1H), 4.77 (d, 1H), 4.01 (m, 1H), 3.64 (m) , 1H), 2.54 (s, 3H), 1.92-1.71 (m, 2H), 1.54-1.34 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.7,169.2,160.2,149.2,142.7,138.3,132.7,129.0,128.6,123.5,122.7,122.1,120.2,108.6,108.3,80.1,58.1,40.7,29.1,27.0,22.5,20.2,14.1; MS (ES + ) m / z 379.5 (M + 1).

Example 1.33 5-Bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="56"><img file="JP5118627B2_D0051.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, Replaced with 3-dihydro-2H-indole-2-one 3- (hydroxymethyl) -3- (5-hydroxy-2-methyl-1,3-benzothiazole-6-yl) -1-pentyl-1, A non-critical modification using 3-dihydro-2H-indol-2-one gave the title compound as a white solid (30%). Melting point: 143 ~ 145 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.35-7.27 (m, 2H), 7.17-6.98 (m, 3H), 6.84 (d, 1H), 6.78-6.73 (m, 2H), 6.40 (d, 1H), 5.07-4.87 (m, 3H), 4.69 (d, 1H); MS (ES +) m / z 464.2 (M + 1), 466.2 (M + 1).

Example 1.34 5-Bromospiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="57"><img file="JP5118627B2_D0052.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Use 3- (5-bromo-2-hydroxyphenyl) -3- (hydroxymethyl) -1,3-dihydro-2H-indole-2-one instead of 3-dihydro-2H-indole-2-one Subcritical modifications were made to give the title compound as a white solid (25%). Melting point: 225 ~ 228 ° C;¹1 H NMR (300MHz, CDCl₃) δ10.65 (s, 1H), 7.35 (dd, 1H), 7.24 (dt, 1H), 7.11 (d, 1H), 6.99-6.88 (m, 3H), 6.83 (d, 1H), 4.81 (d , 1H), 4.69 (d, 1H); MS (ES +) m / z 316.1 (M + 1), 318.1 (M + 1).

Example 1.35 Synthesis of 1'-(diphenylmethyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="58"><img file="JP5118627B2_D0053.tif" /></chemistry> 1- (Diphenylmethyl) -3- (Hydroxymethyl) -3- [2-Hydroxy-4- (trifluoromethoxy) phenyl] -1,3-dihydro-2H-indole-2-one (17.3 mmol) anhydrous Triphenylphosphine (6.34 g, 24.2 mmol) was added to a solution of THF (200 mL), then diethylazodicarboxylate (4.39 mL, 24.2 mmol) was added at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride (40.0 mL). The aqueous mixture was 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 vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/4) to give the title compound (6.00 g, 71%).¹1 H NMR (300MHz, CDCl₃) δ7.45-6.51 (m, 18H), 5.08 (d, 1H), 4.81 (d, 1H); MS (ES +) m / z 488 (M + 1).

Example 1.36 Synthesis of 6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="59"><img file="JP5118627B2_D0054.tif" /></chemistry> 1'-(diphenylmethyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (6.00 g, 12.3 mmol) methanol (100 mL) Palladium on 10% carbon (0.65 g, 0.62 mmol) was added to a suspension of acetic acid (1.00 mL) and the mixture was hydrogenated at an ambient temperature of 130 psi under hydrogen for 5 days. The reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under vacuum. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexanes to give the title compound (2.95 g, 75%) as a white solid. Melting point: 180 ~ 182 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.19 (s, 1H), 7.29-6.92 (m., 4H), 6.86-6.64 (m, 3H), 5.03 (d, 1H), 4.75 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ179.9,161.9,150.6,132.3,129.4,127.4,125.6,124.3,124.2,123.8,120.5,114.1,110.7,104.3,80.8,58.2; MS (ES +) m / z 322 (M + 1).

Example 1.37 Ethyl (4'-Bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H )-Indole) Acetate synthesis

<chemistry num="60"><img file="JP5118627B2_D0055.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-Dihydro-2H-Indole-2-one replaced with ethyl [4-bromo-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2 A non-critical modification using -oxo-2,3-dihydro-1H-indole-1-yl] acetate gave the title compound as a colorless individual (41%). MS (ES +) m / z 445.5 (M + 1).

Example 1.38 Ethyl (4'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H )-Indole) Acetate synthesis

<chemistry num="61"><img file="JP5118627B2_D0056.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-Dihydro-2H-Indole-2-one replaced with ethyl [4-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2 A non-critical modification using -oxo-2,3-dihydro-1H-indole-1-yl] acetate was carried out to give the title compound as a colorless solid in a yield of 63%. MS (ES +) m / z 400.8 (M + 1).

Example 1.39 Ethyl (4'-bromo-6,6-dimethyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole]- Synthesis of 1'(2'H) -yl) acetate

<chemistry num="62"><img file="JP5118627B2_D0057.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3-Dihydro-2H-Indole-2-one replaced with ethyl [4-bromo-3- (6-hydroxy-2,2-dimethyl-2,3-dihydro1-benzofuran-5-yl) -3- ( A non-critical modification using hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate gave the title compound in a yield of 52%.¹1 H NMR (300MHz, CDCl₃) δ7.22-7.10 (m, 2H), 6.70 (d, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 5.0 (d, 1H); 4.86 (d, 1H), 4.63 (d , 1H), 4.35 (d, 1H), 4.28-4.18 (m, 2H), 2.79 (s, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.28 (t, 3H); MS ( ES +) m / z 472.5 (M + 1), 474.5 (M + 1).

Example 1.40 Synthesis of Ethyl (4'-Bromo-5,6-Difluoro-2'-Oxospiro [1-Benzofuran-3,3'-Indole] -1'(2'H) -Il) Acetate

<chemistry num="63"><img file="JP5118627B2_D0058.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one and ethyl [4-bromo-3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3- A non-critical modification using dihydro-1H-indole-1-yl] acetate gave the title compound in 81% yield. MS (ES +) m / z 438.4 (M + 1), 440.4 (M + 1).

Example 1.41 Ethyl (5'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H )-Indole) Acetate synthesis

<chemistry num="64"><img file="JP5118627B2_D0059.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-Dihydro-2H-Indole-2-one replaced with ethyl [5-chloro-3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl) -2 Non-critical modifications were made using -oxo-2,3-dihydro-1H-indole-1-yl] acetate to give the title compound as a colorless solid in 90% yield. MS (ES +) m / z 400.8 (M + 1).

Example 1.42 7'-Fluorospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="65"><img file="JP5118627B2_D0060.tif" /></chemistry> 7-Fluoro-3- (6-hydroxy-1,3-benzodioxole-5-yl) -1,3-dihydro-2H-indole-2-one (2.00 g, 7.00 mmol) and paraformaldehyde (2.10) A solution of g, 61.0 mmol) in THF (50 mL) was degassed by bubbling argon for 1 hour, then lithium diisopropylamide (48.8 mL, freshly made 0.50 M solution, 25 mmol) was added slowly at -78 ° C. .. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonia chloride (50.0 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in acetic anhydride (50 mL), then tributylphosphine (2.10 mL, 8.00 mmol) and di-tert-butylazodicarboxylate (1.90 g, 8.00 mmol) were added at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride (30.0 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in methanol (70.0 mL) and saturated sodium hydrogen carbonate solution (30.0 mL) was added. The resulting mixture was refluxed at 100 ° C. for 1 hour. After cooling to ambient temperature, the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (0.27 g, 17%).¹1 H NMR (300MHz, DMSO-d₆) δ11.06 (s, 1H), 7.17-7.08 (m, 1H), 7.00-6.88 (m, 2H), 6.64 (s, 1H), 6.33 (s, 1H), 5.92-5.85 (m, 2H) , 4.74 (d, 1H), 4.62 (d, 1H).

Example 1.43 Synthesis of methyl (6-chloro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetate

<chemistry num="66"><img file="JP5118627B2_D0061.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, Methyl by replacing 3-dihydro-2H-indole-2-one [3- (4-chloro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole- A non-critical modification using 1-yl] acetate gave the title compound as a colorless solid in a yield of 74%.¹1 H NMR (300MHz, CDCl₃) δ7.29 (dt, 1H), 7.14 (dd, 1H), 7.06 (t, 1H), 6.95 (d, 1H), 6.81-6.74 (m, 3H), 5.03 (d, 1H), 4.74 (d , 1H), 4.65 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS (ES +) m / z 344.5 (M + 1), 346.5 (M + 1).

Example 1.44 Synthesis of Ethyl (5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetate

<chemistry num="67"><img file="JP5118627B2_D0062.tif" /></chemistry> Following the procedure described in Example 1.22, 4,7-dichloro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-pentyl-1, 3-Dihydro-2H-Indole-2-one replaced with ethyl [3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H- A non-critical modification using indole-1-yl] acetate gave the title compound as a pale yellow oil in a yield of 46%.¹1 H NMR (300MHz, CDCl₃) δ7.31 (dt, 1H), 7.16 (dd, 1H), 7.08 (dt, 1H), 6.81-6.71 (m, 2H), 6.67 (dd, 1H), 4.98 (d, 1H), 4.74 (d , 1H), 4.64 (d, 1H), 4.37 (d, 4.24 (q, 7.1Hz), 1.28 (t, 3H); MS (ES +) m / z 360.5 (M + 1).

Example 1.45 Synthesis of Ethyl (2'-oxo-6,7-dihydro-5H-Spiro [Indeno [5,6-b] Fran-3,3'-Indole] -1'(2'H) -Il) Acetate

<chemistry num="68"><img file="JP5118627B2_D0063.tif" /></chemistry> Ethyl [3- (6-Hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indole-1-yl] acetate Triphenylphosphine (1.43 g, 5.46 mmol) and diethyl azodicarboxylate (0.95 g, 5.46 mmol) were added to a solution of (4.20 mmol) anhydrous THF (60.0 mL) at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with saturated ammonia chloride (20.0 mL). The mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/4) to give the title compound (0.25 g, 16% in 3 steps).¹1 H NMR (300MHz, CDCl₃) δ7.29 (td, 1H), 7.22-7.17 (m, 1H), 7.07 (t, 1H), 6.81 (s, 1H), 6.78 (d, 1H), 6.65 (s, 1H), 4.95 (d , 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.42 (d, 1H), 4.24 (q, 2H), 2.84 (t, 2H), 2.73-2.65 (m, 2H), 2.10- 1.95 (m, 2H), 1.29 (t, 3H); MS (ES +) m / z 364 (M + 1).

Example 1.46 Synthesis of Ethyl (2-oxo-5', 6', 7', 8'-Tetrahydrospiro [Indole-3,3'-Naft [2,3-b] Franc] -1 (2H) -Il) Acetate

<chemistry num="69"><img file="JP5118627B2_D0064.tif" /></chemistry> Following the procedure described in Example 1.45, ethyl [3- (6-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro -1H-Indole-1-yl] Replaced with acetate and ethyl [3- (hydroxymethyl) -3- (3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl) -2-oxo-2 A non-critical modification using a, 3-dihydro-1H-indole-1-yl] acetate gave the title compound (24% in 3 steps).¹1 H NMR (300MHz, CDCl₃) δ7.29 (td, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.79 (d, 1H), 6.66 (s, 1H), 6.51 (s, 1H),), 4.91 (d , 1H), 4.67 (d, 1H), 4.52 (ABq, 2H), 4.24 (q, 2H), 2.77-2.51 (m, 4H), 1.77-1.64 (m, 4H), 1.29 (t, 3H); MS (ES +) m / z 378 (M + 1).

Example 1.47 Synthesis of Ethyl (4'-Bromo-5,6-Difluoro-2'-Oxospiro [1-Benzofuran-3,3'-Indole] -1'(2'H) -Il) Acetate

<chemistry num="70"><img file="JP5118627B2_D0065.tif" /></chemistry> Following the procedure described in Example 1.45, ethyl [3- (6-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro Replaced with -1H-indole-1-yl] acetate and ethyl [4-bromo-3- (4,5-difluoro-2-hydroxyphenyl) -3- (hydroxymethyl) -2-oxo-2,3-dihydro A non-critical modification using -1H-indole-1-yl] acetate gave the title compound (41%). Melting point: 133 ~ 134 ° C¹1 H NMR (300MHz, CDCl₃) δ7.26-7.15 (m, 3H), 6.78-6.58 (m, 2H), 5.08 (d, 1H), 4.91 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.24 (q, 2H), 1.29 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.5,166.8,157.1,143.7,130.7,129.0,127.8,120.0,111.8,111.6,107.5,99.8,99.5,62.2,59.1,41.7,14.1; MS (ES +) m / z 438 (M + 1), 440 (M + 1), 460 (M + 23), 462 (M + 23).

Example 1.48 1'-(diphenylmethyl) -6,7-dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole] -2'(1'H) -on Synthetic

<chemistry num="71"><img file="JP5118627B2_D0066.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 1- (diphenylmethyl) -3- (5-hydroxy-2,3-dihydro-1-benzofuran-6-yl) -3- (hydroxymethyl)- A non-critical modification using 1,3-dihydro-2H-indole-2-one gave the title compound (43%). MS (ES +) m / z 446.4 (M + 1).

Example 1.49 6,7-Dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole] -2'(1'H) -on synthesis

<chemistry num="72"><img file="JP5118627B2_D0067.tif" /></chemistry> 1'-(diphenylmethyl) -6,7-dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole] -2'(1'H) -on ( A mixture of 0.29 g, 0.65 mmol) and palladium hydroxide (0.10 g, 20% on activated carbon) was hydrogenated in acetic acid (20.0 mL) at a hydrogen normal pressure of 60 ° C. for 20 hours. The reaction mixture was filtered through Celite and washed with acetone (50.0 mL). The filtrate was concentrated to dryness under vacuum to give the title compound (0.13 g, 69%). MS (ES +) m / z 280.2 (M + 1).

Example 1.50 1'-(diphenylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on Synthetic

<chemistry num="73"><img file="JP5118627B2_D0068.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 1- (diphenylmethyl) -3- (6-hydroxy-2,3-dihydro-1-benzofuran-5-yl) -3- (hydroxymethyl)- A non-critical modification using 1,3-dihydro-2H-indole-2-one gave the title compound as a white solid (51%). MS (ES +) m / z 446.3 (M + 1).

Example 1.51 5,6-Dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on synthesis

<chemistry num="74"><img file="JP5118627B2_D0069.tif" /></chemistry> Following the procedure described in Example 1.49, 1'-(diphenylmethyl) -6,7-dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole]- 2'(1'H)-Replace with on 1'-(diphenylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -2'(1'H)-A non-critical modification using on gave the title compound (68%). Melting point: 208-210 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.53 (s, 1H), 7.39-6.76 (m, 4H), 6.45 (s, 1H), 6.35 (s, 1H), 4.68 (ABq, 2H), 4.45 (t, 2H), 2.92 (t) , 2H); MS (ES +) m / z 280.2 (M + 1).

Example 1.52 Ethyl (2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -yl) acetate Synthesis of

<chemistry num="75"><img file="JP5118627B2_D0070.tif" /></chemistry> 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] 2'(1'H) -on (0.28 g, 1.00 mmol), ethyl 2 -A mixture of bromoacetate (0.17 g, 1.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) was stirred in acetone (20.0 mL) for 5 hours with reflux. The mixture was cooled to ambient temperature and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to column chromatography to give the title compound (0.23 g, 63%) as a white solid. MS (ES +) m / z 366.4 (M + 1).

Example 1.53 4'-Methoxy-1'{[5- (trifluoromethyl) -2-furyl] methyl} spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H)-On synthesis

<chemistry num="76"><img file="JP5118627B2_D0071.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, 3- (6-Hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -4-methoxy-1-{[[ A non-critical modification using 5- (trifluoromethyl) -2-furyl] methyl} -1.3-dihydro-2H-indole-2-one gave the title compound as a white solid (33%). Melting point: 149 ~ 153 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.32-7.24 (m, 1H), 6.82-6.62 (m, 3H), 6.46 (s, 1H), 6.40 (d, 1H), 6.08 (s, 1H), 5.87 (ABq, 2H), 4.92 (ABq, 2H), 4.82 (ABq, 2H), 3.70 (s, 3H); MS (ES +) m / z 460.3 (M + 1).

Example 1.54 7'-Fluoro-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="77"><img file="JP5118627B2_D0072.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one, 7-fluoro-3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1-{[ A non-critical modification using 5- (trifluoromethyl) -2-furyl] methyl} -1,3-dihydro-2H-indole-2-one gave the title compound as a white solid (32%). .. Melting point: 116 ~ 118 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.36-6.88 (m, 4H), 6.67 (s, 1H), 6.62 (d, 1H), 6.19 (s, 1H), 5.90 (d, 2H), 5.07 (q, 2H), 4.75 (dd , 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,155.8,154.1,149.1,148.8,145.6,142.4,140.9,140.3,139.2,139.2,135.2,135.2,128.5,128.4,124.9,128.4,124.9,124.8,124.7,121.2,120.4,120.4,119.8,117.6 , 117.2,117.0,114.5,114.5,109.5,103.2,102.0,93.8,80.1,58.3,58.2,39.0,38.9; MS (ES +) m / z 448.3 (M + 1).

Example 2 (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Synthesis of acetic acid

<chemistry num="78"><img file="JP5118627B2_D0073.tif" /></chemistry> Ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) acetate (10.5 g, 24.5 mmol) Lithium hydroxide monohydrate (3.98 g, 95.0 mmol) was added to a suspension of THF (200 mL) and water (100 mL) in) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and at ambient temperature for 17 hours. The mixture was neutralized with 4M HCl (15.0 mL). The residue obtained by removing the solvent was acidified to pH 3 by adding 4M HCl (6.2 mL). The solid was filtered, washed with water and hexane and dried under reduced pressure to give the title compound (8.48 g, 87%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.32-7.06 (m, 4H), 6.79 (d, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 5.84 (m, 2H), 4.92 (m, 1H), 4.69-4.63 (m, 2H), 4.45 (m, 1H);¹³C NMR (75MHz, CDCl₃) δ177.8,171.8,155.8,149.0,142.4,141.2,132.0,129.0,124.1,124.0,119.2,108.3,103.4,101.5,93.5,80.2,58.2,41.1; MS (ES-) m / z 338.2 (M-1) ).

Example 2.1 (2'-oxo-6,7-dihydro-5H-spiro [indeno [5,6-b] furan-3,3'-indole] -1'(2'H) -yl) acetic acid synthesis

<chemistry num="79"><img file="JP5118627B2_D0074.tif" /></chemistry> Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (2'-oxo-6,7-dihydro-5H-spiro [indeno [5,6-b] furan-3,3'-indole] -1'(2'H)- A non-critical modification using yl) acetate gave the title compound in 74% yield. MS (ES-) m / z 354 (M-1).

Example 2.2 (4'-Chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -Indole) Synthesis of acetic acid

<chemistry num="80"><img file="JP5118627B2_D0075.tif" /></chemistry> Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (4'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] A non-critical modification using -1'(2'H) -yl) acetate gave the title compound as a colorless solid in 92% yield. Melting point: 228 ~ 229 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.26-7.21 (m, 1H), 7.03 (dd, 1H), 6.71 (dd, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.8,170.9,162.1,162.1,143.1,131.7,130.0,128.6,124.7,119.6,118.7,117.0,106.7,92.8,77.2,72.3,58.1,41.2,28.9; MS (ES-) m / z 370.4 (M) -1).

Example 2.3 (4'-Bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -Il) Synthesis of acetic acid

<chemistry num="81"><img file="JP5118627B2_D0076.tif" /></chemistry> Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (4'-bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] A non-critical modification using -1'(2'H) -yl) acetate gave the title compound as a colorless solid (98%). MS (ES-) m / z 415.2 (M-1).

Example 2.4 (5'-Chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -Indole) Synthesis of acetic acid

<chemistry num="82"><img file="JP5118627B2_D0077.tif" /></chemistry> Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (5'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] A non-critical modification was made using -1'(2'H) -yl) acetate to give the title compound as a colorless solid in 98% yield.¹1 H NMR (300MHz, CDCl₃) δ7.27-7.25 (m, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.8,170.9,162.1,162.1,143.1,131.7,130.0,128.6,124.7,119.6,118.7,117.0,106.7,92.8,77.2,72.3,58.1,41.2,28.9; MS (ES-) m / z 370.4 (M) -1).

Example 2.5 (2-oxo-5', 6', 7', 8'-tetrahydrospiro [indole-3,3'-naphtho [2,3-b] furan] -1 (2H) -yl) acetic acid synthesis

<chemistry num="83"><img file="JP5118627B2_D0078.tif" /></chemistry> Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (2-oxo-5', 6', 7', 8'-tetrahydrospiro [indole-3,3'-naphtho [2,3-b] furan] -1 (2H) A non-critical modification using -yl) acetate gave the title compound (99%). MS (ES-) m / z 348 (M-1).

Example 2.6 (2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -yl) of acetic acid Synthetic

<chemistry num="84"><img file="JP5118627B2_D0079.tif" /></chemistry> Ethyl (2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H) -yl) acetate A mixture of (0.23 g, 0.63 mmol) and LiOH (0.10 g, 4.20 mmol) in MeOH / H₂The mixture was stirred in O (1 / 1,20.0 mL) at an ambient temperature for 20 hours. The mixture was acidified with 0.1 M HCl to pH 2-3. The solid was collected by filtration and dried to give the title compound (0.15 g, 70%). MS (ES-) m / z 336.3 (M-1).

Example 3 N- (4-Chlorobenzyl) -2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -Indole synthesis of acetamide

<chemistry num="85"><img file="JP5118627B2_D0080.tif" /></chemistry> A. Isobutyl (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) acetylcarbonate stock solution Preparation (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -yl) acetic acid (0.30 g, 0.88 mmol) N-Methylmorpholine (0.09 g, 0.88 mmol) and isobutyl chloroformate (0.12 g, 0.88 mmol) were added dropwise to a solution of dichloromethane (12.5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1.5 hours and at ambient temperature for 3 hours. This mixture was used as a mixed anhydride for amide formation in the next step.

BN- (4-Chlorobenzyl) -2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -Indole synthesis of acetamide A dichloromethane solution of 4-chlorobenzylamine (0.35 mL, 0.50 M, 0.18 mmol) was added to the mixed anhydride stock solution (2.50 mL, 0.18 mmol) at an ambient temperature. The reaction mixture was stirred at ambient temperature for 23 hours and washed with saturated aqueous sodium carbonate solution and water. After removing the solvent, diethyl ether was added and the precipitate was collected by filtration to give the title compound (0.04 g, 46%).¹1 H NMR (300MHz, CDCl₃) δ7.39-6.97 (m, 8H), 6.49 (s, 1H), 6.29 (br, 1H), 6.01 (s, 1H), 5.85 (m, 2H), 4.87 (m, 1H), 4.65 (m , 1H), 4.53-4.29 (m, 4H); MS (ES +), m / z 485.2 (M + 23).

Example 3.1 The compounds listed in the table below were synthesized using conditions similar to those described in Example 3. The compound numbers listed below do not correspond to the compound numbers assigned in the general reaction scheme above.

<tables num="1-1"><img file="JP5118627B2_D0081.tif" /></tables>

<tables num="1-2"><img file="JP5118627B2_D0082.tif" /></tables>

<tables num="1-3"><img file="JP5118627B2_D0083.tif" /></tables>

<tables num="1-4"><img file="JP5118627B2_D0084.tif" /></tables>

<tables num="1-5"><img file="JP5118627B2_D0085.tif" /></tables>

<tables num="1-6"><img file="JP5118627B2_D0086.tif" /></tables>

<tables num="1-7"><img file="JP5118627B2_D0087.tif" /></tables> Example 3.2 N- (2-fluorophenyl) -2- (2'-oxo-6,7-dihydro 5H-spiro [indeno [5,6-b] furan-3,3'-indole] -1'(2'H )-Indole) Synthesis of acetamide

<chemistry num="86"><img file="JP5118627B2_D0088.tif" /></chemistry> 2'-oxo-6,7-dihydro5H-spiro [indeno [5,6-b] furan-3,3'-indole] -1'(2'H) -yl) acetic acid (0.18g, 0.54 mmol) Oxalyl chloride (0.09 mL, 1.07 mmol) was added to a solution of chloroform (5.00 mL) with 1 drop of DMF. The mixture was refluxed for 2 hours and evaporated to dryness under vacuum. Et to the above residue₃N (0.66 mL, 4.72 mmol), 2-fluoroaniline (0.10 mL, 1.00 mmol) and THF (5.00 mL) were added. The reaction mixture was stirred at ambient temperature overnight and evaporated to dryness. The residue was subjected to a column chromatograph (25% ethyl acetate in hexane) to give the title compound (0.04 g, 17%).¹1 H NMR (300MHz, CDCl₃) δ8.26 (t, 1H), 8.05-7.90 (br, 1H), 7.33 (td, 1H), 7.26-6.96 (m, 6H), 6.83 (s, 1H), 6.61 (s, 1H), 4.98 (d, 1H), 4.73 (d, 1H), 4.71 (d, 1H), 4.52 (d, 1H), 2.85 (t, 2H), 2.69 (t, 2H), 2.12-1.94 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.6,165.0,159.8,146.9,141.5,137.5,132.5,129.2,126.3,125.2,124.8,124.4,124.3,121.9,118.9,115.2,114.9,109.0,106.8,79.9,58.2,45.3,33.2,32.0,26.1 ; MS (ES +) m / z 429 (M + 1), 451 (M + 23).

Example 3.3 N- (2-fluorophenyl) -2- (2-oxo-5', 6', 7', 8'-tetrahydrospiro [indole-3,3'-naphtho [2,3-b] furan] -1 Synthesis of (2H) -yl) acetamide

<chemistry num="87"><img file="JP5118627B2_D0089.tif" /></chemistry> Following the procedure described in Example 3.2, 2'-oxo-6,7-dihydro-5H-spiro [indeno [5,6-b] furan-3,3'-indole] -1'(2'H) -Il) Replaced with acetic acid (2-oxo-5', 6', 7', 8'-tetrahydrospiro [indole-3,3'-naphtho [2,3-b] furan] -1 (2H)- A non-critical modification using i. Acetic acid was performed to give the title compound in 5% yield.¹1 H NMR (300MHz, CDCl₃) δ8.27 (t, 1H), 8.04-7.90 (br, 1H), 7.33 (td, 1H), 7.26-6.97 (m, 6H), 6.69 (s, 1H), 6.48 (s, 1H), 4.94 (d, 1H), 4.69 (d, 1H), 4.71 (d, 1H), 4.52 (d, 1H), 2.81-2.45 (m, 4H), 1.82-1.60 (m, 4H); MS (ES +) m / z 443 (M + 1), 465 (M + 23).

Example 3.4 2- (4'-Bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide Synthesis of

<chemistry num="88"><img file="JP5118627B2_D0090.tif" /></chemistry> A. Synthesis of (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetic acid Following the procedure described in Example 2, ethyl (2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -Use ethyl (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetate in place of -yl) acetate The title compound was obtained in 100% yield. The product was used directly in the next step.

B.2-(4'-Bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluoro Synthesis of phenyl) acetamide (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetic acid (0.24 g, 0.59 mmol) and oxalyl chloride To a solution of (0.15 mL, 1.76 mmol) in toluene (7.00 mL) was added 1 drop of DMF and the resulting mixture was stirred at ambient temperature overnight. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2-fluoroaniline (0.18 mL, 1.89 mmol) was added at ambient temperature. The mixture was stirred at ambient temperature for 1 hour. Further dichloromethane (100 mL) was added. The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (0.23 g, 76%).¹1 H NMR (300MHz, CDCl₃) δ8.20 (t, 1H), 7.80 (br, 1H), 7.27-7.17 (m, 2H), 7.16-7.03 (m, 3H), 6.97-6.88 (m, 1H), 6.78-6.60 (m, 2H), 5.08 (d, 1H), 4.93 (d, 1H), 4.68 (d, 1H), 4.49 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ177.1,163.9,157.8,143.6,131.0,128.8,128.1,124.7,121.8,120.0,115.0,111.6,108.1,99.8,77.5,59.2,44.7; MS (ES +) m / z 503.4 (M + 1), 505.4 (M + 1).

Example 3.5 2- (4'-bromo-6,6-dimethyl-2'-oxo-5,6-Jihidorosupi b [benzo [1,2-b: 5,4-b '] difuran-3,3'-indol] - Synthesis of 1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="89"><img file="JP5118627B2_D0091.tif" /></chemistry> A. (4'-Bromo-6,6-dimethyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] Synthesis of -1'(2'H) -yl) acetic acid Following the procedure described in Example 2, ethyl (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Replace with acetate and ethyl (4'-bromo-6,6-dimethyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 A non-critical modification using, 3'-indole] -1'(2'H) -yl) acetate was performed to give the title compound. The product was used directly in the next step.

B.2-(4'-Bromo-6,6-dimethyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'- Indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide synthesis Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Replaced with acetic acid (4'-bromo-6,6-dimethyl2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -1'(2'H) -yl) A non-critical modification using acetic acid was performed to give the title compound (61% in 2 steps). MS (ES +) m / z 537.4 (M + 1), 539.4 (M + 1).

Example 3.6 2- (4'-Chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2') Synthesis of H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="90"><img file="JP5118627B2_D0092.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Replaced with acetic acid (4'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'( A non-critical modification using 2'H) -yl) acetic acid gave the title compound as a colorless solid (69%). Melting point: 243 ~ 245 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.19 (t, 1H), 7.96 (s, 1H), 7.21-7.27 (m, 1H), 7.10-7.02 (m, 4H), 6.88 (d, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 4.96 (dd, 2H), 4.70 (d, 1H), 4.57-4.53 (m, 3H), 2.97 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ178.2,164.4,162.2,162.1,143.2,131.6,130.2,128.5,125.2,125.1,124.9,124.6,121.9,119.7,118.6,116.8,115.1,114.8,107.3,92.9,77.2,72.4,58.2,44.9,28.9 ; MS (ES +) m / z 465.5 (M + 1).

Example 3.7 2- (5'-Chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2' Synthesis of H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="91"><img file="JP5118627B2_D0093.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Replaced with acetic acid (5'-chloro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'( A non-critical modification using 2'H) -yl) acetic acid gave the title compound as a colorless solid (91%). Melting point: 229 ~ 230 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.21 (t, 1H), 7.88 (s, 1H), 7.28-7.25 (m, 1H), 7.18 (d, 1H), 7.13-7.04 (m, 3H), 6.90 (d, 1H), 6.57 (s, 1H), 6.40 (s, 1H), 4.95 (d, 1H), 4.70-4.66 (m, 2H), 4.56-4.43 (m, 3H), 2.99 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.8,170.9,162.1,162.1,143.1,131.7,130.0,128.6,124.7,119.6,118.7,117.0,106.7,92.8,77.2,72.3,58.1,41.2,28.9; MS (ES +) m / z 465.4 (M +) 1).

Example 3.8 Synthesis of 2- (6-chloro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="92"><img file="JP5118627B2_D0094.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Substitute acetic acid (6-chloro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) with acetic acid to make a non-critical modification to the title compound Obtained as a white solid (10%). Melting point: 70 ~ 75 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.21 (t, 1H), 7.99 (br, 1H), 7.32 (dt, 1H), 7.19-6.93 (m, 7H), 6.80 (dd, 1H), 6.73 (d, 1H), 5.01 (d , 1H), 4.75 (d, 1H), 4.69 (d, 1H), 4.50 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ177.7,164.6,161.4,141.4,135.5,131.6,129.4,127.3,125.2,125.0,124.7,124.6,124.4,124.3,124.1,121.9,121.8,115.1,114.8,111.3,109.0,80.3,57.6,44.9; MS (ES +) m / z 423.4 (M + 1).

Example 3.9 Synthesis of 2- (5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="93"><img file="JP5118627B2_D0095.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetic acid Substituted with (5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetic acid to make a non-critical modification and the title compound Obtained as a white solid (35%). Melting point: 97 ~ 100 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.20-8.10 (m, 2H), 7.31 (dt, 1H), 7.19-7.00 (m, 5H), 6.95 (d, 1H), 6.77-6.40 (m, 2H), 5.02 (d, 1H) , 4.74 (d, 1H), 4.69 (d, 1H), 4.51 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ177.4,164.3,141.4,131.2,129.7,125.6,125.5,125.3,125.2,125.1,124.7,124.4,124.1,121.8,115.1,114.9,112.1,111.8,109.1,100.3,100.0,80.7,57.9; MS (ES + ) m / z 425.5 (M + 1).

Example 3.10 Synthesis of 2- (5-bromo-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="94"><img file="JP5118627B2_D0096.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Sub-critical changes were made using acetic acid (5-bromo-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetic acid to replace the title compound. Obtained as a pale yellow solid (94%). Melting point: 100 ~ 103 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.26 (dd, 1H), 7.92 (br, 1H), 7.39-7.31 (m, 2H), 7.22-7.01 (m, 6H), 6.91 (d, 1H), 6.87 (d, 1H), 5.02 (d, 1H), 4.76 (d, 1H), 4.67 (d, 1H), 4.57 (d, 1H); MS (ES +) m / z 467.3 (M + 1).

Example 3.11 2- (4'-Fluoro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2') Synthesis of H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="95"><img file="JP5118627B2_D0097.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Replaced with acetic acid (4'-fluoro-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'( A non-critical modification using 2'H) -yl) acetic acid was performed to give the title compound.¹1 H NMR (300MHz, CDCl₃) δ8.20 (t, 1H), 7.91 (s, 1H), 7.29 (dt, 1H), 7.13-7.04 (m, 3H), 6.81-6.75 (m, 2H), 6.61 (s, 1H), 6.39 (s, 1H), 4.95-4.87 (m, 2H), 4.70 (d, 1H), 4.55-4.44 (m, 3H), 2.98 (t, 2H); MS (ES +) m / z 449.5 (M + 1) ) Example 3.12 2- (4'-Bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2') Synthesis of H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="96"><img file="JP5118627B2_D0098.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl). Replaced with acetic acid (4'-bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'( A non-critical modification using 2'H) -yl) acetic acid gave the title compound as a colorless solid (75%). Melting point: 245 ~ 246 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.20 (t, 1H), 7.90 (s, 1H), 7.20-7.03 (m, 5H), 6.92 (dd, 1H), 6.53 (s, 1H), 6.36 (s, 1H), 5.05 (d , 1H), 4.90 (d, 1H), 4.69 (d, 1H), 4.55-4.43 (m, 3H), 2.97 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ178.3,164.3,162.4,162.2,143.4,130.4,130.0,128.0,125.5,125.2,124.7,121.9,120.0,119.7,118.6,116.7,115.1,114.8,107.8,92.8,77.2,72.4,59.1,44.9,28.9 ; MS (ES +) m / z 509 (M + 1), 511 (M + 1).

Example 3.13 N- (2-fluorophenyl) -2- (2'-oxo-5,6-dihydrospiro] [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1 '(2'H) -yl) acetamide

<chemistry num="97"><img file="JP5118627B2_D0099.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) Replaced with acetic acid (2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H)- Indole) A non-critical modification using acetic acid gave the title compound as a white solid (68%). Melting point: 210 ~ 212 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.18 (s, 1H), 8.17-7.67 (m, 1H), 7.55-6.90 (m, 7H), 6.54 (s, 1H), 6.38 (s, 1H), 4.68 (m, 4H), 4.46 (t, 2H), 2.93 (t, 2H); MS (ES +) m / z 431.4 (M + 1).

Example 3.14 2- (4'-fluoro-7'-methyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole]- Synthesis of 1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="98"><img file="JP5118627B2_D0100.tif" /></chemistry> Following the procedure described in Example 3.4B, (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) Replaced with acetic acid (4'-fluoro-7'-methyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -1'(2'H) -yl) A non-critical modification using acetic acid gave the title compound as a white solid (21%). Melting point: 250 ~ 255 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.23 (s, 1H), 7.99-7.69 (m, 1H), 7.36-7.01 (m, 4H), 6.74 (t, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 5.90 (d, 2H), 4.88 (t, 2H), 4.76 (ABq, 2H), 3.30 (s, 3H); MS (ES +) m / z 463.4 (M + 1).

Example 4 4'-[6- (dimethylamino) pyridine-3-yl] -1'-Pentyl spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2 '(1' H)-On Synthesis

<chemistry num="99"><img file="JP5118627B2_D0101.tif" /></chemistry> In an oven-dried flask, [6- (dimethylamino) pyridine-3-yl] boronic acid (37.0 mg, 0.17 mmol), Pd (PPh)₃)₄It was charged with (13.5 mg, 0.012 mmol) and then flushed with nitrogen. In the flask, 4'-bromo-1'-pentylspiro [Flo [2,3-f] [1,3] benzodioxane-7,3'-indole] -2'(1'H) -on A solution of (50.0 mg, 0.12 mmol) anhydrous dioxane (2.00 mL), followed by 2.0 M Na₂CO₃(0.24 mL) was added. The reaction mixture was heated to reflux for 48 hours. After cooling to the ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (2.00 mL), washed with saturated ammonia chloride (2.00 mL) and concentrated to dryness under reduced pressure. The residue was subjected to column chromatography to give the title compound.¹1 H NMR (300MHz, CDCl₃) δ7.77 (d, 1H), 7.32 (t, 1H), 6.87 (dd, 2H), 6.71 (dd, 1H), 6.23 (d, 1H), 6.20 (s, 1H), 5.88 (d, 2H) ), 4.56 (ABq, 2H), 3.89-3.80 (m, 1H), 3.69-3.59 (m, 1H), 3.05 (s, 6H), 1.78-1.69 (m, 2H), 1.39-1.35 (m, 4H) ), 0.90 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.9,158.3,156.1,148.8,147.3,142.9,142.0,137.8,137.2,129.9,128.9,125.6,122.0,121.0,107.6,104.3,102.5,101.5,93.6,77.8,58.5,40.5,38.2,29.1,27.2 , 22.4,14.0; MS (ES +, m / z) 472.0 (M + 1).

Example 4.1 The compounds listed in the table below were synthesized using conditions similar to those described in Example 4. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="2-1"><img file="JP5118627B2_D0102.tif" /></tables>

<tables num="2-2"><img file="JP5118627B2_D0103.tif" /></tables>

<tables num="2-3"><img file="JP5118627B2_D0104.tif" /></tables>

<tables num="2-4"><img file="JP5118627B2_D0105.tif" /></tables>

<tables num="2-5"><img file="JP5118627B2_D0106.tif" /></tables>

<tables num="2-6"><img file="JP5118627B2_D0107.tif" /></tables>

<tables num="2-7"><img file="JP5118627B2_D0108.tif" /></tables> Example 4.2 2- (5,6-difluoro-2'-oxo-4'-pyrimidine-5-ylspiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2 -Synthesis of fluorophenyl) acetamide

<chemistry num="100"><img file="JP5118627B2_D0109.tif" /></chemistry> 2- (4'-Bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) Pd (PPh) in an anhydrous 1,4-dioxane (5.00 mL) solution of acetamide (0.15 g, 0.30 mmol)₃)₄(0.03 g, 0.03 mmol) was added, and the mixture was stirred at ambient temperature for 10 minutes. Pyrimidine-5-boronic acid (0.06 g, 0.45 mmol) and sodium carbonate (0.90 mL 2M solution, 1.80 mmol) were added. The reaction mixture was refluxed at 120 ° C. for 16 hours and diluted with ethyl acetate (50.0 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was subjected to a column chromatograph (ethyl acetate / hexane, 1/1) to give the title compound (0.13 g, 84%).¹1 H NMR (300MHz, CDCl₃) δ9.13 (s, 1H), 8.29-8.10 (m, 3H), 7.62 (s, 1H), 7.44 (t, 1H), 7.16-7.03 (m, 4H), 6.91 (d, 1H), 6.85 -6.76 (m, 1H), 6.46-6.37 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.47 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.1,163.9,157.7,156.4,155.7,141.9,132.9,130.0,126.0,124.7,121.9,115.0,111.6,109.8,100.2,79.4,57.9,44.7; MS (ES +) m / z 503.5 (M + 1) ..

Example 4.3 2- (6,6-dimethyl-2'-oxo-4'-pyrimidine-5-yl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3 Synthesis of'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide

<chemistry num="101"><img file="JP5118627B2_D0110.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro-2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl )-N- (2-Fluorophenyl) Acetamide replaced with 2- (4'-bromo-6,6-dimethyl-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,, Modifications using 4-b'] difuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide gave the title compound (95%). ). Melting point:&gt; 250 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 8.24 (t, 1H), 8.15 (s, 2H), 8.00 (s, 1H), 7.40 (t, 1H), 7.16-7.03 (m, 4H), 6.88 (d , 1H), 6.61 (s, 1H), 5.99 (s, 1H), 4.84-4.73 (m, 2H), 4.54 (d, 1H), 4.44 (d, 1H), 2.79 (s, 2H), 1.45 ( s, 3H), 1.39 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ178.4,164.5,161.1,157.4,155.8,154.1,150.8,141.7,132.9,132.2,131.3,129.4,125.9,125.5,125.2,124.7,121.9,120.8,119.3,118.8,115.0,109.5,93.5,88.5,78.9 , 58.0,45.0,42.0,28.0,27.9; MS (ES +) m / z 537.5 (M + 1).

Example 4.4 4'-(3-Frill) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="102"><img file="JP5118627B2_D0111.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Replace with on 4'-Bromospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On , And [6- (dimethylamino) pyridine-3-yl] boronic acid were replaced with 3-franboronic acid to give the title compound as a colorless solid (66%). Melting point: 270 ~ 272 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.32 (t, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.91 (d, 1H), 6.83 (s, 1H), 6.44 (s, 1H), 6.30 (s, 1H) ), 6.04 (d, 1H), 5.89 (dd, 2H), 4.68 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ180.4,156.2,149.2,142.9,142.1,141.2,140.4,131.3,129.2,128.5,125.3,122.6,120.6,111.0,109.5,102.9,101.6,94.0,77.2,59.0; MS (ES +) m / z 348.4 ( M + 1).

Example 4.5 4'-Dibenzo [b, d] Fran-4-ylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis of

<chemistry num="103"><img file="JP5118627B2_D0112.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Replace with on 4'-Bromospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On , And a non-critical modification using dibenzo [b, d] furan-4-ylboronic acid in place of [6- (dimethylamino) pyridine-3-ylboronic acid] to give the title compound as a colorless solid. (Ten%). Melting point&gt; 230 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.77 (s, 1H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.43-7.42 (m, 3H), 7.34-7.29 (m, 3H), 7.16 (t, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.25 (s, 1H), 5.69 (d, 2H), 4.41 (ABq, 2H); MS (ES +) m / z 448.5 (M + 1).

Example 4.6 4'-(6-Methoxypyridin-3-yl) -1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] benzodio Kisole-7,3'-Indole]-2'(1'H)-On Synthesis

<chemistry num="104"><img file="JP5118627B2_D0113.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -one 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [flo [2,3-f] [1,3] benzodio Replace xol-7,3'-indole] -2'(1'H) -one with [6- (dimethylamino) pyridin-3-yl] boronic acid (6-methoxypyridin-3-yl) ) A non-critical modification using boronic acid gave the title compound as a colorless solid (51%). Melting point: 174 ~ 176 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.73 (d, 1H), 7.69 (d, 1H), 7.34 (t, 1H), 7.03 (d, 1H), 6.89-6.86 (m, 2H), 6.65 (d, 1H), 6.61 (d , 1H), 6.56 (d, 1H), 6.17 (d, 2H), 5.87 (d, 2H), 4.99 (ABq, 2H), 4.56 (ABq, 2H), 3.90 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.7,163.5,158.4,156.1,151.8,151.8,149.2,147.8,146.1,142.3,141.6,138.8,136.9,132.6,130.0,129.1,127.8,127.2,126.2,119.9,112.7,112.7,110.9,109.6,109.5 , 108.5,102.3,101.6,93.6,78.2,58.5,53.6,37.0; MS (ES +) m / z 537.4 (M + 1).

Example 4.7 4'-[6- (Dimethylamino) Pyridine-3-yl] -1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3 ] Benzodioxol-7,3'-indole] -2'(1'H) -on synthesis

<chemistry num="105"><img file="JP5118627B2_D0114.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -on 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [flo [2,3-f] [1,3] benzodio A non-critical modification using xol-7,3'-indole] -2'(1'H) -on gave the title compound as a colorless solid (37%). Melting point: 174 ~ 176 ° C; MS (ES +) m / z 550.4 (M + 1).

Example 4.8 4'-Pyrimidine-5-Ilspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole]-2'(1'H) -On

<chemistry num="106"><img file="JP5118627B2_D0115.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Replace with on 4'-Bromospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On , And a non-critical modification using pyrimidine-5-ylboronic acid in place of [6- (dimethylamino) pyridine-3-yl] boronic acid gave the title compound as a colorless solid (32%). Melting point: 185 ~ 187 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.85 (s, 1H), 9.02 (s, 1H), 8.19 (s, 2H), 7.33 (t, 1H), 7.00 (d, 1H), 6.83 (d, 1H), 6.37 (s, 1H) ), 6.19 (s, 1H), 5.89 (d, 2H);¹³C NMR (75MHz, DMSO-d₆) δ178.7,157.5,156.0,155.6,148.8,142.3,133.1,132.6,131.8,129.5,124.5,120.3,110.9,103.2,101.9,93.3,79.5,66.8,58.5; MS (ES +) m / z 360.4 (M +) 1).

Example 4.9 4'-(3-Frill) -1'-(Pyridine-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -2'(1'H)-On synthesis

<chemistry num="107"><img file="JP5118627B2_D0116.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -one 4'-bromo-1'-(pyridin-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 Make a non-critical change using 3-flamboric acid by replacing, 3'-indole] -2'(1'H) -one with and [6- (dimethylamino) pyridin-3-yl] boronic acid. , The title compound was obtained as a colorless solid (75%). Melting point: 195 ~ 197 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.58 (d, 1H), 7.68 (t, 1H), 7.32-7.21 (m, 4H), 6.97 (d, 1H), 6.92 (d, 1H), 6.77 (s, 1H), 6.60 (s , 1H), 6.35 (s, 1H), 5.99 (s, 1H), 5.12 (ABq, 2H), 4.71 (ABq, 2H), 4.57 (t, 2H), 3.03 (t, 2H); MS (ES +) m / z 437.4 (M + 1).

Example 4.10 1'-(pyridin-2-ylmethyl) -4'-pyrimidine-5-yl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -2'(1'H)-On synthesis

<chemistry num="108"><img file="JP5118627B2_D0117.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -one 4'-bromo-1'-(pyridin-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 Non-critical modification using pyrimidine-5-ylboronic acid, replacing, 3'-indole] -2'(1'H) -one with and [6- (dimethylamino) pyridin-3-yl] boronic acid The title compound was obtained as a colorless solid (16%). Melting point&gt; 200 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H) ), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES +) m / z 449.5 (M + 1).

Example 4.11 4'-Pyridine-3-yl-1'-(Pyridine-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole ] -2'(1'H)-On synthesis

<chemistry num="109"><img file="JP5118627B2_D0118.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -one 4'-bromo-1'-(pyridin-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 Non-critical modification to use pyridine-3-ylboronic acid by replacing, 3'-indole] -2'(1'H) -one with and [6- (dimethylamino) pyridin-3-yl] boronic acid The title compound was obtained as a colorless solid (9%). Melting point&gt; 200 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40 (d, 1H), 7.29 (t, 2H), 7.18-7.08 (m) , 2H), 7.00 (d, 1H), 6.81 (d, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10- 2.90 (m, 2H); MS (ES +) m / z 448.5 (M + 1).

Example 4.12 4'-(3-Frill) -1'-{[5- (Trifluoromethyl) -2-Frill] Methyl} -5,6-dihydrospiro [Benzo [1,2-b: 5,4-b' ] Difran-3,3'-Indole]-2'(1'H)-On Synthesis

<chemistry num="110"><img file="JP5118627B2_D0119.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -one 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b: 5] , 4-b'] Difuran-3,3'-indole] -2'(1'H) -one and replaced with [6- (dimethylamino) pyridine-3-yl] boronic acid 3-furylboronic acid A non-critical modification was made using the title compound as a colorless solid (27%). Melting point&gt; 167 ~ 169 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.34-7.29 (m, 2H), 7.01 (dd, 1H), 6.95 (dd, 1H), 6.77 (dd, 1H), 6.74 (dd, 1H), 6.51 (s, 1H), 6.41 (d , 1H), 6.34 (s, 1H), 6.00 (dd, 1H), 4.97 (ABq, 2H), 4.67 (ABq, 2H), 4.56 (t, 2H), 3.01 (t, 2H); MS (ES +) m / z 494.4 (M + 1).

Example 4.13 4'-quinoline-3-yl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7, 3'-Indole] -2'(1'H)-On synthesis

<chemistry num="111"><img file="JP5118627B2_D0120.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -on 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [flo [2,3-f] [1,3] benzodio Quinoline-3-ylboronic acid is used by substituting xol-7,3'-indole] -2'(1'H) -one with [6- (dimethylamino) pyridine-3-yl] boronic acid. Subcritical modifications were made to give the title compound as a colorless solid (50%).¹1 H NMR (300MHz, CDCl₃) δ8.52 (d, 1H), 8.09 (d, 1H), 7.74-7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.42-7.39 (m, 2H), 7.32 (s, 1H) , 7.09 (d, 1H), 7.01 (d, 1H), 6.78-6.77 (m, 1H), 6.45 (d, 1H), 6.26 (s, 1H), 5.94 (d, 1H), 5.91 (s, 1H) ), 5.89 (d, 1H), 5.03 (ABq, 2H), 4.52 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,156.0,151.8,150.0,149.3,147.0,142.4,141.8,136.8,135.8,131.1,130.2,129.9,129.3,129.0,128.8,128.0,127.1,127.0,126.4,126.0,120.4,112.7,109.5,108.8 , 102.5,101.7,93.7,78.3,58.5,37.1; MS (ES +) m / z 557.4 (M + 1).

Example 4.14 4'-Pyrimidine-5-yl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b: 5,4-b' ] Difran-3,3'-Indole] -2'(1'H)-On Synthesis

<chemistry num="112"><img file="JP5118627B2_D0121.tif" /></chemistry> 4'-Bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 , 3'-indole] -2'(1'H) -one (0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol), tetrakis (triphenylphosphine) palladium (0) (0.03) A mixture of g, 0.02 mmol), 2.00 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heated under nitrogen with reflux for 16 hours. After vacuum evaporation of the organic solvent, the black residue was extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate: hexane (35%) to give the title compound (0.03 g, 26%). Melting point: 263 ~ 266 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 8.14 (s, 2H), 7.39 (t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 2H), 4.58 (ABq, 2H), 3.01 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.3,162.5,161.0,157.4,155.9,151.6,142.2,141.7,132.8,132.3,131.3,129.3,125.7,120.6,120.2,118.3,117.0,112.7,109.7,109.4,93.5,78.9,72.5,57.7,37.1 , 28.9; MS (ES +) m / z 506.5 (M + 1).

Example 4.15 tert-Butyl 4-[(2'-oxo-4'-pyrimidine-5-ylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'( Synthesis of 2'H) -yl) methyl] piperidine-1-carboxylate

<chemistry num="113"><img file="JP5118627B2_D0122.tif" /></chemistry> Following the procedure described in Example 4.14, 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b:: 5,4-b'] Difuran-3,3'-Indole] -2'(1'H)-Replaced with on tert-butyl 4-[(4'-Bromo-2'-oxospiro [Flo [2,, 3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -yl) methyl] piperidine-Made a non-critical modification using -1-carboxylate, The title compound was obtained as a colorless solid (91%).¹1 H NMR (300MHz, CDCl₃) δ9.13 (s, 1H), 8.23 (s, 2H), 8.24-7.37 (m, 5H), 7.01 (d, 1H), 6.85 (d, 1H), 6.14 (dd2H), 5.91 (d, 2H) ), 4.55 (ABq, 2H), 4.15 (d, 2H), 3.84-3.58 (m, 3H), 2.69 (t, 2H), 1.44 (s, 9H); MS (ES +) m / z 557.5 (M +) 1).

Example 4.16 1'-Methyl-4'-Pyrimidine-5-Ilspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthetic

<chemistry num="114"><img file="JP5118627B2_D0123.tif" /></chemistry> Following the procedure described in Example 4.14, 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b:: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on 4'-Bromo-1'-Methyl Spiro [Flo [2,3-f] [1, 3] A non-critical modification using benzodioxol-7,3'-indole] -2'(1'H) -one gave the title compound as a colorless solid (22%).¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 8.18 (s, 2H), 7.41 (t, 1H), 7.00 (d, 1H), 6.85 (d, 1H), 6.20 (s, 1H), 6.12 (s, 1H) ), 5.87 (d, 2H), 4.54 (ABq, 2H), 3.32 (s, 1H); MS (ES +) m / z 374.5 (M + 1).

Example 4.17 4'-(3-Frill) -1'-Methylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthetic

<chemistry num="115"><img file="JP5118627B2_D0124.tif" /></chemistry> Following the procedure described in Example 4.14, 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b:: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on 4'-Bromo-1'-Methyl Spiro [Flo [2,3-f] [1, 3] Benzodioxol-7,3'-indole] -2'(1'H) -one was replaced with pyrimidine-5-boronic acid to make a non-critical change using 3-franboronic acid. The title compound was obtained as a colorless solid (81%).¹1 H NMR (300MHz, CDCl₃) δ7.40-7.28 (m, 2H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 2H), 6.45-6.38 (m, 1H), 6.23-6.16 (m, 1H), 6.07- 5.97 (m, 1H), 5.97-5.80 (m, 2H), 4.75-4.50 (m, 2H), 3.30-3.22 (m, 3H); MS (ES +) m / z 362.4 (M + 1).

Example 4.18 4'-(6-fluoropyridin-3-yl) -1'-methylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1' H)-On synthesis

<chemistry num="116"><img file="JP5118627B2_D0125.tif" /></chemistry> Following the procedure described in Example 4.14, 4'-bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b:: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on 4'-Bromo-1'-Methylspiro [Flo [2,3-f] [1, 3] Use (6-fluoropyridin-3-yl) boronic acid by replacing benzodioxol-7,3'-indole] -2'(1'H) -one with pyrimidine-5-boronic acid. The title compound was obtained as a colorless solid (100%).¹1 H NMR (300MHz, CDCl₃) δ7.75-7.65 (m, 1H), 7.42-7.30 (m, 1H), 7.19-7.05 (m, 1H), 7.00-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.78- 6.64 (m, 1H), 6.24-6.12 (m, 2H), 5.92-5.79 (m, 2H), 4.74-4.63 (m, 1H), 4.40-4.29 (m, 1H), 3.34-3.26 (m, 3H) ); MS (ES +) m / z 391.4 (M + 1).

Example 4.19 1'-(2-Cyclopropylethyl) -4'-quinoline-3-ylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1 'H)-On synthesis

<chemistry num="117"><img file="JP5118627B2_D0126.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -on 4'-bromo-1'-(2-cyclopropylethyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole ] -2'(1'H) -one is replaced with [6- (dimethylamino) pyridine-3-yl] boronic acid to make a non-critical modification using quinoline-3-ylboronic acid, the title compound. Got MS (ES +) m / z 477.5 (M + 1).

Example 4.20 N- (2-fluorophenyl) -2- (2'-oxo-4'-pyrimidine-5-yl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran- 3,3'-Indole] -1'(2'H) -Il) Synthesis of acetamide

<chemistry num="118"><img file="JP5118627B2_D0127.tif" /></chemistry> Following the procedure described in Example 4, 4'-bromo-1'-pentylspiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Replaced with 1'H) -on 2- (4'-bromo-2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3' -Indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide and replaced with [6- (dimethylamino) pyridine-3-yl] boronic acid to replace pyrimidine-5-boron A non-critical modification using an acid gave the title compound as a colorless solid (53%). Melting point: 229 ~ 230 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 8.26-8.15 (m, 3H), 7.98 (s, 1H), 7.41 (t, 1H), 7.15-7.05 (m, 4H), 6.89 (d, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.81-4.76 (m, 2H), 4.59-4.42 (m, 4H), 3.00 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ178.2,164.4,162.5,161.0,157.0,155.8,141.8,132.6,131.1,129.4,125.8,125.5,125.4,125.2,125.1,124.7,121.9,120.6,119.9,118.7,115.1,114.8,109.5,93.4,79.0 , 72.4,57.8,44.9,28.9; MS (ES +) m / z 509.5 (M + 1).

Example 5 4'-[(6-Methoxypyridin-3-yl) amino] -1'-Pentyl spiro [Flo [2,3-F] [1,3] Benzodioxole-7,3'-Indole] -2 '(1' H)-On synthesis

<chemistry num="119"><img file="JP5118627B2_D0128.tif" /></chemistry> 4'-Pyridine-1'-Pentyl Spiro- (6,7-Dihydroflo- [2,3-f] [1,3] Benzodioki in an oven-dried, cooler-equipped 2-neck 25 mL round-bottom flask Sole-7,3'-indole) -2'-(1'H) -one (50.5 mg, 0.12 mmol), 5-amino-2-methoxypyridine (22.3 mg, 0.18 mmol), Pd₂(dba)₃It was loaded with (10 mol%), BINAP (10 mol%) and sodium methoxide (12.9 mg, 0.24 mmol). Nitrogen was flowed through the flask for 5 minutes, then degassed toluene (5.00 mL) was added. The reaction mixture was heated to reflux for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL), washed with saturated ammonia chloride (10.0 mL) and brine (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The brown residue was subjected to column chromatography eluting with ethyl acetate hexane (20% -50%) to give the title compound (30.0 mg) in 54% yield. MS (ES +), m / z 474.3 (M + 1).

Example 5.1 The compounds listed in the table below were synthesized using conditions similar to those described in Example 5. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="3"><img file="JP5118627B2_D0129.tif" /></tables> Example 5.2 4'-Bromo-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="120"><img file="JP5118627B2_D0130.tif" /></chemistry> 4'-Bromo-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole]-2'(1'H) -On (0.05g, 0.12 mmol), 3- (trifluoromethyl) aniline (0.03 g, 0.17 mmol), Pd₂(dba)₃A mixture of (0.02 g, 0.01 mmol), xanthophos (0.007 g, 0.01 mmol) and sodium tert-butoxide (0.02 g, 0.17 mmol) was heated in toluene (5.00 mL) at 110 ° C. for 4 days. After cooling to ambient temperature, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate / hexane to give the title compound (0.06 g, 71%) as a solid. MS (ES +) m / z 511.5 (M + 1).

Example 5.3 The compounds listed in the table below were synthesized using conditions similar to those described in Example 5.2. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="4"><img file="JP5118627B2_D0131.tif" /></tables> Example 6 2-[(2'-oxospiro [Flo [2,3-F] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] of benzoic acid Synthetic

<chemistry num="121"><img file="JP5118627B2_D0132.tif" /></chemistry> Methyl 2-[(2'-oxospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -yl) methyl] benzoate ( Lithium hydroxide monohydrate (1.48 g, 35.2 mmol) was added to a solution of 7.56 g, 17.6 mmol) in THF / water (2 / 1v / v, 180 mL) mixture. The resulting mixture was stirred at ambient temperature overnight, concentrated in vacuo, then water (150 mL) was added. The mixture was extracted with ethyl acetate / hexane (1 / 3v / v, 50.0 mL). The aqueous layer was acidified with a 1N solution of HCl until the pH value reached 2. The precipitate was filtered and dried to give the title compound (7.30 g, 100%) as a white solid. Melting point:&gt; 250 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ13.25 (s, 1H), 7.95 (dd, 1H), 7.49 (dt, 1H), 7.37 (t, 1H), 7.24-7.16 (m, 2H), 7.11-6.98 (m, 2H), 6.80 (d, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.91 (s, 2H), 5.37-5.19 (m, 2H), 4.88-4.68 (m, 2H);¹³C NMR (75MHz, DMSO-d₆) δ177.6,168.8,156.0,148.8,143.0,142.3,137.6,133.1,132.1,131.5,129.9,129.4,127.7,126.5,124.2,123.6,120.1,109.8,103.8,101.9,93.8,80.5,58.0,42.6.

Example 7 N- [2- (4-chlorophenyl) ethyl] -2-[(2'-oxospiro [Flo [2,3-F] [1,3] benzodioxol-7,3'-indole] -1' Synthesis of (2'H) -yl) methyl] benzamide

<chemistry num="122"><img file="JP5118627B2_D0133.tif" /></chemistry> A.2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] chloride Preparation of undiluted solution of benzoyl 2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -yl) methyl] benzoic acid ( A solution of 0.21 g, 0.50 mmol), oxalyl chloride (0.09 mL, 1.00 mmol) and 1 drop of DMF in toluene (10.0 mL) was stirred overnight at ambient temperature. The mixture was concentrated in vacuo to give a solid, which was dissolved in dichloromethane (5.00 mL) to give the acid chloride stock solution (0.10 mmol / mL) for use.

BN- [2- (4-chlorophenyl) ethyl] -2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1' Synthesis of (2'H) -yl) methyl] benzamide The acid chloride stock solution (1.00 mL, 0.10 mmol) obtained above was added to a mixture of 2- (4-chlorophenyl) ethylamine (0.02 g, 0.13 mmol) and triethylamine (0.14 mL, 1.00 mmol) in dichloromethane (1.00 mL). added. The resulting mixture was stirred at ambient temperature overnight and diluted with dichloromethane (5.00 mL). The mixture was washed with 1N HCl, saturated sodium hydrogen carbonate solution, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum to give the title compound as a white powder.¹1 H NMR (300MHz, CDCl₃) δ7.70-7.13 (m, 10H), 7.10-6.96 (m, 2H), 6.65-6.54 (br, 1H), 6.50 (s, 1H), 6.11 (s, 1H), 5.89-5.82 (m, 2H), 5.09-4.88 (m, 3H), 4.68 (d, 1H), 3.79-3.66 (m, 2H), 2.93 (t, 2H); MS (ES +), m / z 553.3 (M + 1), 575.3 (M + 23).

Example 7.1 The compounds listed in the table below were synthesized using conditions similar to those described in Example 7. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="5-1"><img file="JP5118627B2_D0134.tif" /></tables>

<tables num="5-2"><img file="JP5118627B2_D0135.tif" /></tables>

<tables num="5-3"><img file="JP5118627B2_D0136.tif" /></tables>

<tables num="5-4"><img file="JP5118627B2_D0137.tif" /></tables>

<tables num="5-5"><img file="JP5118627B2_D0138.tif" /></tables>

<tables num="5-6"><img file="JP5118627B2_D0139.tif" /></tables>

<tables num="5-7"><img file="JP5118627B2_D0140.tif" /></tables> Example 8 3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] of benzoic acid Synthetic

<chemistry num="123"><img file="JP5118627B2_D0141.tif" /></chemistry> Following the procedure described in Example 6, methyl 2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'( Replaced with 2'H) -yl) methyl] benzoate and methyl 3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1 A non-critical modification using'(2'H) -yl) methyl] benzoate gave the title compound (100%).¹1 H NMR (300MHz, CDCl₃) δ13.03 (s, 1H), 7.86-7.80 (m, 2H), 7.59-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.25-7.16 (m, 2H), 7.03-6.95 ( m, 2H), 6.68 (s, 1H), 6.18 (s, 1H), 5.90 (s, 2H), 5.05 (ABq, 2H), 4.75 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,167.5,155.9,148.9,142.5,142.3,137.3,132.2,131.7,129.6,129.4,128.8,128.1,124.3,123.7,120.1,109.9,103.3,101.9,93.9,80.3,58.0,43.2; MS (ES + ) m / z 416.2 (M + 1).

Example 9 N- [2- (3-Chlorophenyl) ethyl] -3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1' Synthesis of (2'H) -yl) methyl] benzamide

<chemistry num="124"><img file="JP5118627B2_D0142.tif" /></chemistry> A.3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] chloride Preparation of undiluted solution of benzoyl 3-[(2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] benzoic acid ( Oxalyl chloride (0.95 g, 7.5 mmol) was added to this while stirring a 2.08 g, 5.00 mmol) dry chloroform (50.0 mL) slurry, followed by a drop of DMF. The mixture was stirred at ambient temperature overnight and evaporated to dryness in vacuo. The residue was dissolved in dry dichloromethane (60.0 mL) to give the acid chloride stock solution to be used.

BN- [2- (3-Chlorophenyl) ethyl] -3-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1' Synthesis of (2'H) -yl) methyl] benzamide The acid chloride stock solution (2.0 mL, 0.081 in dichloromethane) obtained above in a solution of 2- (3-chlorophenyl) ethylamine (0.02 mL, 0.24 mmol) in dry dichloromethane (2.00 mL) and triethylamine (0.05 mL, 0.32 mmol). M) was added at ambient temperature. The mixture was stirred for 2 hours and washed with 15% HCl solution and water. Separate the organic layer and Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate and the product was precipitated by addition to hexane. The white solid was filtered and collected to give the title compound (0.06 g) in 65% yield.¹1 H NMR (300MHz, CDCl₃) δ7.97-7.95 (m, 2H), 7.53-7.50 (m, 1H), 7.45-7.40 (m, 1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.73- 6.71 (m, 1H), 6.52 (s, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 5.18 (d, 1H), 4.72 (d, 1H), 4.80 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H); MS (ES +) m / z 554.0 (M + 1).

Example 9.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 9. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="6-1"><img file="JP5118627B2_D0143.tif" /></tables>

<tables num="6-2"><img file="JP5118627B2_D0144.tif" /></tables>

<tables num="6-3"><img file="JP5118627B2_D0145.tif" /></tables>

<tables num="6-4"><img file="JP5118627B2_D0146.tif" /></tables>

<tables num="6-5"><img file="JP5118627B2_D0147.tif" /></tables>

<tables num="6-6"><img file="JP5118627B2_D0148.tif" /></tables>

<tables num="6-7"><img file="JP5118627B2_D0149.tif" /></tables> Example 10 Synthesis of 1'-(4-fluorobenzyl) spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one

<chemistry num="125"><img file="JP5118627B2_D0150.tif" /></chemistry> Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -one (0.16 g, 0.57 mmol) ethyl methyl ketone (5.00) mL) Cs in solution₂CO₃(0.40 g, 1.20 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 minutes, then 4-fluorobenzyl bromide (0.20 g, 1.0 mmol) was added. The reaction mixture was refluxed for 4 hours. After the reaction was complete, the mixture was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from EtOAc / Hexane to give the title compound (0.111 g) as a white solid in 50% yield. MS (ES +) m / z 390.3 (M + 1).

Example 10.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 10. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="7-1"><img file="JP5118627B2_D0151.tif" /></tables>

<tables num="7-2"><img file="JP5118627B2_D0152.tif" /></tables>

<tables num="7-3"><img file="JP5118627B2_D0153.tif" /></tables>

<tables num="7-4"><img file="JP5118627B2_D0154.tif" /></tables>

<tables num="7-5"><img file="JP5118627B2_D0155.tif" /></tables>

<tables num="7-6"><img file="JP5118627B2_D0156.tif" /></tables> Example 10.2 1'-(Piperidin-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="126"><img file="JP5118627B2_D0157.tif" /></chemistry> Following the procedure described in Example 10, a non-critical modification was made using tert-butyl 4- (bromomethyl) peridine-1-carboxylate in place of 4-fluorobenzyl bromide and the intermediate was acidic with 33% HBr. The title compound was obtained as a white solid in a yield of 67%. MS (ES +) m / z 379.3 (M + 1).

Example 10.3 1'-[(1-Methylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-Synthesis of on-chloride

<chemistry num="127"><img file="JP5118627B2_D0158.tif" /></chemistry> 1'-(Piperidin-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole]-2'(1'H) -On (0.19g) Formaldehyde (0.10 mL, 33% solution, 0.03 g, 1.10 mmol) and sodium triacetoxybohydride (0.30 g, 1.40 mmol) were added to a solution of dichloroethane (5.00 mL) at 0.50 mmol). After stirring at ambient temperature for 20 hours, the reaction mixture was diluted with dichloromethane (20.0 mL) and washed with water (2 x 20.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography, the product was dissolved in dichloromethane (5.00 mL) and excess HCl in ether was added. The precipitate was filtered to give the title compound in 20% yield. MS (ES +) m / z 393.3 (M + 1).

Example 10.4 1'-[(1-ethylpiperidine-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-Synthesis of on-chloride

<chemistry num="128"><img file="JP5118627B2_D0159.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using acetalhide instead of formalin to give the title compound as a white solid in 20% yield. MS (ES +) m / z 407.3 (M + 1).

Example 10.5 1'-[(1-cyclohexylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-Synthesis of on-chloride

<chemistry num="129"><img file="JP5118627B2_D0160.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using cyclohexanone in place of formalin to give the title compound as a white solid in a yield of 24%. MS (ES +) m / z 461.5 (M + 1).

Example 10.6 1'-{[1-Cyclopropylmethyl) Piperidine-4-yl] Methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'( 1'H)-Synthesis of on-chloride

<chemistry num="130"><img file="JP5118627B2_D0161.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using cyclopropanecarbaldehyde in place of formalin to give the title compound as a white solid in 14% yield. MS (ES +) m / z 433.5 (M + 1).

Example 10.7 1'-[(1-Cyclopentylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-Synthesis of on-chloride

<chemistry num="131"><img file="JP5118627B2_D0162.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using cyclopentanone in place of formalin to give the title compound as a white solid in 37% yield. MS (ES +) m / z 447.3 (M + 1).

Example 10.8 1'-{[1- (pyridin-3-ylmethyl) piperidine-4-yl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole]- 2'(1'H)-Synthesis of on-chloride

<chemistry num="132"><img file="JP5118627B2_D0163.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using nicotine aldehyde in place of formalin to give the title compound as a white solid in 11% yield. MS (ES +) m / z 470.4 (M + 1).

Example 10.9 1'-{[1- (3-Methylbutyl) piperidine-4-yl] methyl} spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2' (1'H)-Synthesis of on-chloride

<chemistry num="133"><img file="JP5118627B2_D0164.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using 3-methylbutanal in place of formalin to give the title compound as a white solid in 15% yield. MS (ES +) m / z 449.5 (M + 1).

Example 10.10 1'-{[1- (1-ethylpropyl) piperidine-4-yl] methyl} spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2 '(1' H)-Synthesis of on-chloride

<chemistry num="134"><img file="JP5118627B2_D0165.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using pentane-3-one in place of formalin to give the title compound as a white solid in 17% yield. MS (ES +) m / z 449.4 (M + 1).

Example 10.11 1'-[(1-Cyclobutylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1' H)-Synthesis of on-chloride

<chemistry num="135"><img file="JP5118627B2_D0166.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using cyclobutanone in place of formalin to give the title compound as a white solid in 31% yield. MS (ES +) m / z 433.4 (M + 1).

Example 10.12 1'-[(1-Isopropylpiperidine-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1' H)-Synthesis of on-chloride

<chemistry num="136"><img file="JP5118627B2_D0167.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using acetone in place of formalin to give the title compound as a white solid in 31% yield.¹1 H NMR (300MHz, DMSO-d₆) δ10.36 (s, 1H), 7.79-6.87 (m, 4H), 6.82-6.48 (m, 1H), 6.38-6.15 (m, 1H), 5.89 (s, 2H), 4.67 (ABq, 2H) , 4.12 (s, 1H), 3.79-0.60 (m, 16H); MS (ES +) m / z 421.4 (M + 1).

Example 10.13 1'-{[1- (pyridin-2-ylmethyl) piperidine-4-yl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole]- 2'(1'H)-Synthesis of on-chloride

<chemistry num="137"><img file="JP5118627B2_D0168.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using picoline aldehyde in place of formalin to give the title compound as a white solid in 15% yield. MS (ES +) m / z 470.4 (M + 1).

Example 10.14 1'-{[1- (2-thienylmethyl) piperidine-4-yl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2 '(1' H)-Synthesis of on-chloride

<chemistry num="138"><img file="JP5118627B2_D0169.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using thiophen-2-carbaldehyde in place of formalin to give the title compound as a white solid in 21% yield. MS (ES +) m / z 475.3 (M + 1).

Example 10.15 1'-({1- [3- (methylthio) propyl] piperidine-4-yl} methyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H)-Synthesis of on-chloride

<chemistry num="139"><img file="JP5118627B2_D0170.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using 3- (methylthio) propanal in place of formalin to give the title compound as a white solid in 7% yield. MS (ES +) m / z 467.5 (M + 1).

Example 10.16 1'-{[1- (Tetrahydro-2H-pyran-4-yl) piperidine-4-yl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3' -Indole] -2'(1'H)-Synthesis of on hydrochloride

<chemistry num="140"><img file="JP5118627B2_D0171.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using tetrahydro-4H-pyran-4-one in place of formalin to give the title compound as a white solid in 33% yield. MS (ES +) m / z 463.4 (M + 1).

Example 10.17 1'-{[1- (3,3-dimethylbutyl) piperidine-4-yl] methyl} spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H)-Synthesis of on-chloride

<chemistry num="141"><img file="JP5118627B2_D0172.tif" /></chemistry> Following the procedure described in Example 10.3, a non-critical modification was made using 3,3-dimethylbutanal in place of formalin to give the title compound as a white solid in 19% yield. MS (ES +) m / z 463.5 (M + 1).

Example 10.18 tert-Butyl 4-[(5,5-dimethyl2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1 Synthesis of'(2'H) -yl) methyl] piperidine-1-carboxylate

<chemistry num="142"><img file="JP5118627B2_D0173.tif" /></chemistry> Follow the procedure described in Example 10 and replace with spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on. 5,5-Dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on, and A non-critical modification was made using tert-butyl 4- (tosyloxymethyl) piperidine-1-carboxylate in place of 4-fluorobenzyl bromide to give the title compound in 70% yield. Melting point: 65-75 ° C¹1 H NMR (300MHz, CDCl₃) δ7.30 (td, 1H), 7.18 (d, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.38 (s, 1H), 6.28 (s, 1H), 4.88 (d, 1H) ), 4.64 (d, 1H), 4.18 (s, 2H), 4.17-4.01 (br, 2H), 3.74-3.53 (m, 2H), 2.74-2.59 (m, 2H), 2.11-1.92 (m, 1H) ), 1.70-1.59 (m, 2H), 1.43 (s, 9H), 1.37-1.19 (m, 2H), 1.17 (s, 3H), 1.14 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ178.0,161.3,161.0,154.7,142.8,132.6,129.9,128.7,124.2,123.3,120.3,116.2,108.5,93.4,85.4,80.6,79.5,57.7,45.7,41.3,35.0,30.0,28.4,27.8,27.5 ; MS (ES +) m / z 527.5 (M + 23).

Example 10.19 5,5-dimethyl1'-(piperidine-4-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Synthesis of on-chloride

<chemistry num="143"><img file="JP5118627B2_D0174.tif" /></chemistry> tert-Butyl 4-[(5,5-dimethyl2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1 Stirring a 10.0 mL dichloromethane solution of'(2'H) -yl) methyl] piperidine-1-carboxylate (80 mg, 0.16 mmol) to this with hydrobromic acid (0.50 mL hydrobromic acid in glacial acetic acid). 33%, 1.60 mmol) was added slowly at 0 ° C. The mixture was stirred at ambient temperature for 1 hour and concentrated to dryness under vacuum. The residue was treated with 10.0 mL of 2N sodium hydroxide solution and extracted with dichloromethane (3 x 30.0 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (2% methanol in ethyl acetate) and 5,5-dimethyl1'-(piperidine-4-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4]. -b'] Difuran-3,3'-Indole] -2'(1'H) -On (0.03 g, 46%) was obtained and treated with 2.0 M HCl in diethyl ether to give the title compound. Obtained.¹1 H NMR (300MHz, CD₃OD) δ7.41 (td, 1H), 7.25-7.12 (m, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 4.87 (d, 1H), 4.72 (d, 1H), 4.23 ( s, 2H), 3.80 (d, 2H), 3.51-3.38 (m, 2H), 3.11-2.94 (m, 2H), 2.39-2.19 (m, 1H), 2.06-1.94 (m, 2H), 1.67- 1.49 (m, 2H), 1.22 (s, 3H), 1.19 (s, 3H);¹³C NMR (75MHz, CD₃OD) δ181.4,163.9,163.4,144.7,134.7,132.3,131.0,125.9,125.8,122.6,118.4,111.3,94.9,87.4,82.6,60.2,46.7,45.7,45.6,43.3,34.6,28.8,28.7,28.6; MS (ES +) m / z 405.4 (M + 1).

Example 10.20 7'-Fluoro-1'-[(1-Isopropylpiperidine-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2 '(1' H)-Synthesis of on-chloride

<chemistry num="144"><img file="JP5118627B2_D0175.tif" /></chemistry> A. Following the procedure described in Examples 10.18 and 10.19, 5,5-dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)-Replace with on 7'-Fluorospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1' Make a non-critical modification using H) -one and make a 7'-fluoro-1'-(piperidine-4-ylmethyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7 , 3'-Indole] -2'(1'H)-Obtained and used in the next step.

B.7'-Fluoro-1'-(Piperidin-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole]-2'(1' A 5.00 mL dichloromethane solution of H) -one (120 mg, 0.28 mmol) and triethylamine (3.9 μL, 0.028 mmol) was stirred with acetone (4.1 μL, 0.56 mmol) followed by sodium triacetoxybohydride (124 mg, 124 mg,). 0.56 mmol) was added at ambient temperature. The mixture was stirred at ambient temperature overnight and quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3 x 30.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / 2% methanol in hexane) and 7'-fluoro-1'-[(1-isopropylpiperidine-4-yl) methyl] spiro [flo [2,3-f] [ 1,3] Benzodioxol-7,3'-indole] -2'(1'H) -one (85 mg, 69%) was obtained as a white solid, which was treated with 2.0 M HC in diethyl ether. And obtained the title compound. Melting point: 157 ~ 160 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H), 3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m, 2H) ), 1.76-1.52 (m, 2H), 1.34 (d, 6H);¹³C NMR (75MHz, CD₃OD) δ179.7,157.6,150.6,150.4,147.1,143.9,136.6,125.8,121.2,120.3,118.0,103.9,103.0,94.3,81.8,60.1,59.7,47.6,35.33,35.30,28.6,28.5,16.98,16.96; MS (ES +) m / z 439.27 (M + 1).

Example 10.21 5,5-dimethyl1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 , 3'-Indole] -2'(1'H)-On synthesis

<chemistry num="145"><img file="JP5118627B2_D0176.tif" /></chemistry> 5,5-dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on (0.09 g, 2-Bromomethyl-5- (trifluoromethyl) furan (0.08 g, 0.35 mmol) in a 0.29 mmol) 2-butanone (10.0 mL) solution, followed by cesium carbonate (0.19 g, 0.58 mmol) at 0 ° C. added. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (0.06 g, 45%). Melting point: 155 ~ 160 ° C;¹1 H NMR (300MHz, CDCl₃,) δ7.29 (t, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.97 (d, 1H), 6.73 (t, 1H), 6.42-6.37 (m, 2H), 6.30 ( s, 1H), 5.08 (d, 1H), 4.94-4.84 (m, 2H), 4.65 (d, 1H), 4.18 (s, 2H), 1.19 (s, 3H), 1.14 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.5,161.2,161.0,152.0,141.4,132.5,130.1,128.8,124.2,123.8,120.1,116.4,112.6,109.3,108.7,93.4,85.5,80.6,57.7,41.4,36.9,27.6,27.5; MS (ES + ) m / z 456.5 (M + 1).

Example 10.22 5,5-dimethyl1'-(pyridin-3-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Synthesis of on-chloride

<chemistry num="146"><img file="JP5118627B2_D0177.tif" /></chemistry> 5,5-dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on (0.08 g, Sodium hydroxide (0.03 g, 0.78 mmol) was slowly added to a 0.26 mmol) DMF (10 mL) solution at 0 ° C. After 30 minutes, 3- (bromomethyl) -pyridine hydrobromide (0.10 g, 0.39 mmol) was added. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonia chloride (10.0 mL). The mixture was extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 2/1) and 5,5-dimethyl1'-(pyridin-3-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5]. , 4-b'] Difuran-3,3'-Indole] -2'(1'H) -one is obtained as a white solid (0.05 g, 48%), which is treated with 2.0 M HCl in diethyl ether. The title compound was obtained. Melting point: 124 ~ 126 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.96 (br, 1H), 8.82 (br, 1H), 8.62 (d, 1H), 7.3 (t, 1H), 7.32 (td, 1H), 7.23-7.17 (m, 1H), 7.16- 7.08 (m, 2H), 6.42 (s, 1H), 6.32 (s, 1H), 5.35-5.14 (m, 2H), 4.93-4.84 (m, 1H), 4.74 (d, 1H), 4.18 (s, 2H), 1.18 (s, 3H), 1.14 (s, 3H);¹³C NMR (75MHz, CD₃OD) δ178.9,161.6,161.1,145.4,141.3,141.1,132.5,130.1,128.8,124.0,123.9,120.1,116.2,108.8,92.6,85.1,80.2,57.8,41.0,40.5,26.5,26.4; MS (ES +) m / z 399.5 (M + 1).

Example 10.23 5,5-dimethyl1'-(pyridin-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Synthesis of on-chloride

<chemistry num="147"><img file="JP5118627B2_D0178.tif" /></chemistry> Following the procedure described in Example 10.22, a non-critical modification was made to replace 3- (bromomethyl) -pyridine hydrobromide with 2- (bromomethyl) -pyridine hydrobromide to give the title compound. Obtained (45%). Melting point: 145 ~ 147 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.86 (dd, 1H), 8.56 (td, 1H), 8.05-7.97 (m, 2H), 7.37 (td, 1H), 7.31-7.25 (m, 1H), 7.24-7.16 (m, 1H) ), 7.11 (d, 1H), 6.55 (s, 1H), 6.37 (s, 1H), 5.52 (d, 1H), 5.38 (d, 1H), 4.97 (d, 1H), 4.79 (d, 1H) , 4.23 (s, 2H), 1.24 (s, 3H), 1.20 (s, 3H);¹³C NMR (75MHz, CD₃OD) δ177.4,160.0,159.6,150.3,144.7,141.0,139.7,131.0,128.6,127.2,124.3,123.7,122.6,122.4,118.5,114.8,107.2,91.0,83.6,78.7,56.3,40.1,39.4,24.9, 24.8; MS (ES +) m / z 399.5 (M + 1).

Example 10.24 1'-[(6-Methylpyridine-3-yl) Methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-Synthesis of on-chloride

<chemistry num="148"><img file="JP5118627B2_D0179.tif" /></chemistry> Following the procedure described in Example 10.21, replaced with 2-bromomethyl-5- (trifluoromethyl) furan (6-methylpyridine-3-yl) methyl 4-methylbenzenesulfonate, and 5,5-dimethyl- 5,6-Dihydrospiro [Benzene [1,2-b: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on Spiro [Flo [2,, 3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on a non-critical modification using 1'-[(6-methylpyridine) -3-Il) Methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On (56%) , This was treated with 2.0 M HCl in diethyl ether to give the title compound.¹1 H NMR (300MHz, CD₃OD) δ8.77 (s, 1H), 8.46 (dd, 1H), 7.91 (d, 1H), 7.33 (t, 1H), 7.24-7.09 (m, 3H), 6.52 (s, 1H), 6.14 ( s, 1H), 5.86 (s, 2H), 5.18 (s, 2H), 4.93-4.85 (m, 1H), 4.71 (d, 1H), 2.77 (s, 3H);¹³C NMR (75MHz, CD₃OD) δ180.0,157.6,155.1,150.6,146.6,143.8,142.7,141.2,135.7,133.5,130.3,129.5,125.3,125.2,120.5,110.3,103.8,103.0,94.3,81.5,59.7,41.5,19.5; MS ( ES +) m / z 387.4 (M + 1).

Example 10.25 1'-[(6-Methoxypyridin-3-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H )-On synthesis

<chemistry num="149"><img file="JP5118627B2_D0180.tif" /></chemistry> Following the procedure described in Example 10.21, replaced with 2-bromomethyl-5- (trifluoromethyl) furan (6-methoxypyridin-3-yl) methyl 4-methylbenzenesulfonate, and 5,5-dimethyl5. , 6-Dihydrospiro [Benzene [1,2-b: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on Spiro [Flo [2,3' A non-critical modification using -f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one gave the title compound (45%).¹1 H NMR (300MHz, CDCl₃) δ8.19 (d, 1H), 7.59 (dd, 1H), 7.26-7.12 (m, 2H), 7.02 (t, 1H), 6.83 (d, 1H), 6.74 (d, 1H), 6.50 (s , 1H), 6.07 (s, 1H), 5.89-5.82 (m, 2H), 5.00-4.90 (m, 2H), 4.76 (d, 1H), 4.65 (d, 1H), 3.93 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.6,163.7,155.9,149.0,145.3,142.4,141.6,138.9,132.2,129.0,124.4,124.1,123.7,119.2,111.7,109.0,102.9,101.5,93.7,80.4,58.2,53.9,41.1; MS (ES + ) m / z 403.2 (M + 1).

Example 10.26 1'-[(6-chloropyridin-3-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H )-On synthesis

<chemistry num="150"><img file="JP5118627B2_D0181.tif" /></chemistry> Following the procedure described in Example 10.21, 2-bromomethyl-5- (trifluoromethyl) furan was replaced with 2-chloro-5- (chloromethyl) pyridine, and 5,5-dimethyl-5,6-dihydro. Spiro [Benzo [1,2-b: 5,4-b'] Difran-3,3'-Indole] -2'(1'H) -Replace with on Spiro [Flo [2,3-f] [ A non-critical modification using 1,3] benzodioxol-7,3'-indole] -2'(1'H) -one gave the title compound (69%).¹1 H NMR (300MHz, CDCl₃) δ8.42 (d, 1H), 7.63 (dd, 1H), 7.34-7.14 (m, 3H), 7.05 (t, 1H), 6.77 (d, 1H), 6.51 (s, 1H), 6.06 (s , 1H), 5.89-5.84 (m, 2H), 5.07-4.78 (m, 3H), 4.66 (d, 1H); MS (ES +) m / z 407.3 (M + 1).

Example 10.27 1'-{[6- (dimethylamino) pyridine-3-yl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Synthesis of on-chloride

<chemistry num="151"><img file="JP5118627B2_D0182.tif" /></chemistry> In a sealed tube 1 '- ((6-chloropyridin-3-yl) methyl)-6H-spiro [benzofuro [6,5-d] [1, 3] dioxole -7,3'- India phosphate] -2' -On (0.10 g, 0.25 mmol) and dimethylamine (2.00 mL 2M THF solution, 4.00 mmol) were added. The mixture was stirred at 130 ° C. overnight. After cooling to ambient temperature, the mixture was vacuum concentrated. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/2) and 1'-{[6- (dimethylamino) pyridine-3-yl] methyl} spiro [flo [2,3-f] [1, 3] Benzodioxol-7,3'-indole] -2'(1'H) -one was obtained as a white solid (50 mg, 48%), which was treated with 2.0 M HCl in diethyl ether. , The title compound was obtained. Melting point: 146 ~ 150 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.03 (d, 1H), 7.95 (dd, 1H), 7.36 (td, 1H), 7.25-7.12 (m, 4H), 6.57 (s, 1H), 6.09 (s, 1H), 5.90 ( s, 2H), 5.07-4.87 (m, 3H), 4.72 (d, 1H), 3.27 (s, 6H);¹³C NMR (75MHz, CD₃OD) δ179.9,157.6,154.6,150.5,143.8,143.4,142.9,137.7,133.5,130.2,125.1,121.8,120.6,113.2,110.4,103.7,103.0,94.3,81.4,59.7,41.1,39.5; MS (ES +) m / z 416.5 (M + 1).

Example 10.28 1'-[(6-Morpholine-4-ylpyridine-3-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'( 1'H)-Synthesis of on-chloride

<chemistry num="152"><img file="JP5118627B2_D0183.tif" /></chemistry> Following the procedure described in Example 10.27, a non-critical modification was made using morpholine in place of dimethylamine solution to give the title compound (52%). Melting point: 185 ~ 200 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.13-8.04 (m, 2H), 7.45 (d, 1H), 7.37 (t, 1H), 7.26-7.14 (m, 3H), 6.56 (s, 1H), 6.10 (s, 1H), 5.89 (s, 2H), 5.10-4.87 (m, 3H), 4.72 (d, 1H), 3.91-3.84 (m, 4H), 3.73-3.67 (m, 4H);¹³C NMR (75MHz, CD₃OD) δ180.0,157.6,153.7,150.5,145.1,143.8,142.8,136.3,133.5,130.3,125.2,125.1,123.6,120.6,114.6,110.4,103.7,103.0,94.3,81.5,66.7,59.7,47.2,40.9; MS (ES +) m / z 458.5 (M + 1).

Example 10.29 1'-[(6-pyrrolidine-1-ylpyridine-3-yl) methyl] spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Synthesis of on-chloride

<chemistry num="153"><img file="JP5118627B2_D0184.tif" /></chemistry> Following the procedure described in Example 10.27, a non-critical modification was made using pyrrolidine in place of dimethylamine solution to give the title compound (45%). Melting point: 160 ~ 165 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.99-7.91 (m, 2H), 7.33 (td, 1H), 7.22-7.06 (m, 4H), 6.53 (s, 1H), 6.05 (s, 1H), 5.86 (s, 2H), 5.04-4.82 (m, 3H), 4.68 (d, 1H), 3.57 (t, 4H), 2.13 (t, 4H);¹³C NMR (75MHz, CD₃OD) δ177.0,154.6,148.0,147.6,141.1,140.8,139.9,132.5,130.5,127.3,122.2,118.8,117.6,112.0,107.4,100.7,100.0,91.3,78.5,56.7,38.0,23.2; MS (ES +) m / z 442.2 (M + 1).

Example 10.30 1'-(2-Chloro-4-fluorobenzyl) spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -on Synthesis of

<chemistry num="154"><img file="JP5118627B2_D0185.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On, and A non-critical modification was made using 1- (bromomethyl) -2-chloro-4-fluorobenzene in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid ( 54%). Melting point: 174 ~ 175 ° C; MS (ES +) m / z 424.2 (M + 1).

Example 10.31 1'-[(2-Methylcyclopropyl) Methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis of

<chemistry num="155"><img file="JP5118627B2_D0186.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using 1- (bromomethyl) -2-methylcyclopropane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid (37%). .. MS (ES +) m / z 350.3 (M + 1).

Example 10.32 1'-(3-Cyclopropylpropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="156"><img file="JP5118627B2_D0187.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using (3-bromopropyl) cyclopropane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid (51%). Melting point: 111 ~ 113 ° C; MS (ES +) m / z 364.3 (M + 1).

Example 10.33 1'-Butylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="157"><img file="JP5118627B2_D0188.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification using 1-bromobutane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan gave the title compound as a white solid (62%). Melting point: 119 ~ 120 ° C; MS (ES +) m / z 338.3 (M + 1).

Example 10.34 1'-[(5-Methylisoxazole-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'Indole] -2'(1' H)-On synthesis

<chemistry num="158"><img file="JP5118627B2_D0189.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using 4- (bromomethyl) -5-methylisoxazole in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid (25%). ). Melting point: 159 ~ 161 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.39-6.91 (m, 4H), 6.50 (s, 1H), 6.11 (s, 1H), 5.94 (d, 1H), 5.85 (ABq, 2H), 4.95 (ABq, 2H), 4.78 (ABq) , 2H), 2.37 (s, 3H); MS (ES +) m / z 377.3 (M + 1).

Example 10.35 1'-(Tetrahydro-2H-pyran-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole]-2'(1'H)- On synthesis

<chemistry num="159"><img file="JP5118627B2_D0190.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using 4- (bromomethyl) tetrahydro-2H-pyran in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid (25%). Melting point: 142 ~ 144 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.34-6.85 (m, 4H), 6.50 (s, 1H), 6.08 (s, 1H), 5.85 (ABq, 2H), 4.76 (ABq, 2H), 4.18-3.86 (m, 2H), 3.63 (ddd, 2H), 3.34 (t, 2H), 2.38-1.92 (m, 1H), 1.70-1.36 (m, 4H); MS (ES +) m / z 380.3 (M + 1).

Example 10.36 1'[2- (trifluoromethoxy) benzyl] spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -on Synthetic

<chemistry num="160"><img file="JP5118627B2_D0191.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On, and A non-critical modification was made using 1- (bromomethyl) -2- (trifluoromethoxy) benzene in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid ( 77%). Melting point: 130-135 ° C; MS (ES +) m / z 456.3 (M + 1).

Example 10.37 1'[3- (trifluoromethoxy) benzyl] spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one Synthetic

<chemistry num="161"><img file="JP5118627B2_D0192.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On, and A non-critical modification was made using 1- (bromomethyl) -3- (trifluoromethoxy) benzene in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid ( 65%). Melting point: 88-91 ° C; MS (ES +) m / z 456.3 (M + 1).

Example 10.38 1'[4- (trifluoromethoxy) benzyl] spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -on Synthetic

<chemistry num="162"><img file="JP5118627B2_D0193.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On, and A non-critical modification was made using 1- (bromomethyl) -4- (trifluoromethoxy) benzene in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid ( 50%). Melting point: 99 ~ 101 ° C; MS (ES +) m / z 456.3 (M + 1).

Example 10.39 1'-Methylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="163"><img file="JP5118627B2_D0194.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole] -2'(1'H) -On, and A non-critical modification using indole methane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan gave the title compound as a white solid (72%). Melting point: 142 ~ 144 ° C; MS (ES +) m / z 296.2 (M + 1).

Example 10.40 1'-Propyl Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="164"><img file="JP5118627B2_D0195.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using 1-bromopropane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid (64%). Melting point: 158 ~ 160 ° C; MS (ES +) m / z 324.4 (M + 1).

Example 10.41 1'-(2,1,3-benzoxadiazole-5-ylmethyl) spiro [Flo 2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1 'H)-On synthesis

<chemistry num="165"><img file="JP5118627B2_D0196.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and A non-critical modification was made using 5- (bromomethyl) benzo [c] [1,2,5] oxadiazole in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to make the title compound white. Obtained as a solid (17%). Melting point: 163 ~ 165 ° C; MS (ES +) m / z 414.4 (M + 1).

Example 10.42 1'[(1-Methyl-1H-benzotriazole-6-yl) methyl] Spiro [Flo 2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1 'H)-On synthesis

<chemistry num="166"><img file="JP5118627B2_D0197.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on Spiro [Flo [2,3-f] [1,3] Benzotriazole-7,3'-Indole]-2'(1'H)-On, and A non-critical modification was made using 6- (bromomethyl) -1-methyl-1H-benzotriazole in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a white solid ( 17%). Melting point: 230 ~ 235 ° C; MS (ES +) m / z 427.3 (M + 1).

Example 10.43 tert-Butyl 4-[(2'-oxo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -1'(2'H )-Il) Methyl] Piperidine-1-carboxylate synthesis

<chemistry num="167"><img file="JP5118627B2_D0198.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)- Substituted on and replaced with 2- (bromomethyl) -5- (trifluoromethyl) furan and used tert-butyl 4- (bromomethyl) peridine-1-carboxylate to make the title compound a white solid. Obtained as (58%). Melting point: 96-98 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.84-6.85 (m, 4H), 6.40 (s, 1H), 6.37 (s, 1H), 4.68 (ABq, 2H), 4.46 (t, 2H), 4.06-3.73 (m, 2H), 3.68 -3.45 (m, 2H), 2.92 (t, 2H), 2.63 (s, 2H), 2.04-1.82 (m, 1H), 1.76-0.66 (m, 13H); MS (ES +) m / z 477.4 (M) +1).

Example 10.44 1'-(2,3-difluorobenzyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H )-On synthesis

<chemistry num="168"><img file="JP5118627B2_D0199.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)- Substituted on and replaced with 2- (bromomethyl) -5- (trifluoromethyl) furan and used 1- (bromomethyl) -2,3-difluorobenzene to obtain the title compound as a white solid. (67%). Melting point: 156 ~ 158 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.50-6.85 (m, 7H), 6.43 (s, 1H), 6.39 (s, 1H), 5.01 (q, 2H), 4.75 (dd, 2H), 4.46 (t, 2H), 2.92 (t) , 2H); MS (ES +) m / z 406.2 (M + 1).

Example 10.45 1'-(Pyridine-2-ylmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -Synthesis of on-chloride

<chemistry num="169"><img file="JP5118627B2_D0200.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)- A non-critical change was made using 2- (bromomethyl) pyridine hydrobromide by replacing on with 2- (bromomethyl) -5- (trifluoromethyl) furan and 1'-(pyridine-2-). Ilmethyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] 2'(1'H) -one obtained as a white solid (27) %), CH this₂Cl₂In, treatment with excess HCl in ether gave the title compound. Melting point: 208-210 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ8.78-8.53 (m, 1H), 8.05 (t, 1H), 7.64-7.47 (m, 2H), 7.30-6.92 (m, 4H), 6.59 (s, 1H), 6.38 (s, 1H) , 5.24-5.06 (m, 2H), 4.78 (ABq, 2H), 4.46 (t, 2H), 2.94 (t, 2H); MS (ES +) m / z 371.4 (M + 1).

Example 10.46 1'-(4-methoxybenzyl) -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)- On synthesis

<chemistry num="170"><img file="JP5118627B2_D0201.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'( Replaced with 1'H)-on 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H)-on Was replaced with 2- (bromomethyl) -5- (trifluoromethyl) furan and a non-critical modification was made using 1- (chloromethyl) -4-methoxybenzene to give the title compound as a white solid ( 56%). Melting point: 120-121 ° C; MS (ES +) m / z 400.2 (M + 1).

Example 10.47 4'-Bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="171"><img file="JP5118627B2_D0202.tif" /></chemistry> 4'-Bromospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On (0.48 g, 1.33 mmol) N, To a solution of N-dimethylformamide (5.00 mL) was added sodium hydroxide (0.08 g, 1.98 mmol, 60% dispersion in mineral oil) at 0 ° C. a drop. The reaction mixture was stirred for 0.5 hour, then a solution of 2- (bromomethyl) -5-trifluoromethyl) furan in N, N-dimethylformamide (1.00 mL) was added. The reaction mixture was stirred at ambient temperature for 16 hours, water (5.00 mL) was added slowly and quenched. The reaction mixture was extracted with ethyl acetate (3 x 20.0 mL), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate: hexane (35%) to give the title compound (0.46 g, 69%) as a colorless solid.¹1 H NMR (300MHz, CDCl₃) δ7.22-7.14 (m, 2H), 6.94 (dd, 1H), 6.73 (d, 1H), 6.46 (s, 1H), 6.39 (d, 1H), 6.04 (s, 1H) 5.86 (dd, dd, 2H), 4.94 (ABq, 2H), 4.92 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.0,157.2,151.6,151.5,149.3,143.4,142.2,130.5,127.8,129.6,120.1,116.0,112.7,109.5,107.9,102.5,101.6,93.3,77.1,59.6,37.1; MS (ES +) m / z 508.2 (M + 2).

Example 10.48 4'-Bromo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3 , 3'-Indole] -2'(1'H)-On synthesis

<chemistry num="172"><img file="JP5118627B2_D0203.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with 4'-bromo-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'(1'H) -on Subcritical modifications used were made to give the title compound as a colorless solid (76%). Melting point: 182 ~ 184 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.21-7.11 (m, 2H), 6.92 (dd, 1H), 6.74 (d1H), 6.41 (d, 1H), 6.38 (s, 1H), 6.37 (s, 1H), 5.10 (d, 1H) ), 5.02 (d, 1H), 4.87 (d, 1H), 4.81 (d, 1H), 4.53 (t, 2H), 2.98 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.3,162.4,162.2,151.5,143.4,130.2,127.7,120.5,120.0,119.7,118.4,117.0,112.7,112.6,109.5,107.8,92.9,77.1,72.4,59.1,37.0,28.9; MS (ES +) m / z 506.3 (M + 1).

Example 10.49 4'-Bromo-1'-Methylspiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="173"><img file="JP5118627B2_D0204.tif" /></chemistry> Following the procedure described in Example 10.47, a non-critical modification was made using indomethane in place of 2- (bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a colorless solid (79%). ). Melting point: 155 ~ 157 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.19 (d, 1H), 7.17 (s, 1H), 6.84 (dd, 1H), 6.46 (s, 1H), 6.08 (s, 1H), 5.86 (dd, 2H), 4.90 (ABq, 2H) ), 3.25 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.3,157.2,149.2,145.1,142.0,130.4,129.9,127.3,119.9,116.3,107.3,102.7,101.5,93.3,77.3,59.7,26.9; MS (ES +) m / z 376.4 (M + 2).

Example 10.50 tert-Butyl 4-[(4'-Bromo-2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -Il) Methyl] Piperidine-1-carboxylate synthesis

<chemistry num="174"><img file="JP5118627B2_D0205.tif" /></chemistry> Following the procedure described in Example 10.47, tert-butyl 4-({[(4-methylphenyl) sulfonyl] oxy} methyl) piperidine-1 was replaced with 2- (bromomethyl) -5- (trifluoromethyl) furan. A non-critical modification using -carboxylate gave the title compound as a colorless solid (43%).¹1 H NMR (300MHz, CDCl₃) δ7.17 (d, 2H), 6.83 (t, 1H), 6.46 (s, 1H), 6.04 (s, 1H), 5.87 (d, 2H), 4.89 (ABq, 2H), 4.11 (d, 2H) ), 3.73-3.42 (m, 3H), 2.66 (t, 2H), 2.03-1.90 (m, 1H), 1.43 (s, 9H);¹³C NMR (75MHz, CDCl₃) δ177.6,157.3,154.7,149.2,144.8,142.1,130.3,129.8,127.3,120.2,116.3,107.6,102.4,101.6,93.4,79.6,77.2,59.6,46.1,43.4,34.9,28.4; MS (ES +) m / z 581.4 (M + 23), 579.4 (M + 23), 503.3 (M-57), 501.3 (M-57).

Example 10.51 1'-[(3,5-dimethylisoxazole-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="175"><img file="JP5118627B2_D0206.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -on, and 2- (Bromomethyl) -5 A non-critical modification was made using 4- (chloromethyl) -3,5-dimethylisoxazole in place of-(trifluoromethyl) furan to give the title compound as a colorless solid (35%). Melting point: 165 ~ 167 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.24 (t, 1H), 7.16 (d, 1H), 7.05 (t, 1H), 6.72 (d, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 5.85 (d, 2H) ), 4.75 (ABq, 2H), 4.67 (ABq, 2H), 2.46 (s, 3H), 2.22 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.5,167.1,159.1,156.1,149.1,142.4,141.7,131.8,129.0,124.3,123.8,118.9,108.8,108.6,102.9,101.6,93.8,80.6,58.2,33.3,11.5,10.7; MS (ES +) m / z 391.3 (M + 1).

Example 10.52 1'-(2-Frillmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="176"><img file="JP5118627B2_D0207.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification was made using 2-chloromethylfuran in place of-(trifluoromethyl) furan to give the title compound (40%) as a colorless solid. Melting point: 110 ~ 112 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.1,155.9,149.0,148.9,142.6,142.3,141.8,132.2,128.9,123.8,123.5,119.5,110.6,109.3,108.7,103.1,101.5,93.6,80.4,58.2,37.1; MS (ES +) m / z 362.5 (M + 1).

Example 10.53 Synthesis of ethyl 5- (2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) pentanoate

<chemistry num="177"><img file="JP5118627B2_D0208.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification using ethyl 5-bromovalerate in place of-(trifluoromethyl) furan gave the title compound as a gum-like material (62%).¹1 H NMR (300MHz, CDCl₃) δ7.28 (t, 1H), 7.14 (d, 1H), 7.03 (t, 1H), 6.88 (d, 1H), 6.48 (s, 1H), 6.13 (s, 1H), 5.84 (d, 2H) ), 4.76 (ABq, 2H), 4.07 (q, 2H), 3.87-3.65 (m, 2H), 2.35 (t, 2H), 1.80-1.64 (m, 4H), 1.20 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.4,173.1,155.9,148.8,142.3,142.2,132.5,128.9,124.04,123.3,119.5,108.6,103.0,101.5,93.6,80.5,60.4,58.2,39.9,33.7,26.8,22.2,14.2; MS (ES + ) m / z 432.09 (M + 23).

Example 10.54 Synthesis of Ethyl 4- (2'-Oxospiro [Flo [2,3-f] [1,3] Benodioxole-7,3'-Indole] -1'(2'H) -Il) Butanoate

<chemistry num="178"><img file="JP5118627B2_D0209.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification using ethyl 4-bromobutyrate in place of-(trifluoromethyl) furan gave the title compound as a gum-like material (80%).¹1 H NMR (300MHz, CDCl₃) δ7.29 (t, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.84 (d, 2H) ), 4.76 (ABq, 2H), 4.11 (q, 2H), 3.88-3.71 (m, 2H), 2.40 (t, 2H), 2.03 (t, 2H), 1.21 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.4,172.8,156.0,148.9,142.4,142.2,132.4,129.0,124.0,123.3,119.4,108.7,103.0,101.5,93.6,80.5,60.7,58.2,39.6,31.2,22.6,14.3; MS (ES +) m / z 418.08 (M + 23), 396.1 (M + 1).

Example 10.55 1'-(1,2,4-oxadiazole-3-ylmethyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1 'H)-On synthesis

<chemistry num="179"><img file="JP5118627B2_D0210.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification was made using 3- (chloromethyl) -1,2,4-oxadiazole in place of-(trifluoromethyl) furan to give the title compound as a colorless solid (36%). Melting point: 160 ~ 162 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.39 (dt, 1H), 7.20-7.13 (m, 3H), 7.05 (d, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 5.86 (dd, 2H), 4.78 (ABq) , 2H), 4.68 (s, 2H);¹³C NMR (75MHz, CDCl₃) δ176.7,156.0,149.3,142.5,139.6,131.6,129.4,124.8,124.5,118.4,113.6,108.7,103.0,101.7,93.7,80.3,58.2,29.7,28.0; MS (ES +) m / z 365.2 (M +) 1).

Example 10.56 1'-{[5- (3-chlorophenyl) -2-furyl] methyl} spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-On synthesis

<chemistry num="180"><img file="JP5118627B2_D0211.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -on, and 2- (Bromomethyl) -5 A non-critical modification was made using 2- (chloromethyl) -5- [3-chlorophenyl] furan in place of-(trifluoromethyl) furan to give the title compound as a colorless solid (22%). Melting point: 205 ~ 207 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.55 (t, 1H), 7.46 (dt, 1H), 7.28 (d, 2H), 7.21-7.14 (m, 2H), 7.09-7.04 (m, 2H), 6.59 (d, 1H), 6.50 (s, 1H), 6.40 (d, 1H), 6.10 (s, 1H), 5.84 (dd, 2H), 4.98 (ABq, 2H), 4.80 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.2,155.9,152.5,149.2,148.9,142.4,141.7,134.8,132.1,132.0,130.1,128.9,127.5,124.0,123.7,123.6,121.7,119.4,110.8,109.2,106.9,103.0,101.5,93.6,80.4 , 58.2,37.3; MS (ES +) m / z 472.2 (M + 1).

Example 10.57 1'-(3-Chloropropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="181"><img file="JP5118627B2_D0212.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -on, and 2- (Bromomethyl) -5 A non-critical modification was made using 1-bromo-3-chloropropane in place of-(trifluoromethyl) furan to give the title compound as a colorless solid (22%). Melting point: 144 ~ 146 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.31 (dt, 1H), 7.14-7.12 (m, 2H), 7.01 (t, 1H), 6.65 (s, 1H), 6.23 (s, 1H), 5.89 (s, 2H), 4.68 (ABq) , 2H), 3.85-3.79 (m, 2H), 3.67 (t, 2H), 2.06 (t, 1H);¹³C NMR (75MHz, DMSO-d₆) δ177.2,155.8,148.7,142.9,142.2,132.4,129.3,124.1,123.3,120.3,109.3,103.6,101.7,80.3,57.8,43.4,30.6; MS (ES +) m / z 358.2 (M + 1).

Example 10.58 1'-[(2-Isopropyl-1,3-oxazole-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2 '(1' H)-On synthesis

<chemistry num="182"><img file="JP5118627B2_D0213.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification using 4-chloromethyl-2-isopropyloxazole in place of-(trifluoromethyl) furan gave the title compound as a colorless solid (22%). Melting point: 118 ~ 120 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.97 (s, 1H), 7.24 (t, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 6.98 (t, 1H), 6.65 (s, 1H), 6.26 (s, 1H) ), 5.88 (d, 2H), 4.85 (d, 1H), 4.77 (d, 1H), 4.71-4.66 (m, 2H), 3.04-2.95 (m, 1H), 1.18 (dd, 6H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,169.1,155.6,148.7,142.4,142.2,136.8,135.2,132.4,129.2,123.9,123.4,120.5,109.9,103.6,101.9,93.7,79.9,57.9,36.2,28.1,20.7,20.6; MS (ES + ) m / z 405.2 (M + 1).

Example 10.59 1'-[(1-Methyl-1H-benzimidazol-2-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="183"><img file="JP5118627B2_D0214.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -on, and 2- (Bromomethyl) -5 A non-critical modification was made using 2- (bromomethyl) -1-methyl-1H-benzimidazole in place of-(trifluoromethyl) furan to give the title compound as a colorless solid (22%). Melting point:&gt; 250 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.71 (d, 1H), 7.65 (d, 1H), 7.54 (t, 1H), 7.39 (t, 1H), 7.30-7.24 (m, 1H), 7.16 (d, 1H), 7.05 (d , 2H), 6.63 (s, 1H), 6.49 (s, 1H), 6.44 (d, 1H), 6.11 (s, 1H), 5.83 (d, 2H), 4.99 (ABq, 2H), 4.80 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.2,155.9,150.6,149.6,148.9,142.3,141.7,132.1,131.8,129.8,128.9,127.9,126.8,126.7,126.6,123.9,123.6,119.4,111.0,110.9,110.6,109.3,103.1,101.5,93.6 , 80.4,58.2,37.3; MS (ES +) m / z 506.3 (M + 1).

Example 10.60 1'-[(2-oxo-1,3-benzothiazole-3 (2H) -yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'- Indole] -2'(1'H)-On synthesis

<chemistry num="184"><img file="JP5118627B2_D0215.tif" /></chemistry> Following the procedure described in Example 10.47, 4''-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3''-indole] -2'' (1'' H)-Replace with on Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3''-indole] -2'' (1'' H) -on, and A non-critical modification was made using 3- (bromomethyl) -benzo [d] thiazole-2 (3H) -one instead of 2- (bromomethyl) -5- (trifluoromethyl) furan to make the title compound a colorless solid. Obtained as (31%).¹1 H NMR (300MHz, DMSO-d₆) δ7.67 (d, 1H), 7.41 (d, 1H), 7.35-7.29 (m, 3H), 7.23-7.14 (m, 2H), 7.05 (t, 1H), 6.68 (s, 1H), 5.94 -5.85 (m, 5H), 4.69 (td, 1H);¹³C NMR (75MHz, DMSO-d₆) δ178.1,170.6,155.9,148.9,142.2,141.0,136.1,131.8,129.6,127.3,124.5,124.4,124.3,123.7,121.5,119.8,112.1,110.0,103.4,101.9,93.8,80.3,58.3,47.9; MS (ES +) m / z 467.2 (M + 23).

Example 10.61 1'-[(5-chloro-2-thienyl) methyl] -5'-fluorospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2' (1'H)-On synthesis

<chemistry num="185"><img file="JP5118627B2_D0216.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with 5'-fluorospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on, and 2-( A non-critical modification was made using 5-chloro-2- (chloromethyl) thiophene in place of bromomethyl) -5- (trifluoromethyl) furan to give the title compound as a colorless solid (76%). Melting point: 142 ~ 144 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.22-7.17 (m, 1H), 7.14-7.13 (m, 1H), 7.12-7.10 (m, 2H), 6.96 (d, 1H), 6.68 (s, 1H), 6.13 (s, 1H) , 5.91 (d, 2H), 5.02 (ABq, 2H), 4.73 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,161.0,157.8,156.0,149.0,142.2,138.3,138.2 (d,⁴J_CF= 7.0Hz) 133.6 (d,³J_CF= 33Hz), 128.3,127.8,127.1,119.5,115.6 (d,¹J_CF= 93Hz), 112.5 (d,¹J_CF= 100Hz), 110.8 (d,³J_CF= 32Hz), 103.2,102.0,93.9,79.8,58.2 (d,⁴J_CF= 7.0Hz), 39.0; MS (ES +) m / z 430.1 (M + 1).

Example 10.62 1'-[(5-chloro-2-furyl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H) -On synthesis

<chemistry num="186"><img file="JP5118627B2_D0217.tif" /></chemistry> Triethylamine (4.64 g, 45.9 mmol) followed by thionyl chloride (3.64 g, 30.6 mmol) in an anhydrous dichloromethane (50.0 mL) solution of ice-cooled (5-chloro-2-furyl) methanol (2.03 g, 15.3 mmol). Was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and quenched with saturated ammonia chloride (25.0 mL). After separating the aqueous layer, the organic layer was washed with 10% aqueous HCl solution (20.0 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum to give 5-chloro-2-chloromethylfuran as a yellow oil. Spiro [Flo [2,3-f] [1,3] in anhydrous N, N-dimethylformamide (9.00 mL) directly in anhydrous N, N-dimethylformamide (9.00 mL) without further purification of this oily anhydrous N, N-dimethylformamide (3.00 mL). Benzodioxol-7,3'-indole] -2'(1'H) -one (0.84 g, 3.00 mmol) and sodium hydroxide (0.48 g, 12.0 mmol) were added to the mixture. The reaction mixture was heated at 70 ° C. for 16 hours, cooled to ambient temperature, and then saturated ammonia chloride (5.0) was added. N, N-dimethylformamide was removed in high vacuum. The residue was diluted with ethyl acetate (100 mL), washed with 10% aqueous HCl solution (25.0 mL) and brine (25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The brown residue was subjected to column chromatography eluting with ethyl acetate / hexane (35%) to give the title compound (0.74 g, 62%) as a colorless solid. Melting point: 148 ~ 150 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.29 (t, 1H), 7.15-7.12 (m, 2H), 7.01 (d, 1H), 6.67 (s, 1H), 6.60 (d, 1H), 6.39 (d, 1H), 6.10 (s , 1H), 5.89 (d, 2H), 4.89 (ABq, 2H), 4.72 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9155.8149.7,148.8,142.2,142.1,134.8,132.1,129.3124.1,123.7120.2,112.0,109.9,108.2103.2,101.9,93.8,80.0,57.937.0; MS (ES +) m / z 396 (M + 1).

Example 10.63 1'-[(4-Hydroxy-1,2,2,6,6-pentamethylpiperidine-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7 , 3'-Indole] -2'(1'H)-On synthesis

<chemistry num="187"><img file="JP5118627B2_D0218.tif" /></chemistry> Non-using 5,5,6,7,7-pentamethyl-1-oxa-6-azaspiro [2.5] octane replaced with (5-chloro-2-furyl) methanol according to the procedure described in Example 10.62. Critical changes were made to give the title compound as a colorless solid (70%). Melting point: 210-214 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.29 (d, 1H), 7.24 (t, 1H), 7.10 (d, 1H), 7.01 (t, 1H), 6.66 (s, 1H), 6.45 (s, 1H), 5.90 (d, 2H) ), 5.20 (br, 1H), 4.70 (ABq, 2H), 3.57 (q, 2H), 3.30 (s, 3H), 2.01-1.83 (m, 4H), 1.45 (s, 6H), 1.34 (s, 6H);¹³C NMR (75MHz, DMSO-d₆) δ178.5,156.0,148.7,144.5,142.2,132.3,128.9,123.8,123.2,120.3,110.9,104.1,101.9,93.7,80.9,71.6,65.3,57.8,52.6,30.2,28.7,22.1; MS (ES +) m / z 465.4 (M + 1).

Example 10.64 1'-{[5- (2-chlorophenyl) -2-frill] Methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'( 1'H)-On synthesis

<chemistry num="188"><img file="JP5118627B2_D0219.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification was made to replace (5-chloro-2-furyl) methanol with [5- (2-chlorophenyl) -2-furyl] methanol to replace the title compound. Obtained as a colorless solid (48%). Melting point: 148 ~ 150 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.74 (d, 1H), 7.39 (d, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.19-7.15 (m, 2H), 7.08-7.04 (m, 3H), 6.51 (s, 1H), 6.45 (d, 1H), 6.12 (s, 1H), 6.84 (s, 2H), 4.99 (ABq, 2H), 4.78 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.2,155.9,150.3,149.0,148.6,142.4,141.8,132.1,130.8,130.0,128.9,128.7,128.2,127.7,126.9,123.9,123.6,119.4,111.8,110.7,109.2,103.1,101.5,93.6,80.4 , 58.2,37.3; MS (ES +) m / z 472.2 (M + 1).

Example 10.65 1'-[(5-Methyl-2-frill) Methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On synthesis

<chemistry num="189"><img file="JP5118627B2_D0220.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification was made using (5-methyl-2-furyl) methanol in place of (5-chloro-2-furyl) methanol to give the title compound as a colorless solid. (70%). Melting point: 117 ~ 119 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.26 (t, 1H), 7.12 (t, 2H), 6.99 (t, 1H), 6.67 (s, 1H), 6.32 (d, 1H), 6.07 (s, 1H), 5.97 (d, 1H) ), 5.89 (d, 2H), 4.84 (ABq, 2H), 4.72 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.8,155.7,151.9,148.8,147.7,142.3,142.2,132.1,129.2,124.0,123.5,120.4,110.1,110.0,107.0,103.2,101.9,93.8,79.9,57.9,37.2,13.7; MS (ES +) m / z 376 (M + 1).

Example 10.66 1'-[(5-Bromo-2-furyl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H) -On synthesis

<chemistry num="190"><img file="JP5118627B2_D0221.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification was made to replace (5-chloro-2-furyl) methanol with (5-bromo-2-furyl) methanol to give the title compound as a colorless solid. (76%).¹1 H NMR (300MHz, DMSO-d₆) δ9.29 (s, 1H), 7.69 (dt, 1H), 7.32-7.26 (m, 2H), 7.04 (d, 1H), 6.99 (d, 1H), 6.71 (d, 1H), 6.02 (s , 1H), 4.91 (ABq, 2H), 4.47 (t, 2H), 3.08 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,160.4,156.3,153.8,149.7,146.1,137.5,130.9,130.8,126.5,125.8,123.1,121.5,118.8,116.4,108.3,96.7,76.6,71.9,45.7,29.1; MS (ES +) m / z 440.1 (M + 1), 442.1 (M + 1).

Example 10.67 1'-[(5-chloro-2-thienyl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H) -On synthesis

<chemistry num="191"><img file="JP5118627B2_D0222.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification was made using (5-chloro-2-thienyl) methanol in place of (5-chloro-2-furyl) methanol to give the title compound as a colorless solid. (77%). Melting point: 145 ~ 146 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.28 (t, 1H), 7.20-7.14 (m, 2H), 7.10 (d, 1H), 7.01 (t, 1H), 6.95 (d, 1H), 6.67 (s, 1H), 6.09 (s) , 1H), 5.89 (d, 2H), 5.02 (ABq, 2H), 4.71 (ABq, 2H); MS (ES +) m / z 411.9 (M + 1).

Example 10.68 1'-{[3-Hydroxy-5- (trifluoromethyl) -2-thienyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H)-On synthesis

<chemistry num="192"><img file="JP5118627B2_D0223.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification using 2- (hydroxymethyl) -5- (trifluoromethyl) thiophen-3-ol in place of (5-chloro-2-furyl) methanol The title compound was obtained as a colorless solid (48%). Melting point: 225 ~ 227 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ10.4 (s, 1H), 7.29 (dt, 1H), 7.16-7.10 (m, 3H), 7.01 (dt, 1H), 6.68 (s, 1H), 6.09 (s, 1H), 5.89 (d , 2H), 4.94 (ABq, 2H), 4.70 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ176.9,155.8,152.3,148.9,142.2,141.9,132.1,129.4,125.9,125.4,124.5,124.2,123.8,122.6,120.9,120.0,116.5,109.5,103.3,101.9,93.8,80.2,57.9,34.9; MS (ES +) m / z 460.38 (M-1).

Example 10.69<u style="single">1'-((5- (2- (trifluoromethyl) phenyl) furan-2-yl) methyl) -6H-spiro [benzoflo [6,5-d] [1,3] dioxol-7,3'- Indoline] -2'-on</u>Synthesis of

<chemistry num="193"><img file="JP5118627B2_D0224.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification using {5- [2- (trifluoromethyl) phenyl] -2-furyl} methanol instead of (5-chloro-2-furyl) methanol The title compound was obtained as a colorless solid (28%). Melting point: 124 ~ 126 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.71 (d, 1H), 7.65 (d, 1H), 7.54 (t, 1H), 7.39 (t, 1H), 7.30-7.24 (m, 1H), 7.16 (d, 1H), 7.05 (d , 2H), 6.63 (s, 1H), 6.49 (s, 1H), 6.44 (d, 1H), 6.11 (s, 1H), 5.83 (d, 2H), 4.99 (ABq, 2H), 4.80 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.2,155.9,150.6,149.6,148.9,142.3,141.7,132.1,131.8,129.8,128.9,127.9,126.8,126.7,126.6,123.9,123.6,119.4,111.0,110.9,110.6,109.3,103.1,101.5,93.6 , 80.4,58.2,37.3; MS (ES +) m / z 506.27 (M + 1).

Example 10.70 1'[(2-Chloro-1,3-thiazole-5-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="194"><img file="JP5118627B2_D0225.tif" /></chemistry> Anhydrous CH of (2-chloro-1,3-thiazole-5-yl) methanol (0.30 g, 2.00 mmol)₂Cl₂Thionyl chloride (0.50 g, 4.20 mmol) and then triethylamine (0.40 g, 4.00 mmol) were added to the (20.0 mL) solution at 0 ° C. After stirring at 0 ° C for 1 hour and at ambient temperature for 1 hour, CH the reaction mixture₂Cl₂It was diluted with (50.0 mL) and extracted with water (2 x 20 mL). Organic phase Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in methyl-ethylketone (10.0 mL), then spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H)-. On (0.36 g, 2.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol) were added. The reaction mixture was heated at 70 ° C. overnight, cooled, filtered and the filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to give the title compound (0.032 g, 3.4%) as a colorless solid. Melting point: 195 ~ 198 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.81 (s, 1H), 7.39-6.93 (m, 5H), 6.66 (s, 1H), 6.15-6.12 (m, 1H), 5.89 (d, 2H), 5.10 (s, 2H), 4.70 (dd, 2H); MS (ES +) m / z 413.1 (M + 1).

Example 10.71 1'-{[5- (trifluoromethyl) -2-frill] methyl} -6,7-dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole ] -2'(1'H)-On synthesis

<chemistry num="195"><img file="JP5118627B2_D0226.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2'( Replaced with 1'H)-on 6,7-dihydrospiro [benzo [1,2-b: 4,5-b'] difuran-3,3'-indole] -2'(1'H) -on A non-critical modification was made using indole to give the title compound as a white solid (19%). Melting point: 174 ~ 177 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.33-6.95 (m, 5H), 6.84 (s, 1H), 6.71 (d, 1H), 5.88 (s, 1H), 5.03 (ABq, 2H), 4.70 (ABq, 2H), 4.46-4.31 (m, 2H), 3.07 (t, 2H); MS (ES +) m / z 428.0 (M + 1).

Example 10.72 1'{[5- (trifluoromethyl) -2-frill] methyl} 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] 2 '(1' H)-On synthesis

<chemistry num="196"><img file="JP5118627B2_D0227.tif" /></chemistry> Following the procedure described in Example 10.21, 5,5-dimethyl-5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] -2' (1'H)-Replace with on 5,6-dihydrospiro [benzo [1,2-b: 5,4-b'] difuran-3,3'-indole] 2'(1'H)-on A non-critical modification was made using indole to give the title compound as a white solid (71%). Melting point: 173 ~ 176 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.50-6.90 (m, 5H), 6.73 (d, 1H), 6.38 (s, 1H), 6.32 (s, 1H), 5.04 (ABq, 2H), 4.75 (ABq, 2H), 4.55-4.36 (m, 2H), 2.88 (t, 2H);¹³C NMR (75MHz, DMSO-d₆) δ177.2,161.7,161.0,153.5,142.0,140.3,139.7,139.2,132.6,129.1,124.1,123.8,121.2,121.0,120.3,119.1,117.7,114.6,114.5,110.4,109.6,93.0,80.0,72.5,57.3 , 36.8,28.7; MS (ES +) m / z 428.2 (M + 1).

Example 10.73 1'-{[5- (trifluoromethyl) -2-thienyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'( 1'H)-On synthesis

<chemistry num="197"><img file="JP5118627B2_D0228.tif" /></chemistry> 1'-{[3-Hydroxy-5- (trifluoromethyl) -2-thienyl] methyl} Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indol] Triethylamine (0.49 g, 0.70 mL, 4.85 mmol) and trifluoromethanesulfonic anhydride (0.91 g, 0.50) in a solution of -2'(1'H) -one (0.75 g, 1.62 mmol) anhydrous dichloromethane (12.0 mL). mL, 3.24 mmol) was added at 0 ° C under nitrogen. The reaction mixture was stirred for 30 minutes and quenched with saturated ammonia chloride (15.0 mL). After separating the aqueous layer, the organic layer was washed with 10% HCl (10.0 mL) and brine (10.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to obtain a gum-like substance as a triflate. Of this triflate (15.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.19 g, 0.17 mmol), triethylamine (1.66 g, 2.30 mL, 16.5 mmol) and formic acid (0.76 mg, 0.60 mL, 16.5 mmol) The mixture was heated to reflux in anhydrous dioxane (24 mL) for 16 hours. After cooling the reaction mixture to ambient temperature, the solvent was removed under reduced pressure. The black residue was diluted with ethyl acetate (50.0 mL), washed with 10% HCl (20.0 mL), saturated ammonia chloride (20.0 mL) and brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate: hexane (35%) to give the title compound (0.65 g, 89%) as a colorless solid. Melting point: 127 ~ 130 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.58-7.56 (m, 1H), 7.32-7.27 (m, 2H), 7.22 (s, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 7.09 (dt, 1H), 6.68 (s, 1H), 6.10 (s, 1H), 5.89 (d, 2H), 5.17 (ABq, 2H), 4.72 (ABq, 2H);¹³C NMR (75MHz, DMSO-d₆) δ177.0,155.9,148.9,144.7,142.2,141.8,132.1,130.6,130.5,129.3,128.7,128.0,124.3,123.9,120.0,109.8,103.3,102.0,93.9,80.2,57.8,38.7; MS (ES +) m / z 446.1 (M + 1).

Example 10.74 1'-{[3-Methoxy-5- (trifluoromethyl) -2-thienyl] methyl} spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H)-On synthesis

<chemistry num="198"><img file="JP5118627B2_D0229.tif" /></chemistry> 1'-{[3-Hydroxy-5- (trifluoromethyl) -2-thienyl] methyl} Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] A mixture of -2'(1'H) -one (0.18 g, 0.39 mmol), NaOH (0.08 g, 1.96 mmol) and iodomethane (0.17 g, 1.18 mmol) in anhydrous N, N-dimethylformamide (2.00 mL). , Stirred at ambient temperature for 16 hours. The reaction system was quenched by the addition of saturated ammonia chloride (10.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with water (3 x 20.0 mL) and brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The colorless solid was triturated with ether to give the title compound (0.15 g, 81%). Melting point: 178 ~ 180 ° C;¹1 H NMR (300MHz, DMSO-d₆) δ7.71 (s, 1H), 7.30 (dt, 1H), 7.15 (d, 1H), 7.07-7.02 (m, 2H), 6.68 (s, 1H), 6.08 (s, 1H), 5.89 (d , 2H), 4.95 (ABq, 2H), 4.70 (ABq, 2H), 3.90 (s, 3H);¹³C NMR (75MHz, DMSO-d₆) δ177.0,155.8,154.9,148.9,142.2,141.8,132.1,129.4,125.7,124.3,123.8,120.4,120.3,120.0,119.5,109.4,103.2,102.0,93.9,80.1,59.9,57.9,34.9; MS (ES + ) m / z 476.3 (M + 1).

Example 10.75 4'-Methyl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="199"><img file="JP5118627B2_D0230.tif" /></chemistry> 4'-Bromo-1'-((5- (trifluoromethyl) furan-2-yl) methyl) -6H-spiro [benzoflo [6,5-d] [1,3] dioxol-7,3'- Indoline] -2'-one (0.51 g, 1.00 mmol), lithium chloride (0.09 mg, 2.00 mmol), Pd₂(dba)₃Nitrogen was run through the mixture (0.09 mg, 10 mol%). Anhydrous 1-methyl-2-pyrrolidinone (5.00 mL) and tetramethyltin (0.27 mg, 0.20 mL, 1.50 mmol) were added to the above mixture. The reaction mixture was heated at 60 ° C. for 16 hours and quenched with saturated ammonia chloride (10.0 mL). The reaction mixture was extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate: hexane (20%) to give the title compound (0.07 g, 16%) as a colorless solid. Melting point: 117 ~ 119 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.18 (t, 1H), 6.82 (t, 2H), 6.72 (d, 1H), 6.47 (s, 1H), 6.37 (d, 1H), 6.09 (s, 1H), 5.86 (d, 2H) ), 4.95 (ABq, 2H), 4.83 (ABq, 2H), 2.03 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.6,156.2,152.0,149.1,142.3,141.3,135.6,129.4,128.9,126.0,120.6,117.2,112.7,112.6,109.2,106.5,102.9,101.6,93.3,78.4,58.3,37.0,17.1; MS (ES + ) m / z 444.1 (M + 1).

Example 10.76 5'-Methyl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole ] -2'(1'H)-On synthesis

<chemistry num="200"><img file="JP5118627B2_D0231.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Subcritical modification using 5'-methylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on To obtain the title compound (77%). Melting point: 96-98 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 6.38 (d, 1H), 6.11 (s, 1H) ), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80 (ABq, 2H), 2.29 (s, 3H); MS (ES +) m / z 444.2 (M + 1).

Example 10.77 1'-({5- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazole-3-yl} methyl) Spiro [Flo [2,3-f] [1,3] benzo Dioxol-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="201"><img file="JP5118627B2_D0232.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 Make a non-critical modification using 3-chloromethyl-5- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazole in place of-(trifluoromethyl) furan to make the title compound Obtained (44%).¹1 H NMR (300MHz, CDCl₃) δ8.22 (d, 2H), 7.76 (d, 2H), 7.30-7.18 (m, 2H), 7.06 (t, 1H), 6.91 (d, 1H), 6.51 (s, 1H), 6.40 (s , 1H), 5.88 (s, 2H), 5.17 (ABq, 2H), 4.86 (ABq, 2H); MS (ES +) m / z 508.1 (M + 1).

Example 10.78 1'-(2-thienylmethyl) spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one synthesis

<chemistry num="202"><img file="JP5118627B2_D0233.tif" /></chemistry> Following the procedure described in Example 10.62, a non-critical modification was made using 2-thiophene methanol in place of (5-chloro-2-furyl) methanol to give the title compound as a colorless solid (37%).¹1 H NMR (300MHz, CDCl₃) δ7.26-7.20 (m, 2H), 7.18-7.13 (m, 1H), 7.10-6.98 (m, 2H), 6.97-6.90 (m, 2H), 6.50 (s, 1H), 6.12 (s, 1H), 5.85 (d, 2H), 5.10 (ABq, 2H), 4.79 (ABq, 2H); MS (ES +) m / z 378.19 (M + 1).

Example 10.79 5-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] thiophene-2 -Synthesis of carbonitrile

<chemistry num="203"><img file="JP5118627B2_D0234.tif" /></chemistry> 1'-[(5-Bromo-2-thienyl) methyl] Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -On (0.23 g, 0.49 mmol), zinc cyanide (0.07 g, 0.59 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.10 g, 0.11 mmol), 1,1'-bis (diphenylphosphino) A mixture of ferrocene (0.06 g, 0.11 mmol), N, N-dimethylformamide (6.00 mL) and catalytic amount of water (2 drops) was heated at 120 ° C. for 24 hours. After cooling to ambient temperature, the organic phase was vacuum evaporated. The residue was extracted with ethyl acetate (5 x 15.0 mL) and the combined organic solution was passed through a Celite bed. The filtrate was washed successively with saturated aqueous ammonium chloride solution (25.0 mL), water (2 x 35.0 mL) and saline (40.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with 20-35% ethyl acetate in hexanes to give a solid, which was further purified by preparative thin layer chromatography eluting with 20% ethyl acetate in hexanes to give the title. The compound (0.09 g, 44%) was obtained.¹1 H NMR (300MHz, CDCl₃) δ7.50 (d, 1H), 7.32-7.16 (m, 2H), 7.12-7.04 (m, 2H), 6.86 (d, 1H), 6.51 (s, 1H), 6.08 (s, 1H), 5.87 (d, 2H), 5.10 (ABq, 2H), 4.78 (ABq, 2H); MS (ES +) m / z 403.0 (M + 1).

Example 10.80 5-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] -2- Synthesis of flonitrile

<chemistry num="204"><img file="JP5118627B2_D0235.tif" /></chemistry> Following the procedure described in Example 10.79, 1'-[(5-bromo-2-thienyl) methyl] spiro [flo [2,3-f] [1,3] benzodioxol-7,3'- Indole] -2'(1'H) -Replace with on 1'-[(5-Bromo-2-furyl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole- A non-critical modification using 7,3'-indole] -2'(1'H) -on gave the title compound as a colorless solid (44%). Melting point: 167 ~ 169 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.34-7.27 (m, 1H), 7.21-7.17 (m, 1H), 7.12-7.08 (m, 1H), 7.07-7.03 (m, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.44 (d, 1H), 6.08 (s, 1H), 5.86 (q, 2H), 4.96 (ABq, 2H), 4.78 (ABq, 2H); MS (ES +) m / z 387.2 (M + 1) ).

Example 10.81 1'-{[5- (Methylsulfonyl) -2-frill] Methyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1 'H)-On synthesis

<chemistry num="205"><img file="JP5118627B2_D0236.tif" /></chemistry> 1'-[(5-Bromo-2-furyl) Methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole]-2'(1'H) -On (0.70 g, 1.59 mmol), sodium methanesulfoxide (85%, 0.23 g, 1.91 mmol), copper (I) iodide (0.04 g, 0.22 mmol), L-proline (0.04 g, 0.35 mmol) and A mixture of dimethyl sulfoxide (4.00 mL) was heated at 100 ° C. After 3 days, the reaction mixture was cooled to ambient temperature, quenched with water (50.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography eluting with ethyl acetate: hexane (30-50%) to give the title compound (0.50 g, 71%). Melting point: 177 ~ 179 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.29 (t, 1H), 7.19 (d, 1H), 7.12-7.04 (m, 2H), 6.94 (d, 1H), 6.50 (s, 1H), 6.42 (d, 1H), 6.11 (s , 1H), 5.86 (s, 2H), 5.00 (ABq, 2H), 4.79 (ABq, 2H), 3.11 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.3,155.9,154.5,149.1,149.1,142.4,141.1,131.9,129.1,124.2,124.1,119.0,118.4,109.9,108.7,102.9,101.6,93.7,80.3,58.2,43.4,37.2; MS (ES +) m / z 440.0 (M + 1).

Example 10.82 1'-[(6-oxo-1,6-dihydropyridine-3-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2 '(1' H)-On Synthesis

<chemistry num="206"><img file="JP5118627B2_D0237.tif" /></chemistry> 1'-[(6-methoxypyridin-3-yl) methyl] spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H )-A mixture of on (0.23 g, 0.57 mmol), sodium iodide (0.28 g, 1.87 mmol) and water (2 drops) with 0 chlorotrimethylsilane (0.19 g, 1.78 mmol) in anhydrous acetonitrile (5.00 mL) Added at ° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with sodium bisulfite (0.20 g). The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2 x 25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was triturated with ether (2 x 10.0 mL) to give the title compound (0.16 g, 72%) as a pale yellow solid. Melting point: 247 ~ 250 ° C;¹1 H NMR (300MHz, DMSO-d_6,) δ11.50 (br, 1H), 7.50 (bd, 1H), 7.36-7.24 (m, 2H), 7.17-7.12 (m, 2H), 7.01 (dt, 1H), 6.67 (s, 1H), 6.28 (d, 1H), 6.09 (s, 1H), 5.91-5.88 (m, 2H), 4.78 (d, 1H), 4.67-4.62 (m, 3H); MS (ES +) m / z 389.15 (M + 1) ).

Example 10.83 1'-[(1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'- Indole] -2'(1'H)-On Synthesis

<chemistry num="207"><img file="JP5118627B2_D0238.tif" /></chemistry> Following the procedure described in Production Example 1A, 1'-[(6-oxo-1,6-dihydropyridine-3-yl) methyl] spiro [flo [2,3-f] [1] was replaced with 4-bromoindole. , 3] Benzodioxole-7,3'-indole] -2'(1'H) -one, and 1-bromopentane with a non-critical modification using methyl iodide, the title compound Obtained (78%). Melting point: 115 ~ 118 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.39-7.23 (m, 3H), 7.18 (d, 1H), 7.06 (t, 1H), 6.87 (d, 1H), 6.57-6.48 (m, 2H), 6.02 (s, 1H), 5.87 -5.83 (m, 2H), 4.90 (d, 1H), 4.75-4.52 (m, 3H), 3.51 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,162.5,155.9,149.1,142.4,141.6,139.7,137.6,132.1,129.1,124.4,123.9,121.3,119.1,114.0,108.6,102.8,101.6,93.7,80.3,58.2,40.8,38.0; MS (ES + ) m / z 403.3 (M + 1).

Example 10.84 Synthesis of 5-bromo-1'-[(5-chloro-2-thienyl) methyl] spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="208"><img file="JP5118627B2_D0239.tif" /></chemistry> Follow the procedure described in Example 10 and replace with spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on. Use 2-chloro-5- (chloromethyl) thiophene by substituting 5-bromospiro [1-benzofuran-3,3'-indole] -2'(1'H) -one with and 4-fluorobenzyl bromide. Subcritical modifications were made to give the title compound as a white solid (95%). Melting point: 140 ~ 142 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.33-7.26 (m, 2H), 7.16-7.02 (m, 2H), 6.94 (d, 1H), 6.97-6.75 (m, 4H), 5.07-4.91 (m, 3H), 4.68 (d, 1H); MS (ES +) m / z 446.7 (M + 1), 448.7 (M + 1).

Example 10.85 1'-[(5-Chloro-1,3,4-thiadiazole-2-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-indole] -2'(1'H)-On synthesis

<chemistry num="209"><img file="JP5118627B2_D0240.tif" /></chemistry> Spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on (0.56 g, 1.99 mmol) and (5-chloro- To a solution of 1,3,4-thiadiazole-2-yl) methanol (0.30 g, 1.99 mmol) in anhydrous tetrahydrofuran (12.0 mL) was added tributylphosphine (0.60 g, 2.99 mmol) at 0 ° C. The reaction mixture was stirred for 15 minutes, then N, N, N', N'-tetramethylazodicarboxamide (0.51 g, 2.99 mmol) was added. The reaction mixture was stirred at ambient temperature overnight, quenched with aqueous ammonium chloride (10.0 mL) and diluted with ethyl acetate (350 mL). The organic layer was washed with saturated aqueous sodium chloride solution (2 x 25.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/2) to give the title compound (0.20 g, 24%) as a yellowish solid. Melting point: 194 ~ 197 ° C;¹1 H NMR (300MHz, DMSO-d₆,) δ7.30 (dt, 1H), 7.20-7.12 (m, 2H), 7.05 (dt, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 5.90 (s, 2H), 5.43 ( d, 1H), 5.34 (d, 1H), 4.78 (d, 1H), 4.67 (d, 1H);¹³C NMR (75MHz, DMSO-d₆) δ177.2,168.3,155.8,155.4,148.9,142.2,141.9,132.2,129.4,124.2,124.0,120.1,109.8,103.7,101.9,93.8,80.1,67.5,57.9,25.6; MS (ES +) m / z 414.2 ( M + 1), 416.2 (M + 1).

Example 10.86 1'-[(1-Pyridine-2-ylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="210"><img file="JP5118627B2_D0241.tif" /></chemistry> 1'-(Piperidin-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indol]-2'(1'H) -On hydrogen bromide A mixture of acid salt (0.20 g, 0.44 mmol), 2-bromopyridine (0.16 mL, 0.65 mmol), tetrabutylammonium iodide (0.05 g) and DBU (0.16 mL, 1.09 mmol) in DMF (5.00 mL) 120 Heated at ° C for 15 hours. After cooling to ambient temperature, water (30.0 mL) was added. The above mixture was extracted twice with ethyl acetate (50.0 mL) and the combined organic phases were Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography eluting with 30% ethyl acetate in hexanes to give a white solid (0.05 g, 27%). Melting point: 95 ~ 97 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.17 (d, 1H), 7.47 (td, 1H), 7.31 (t, 1H), 7.18 (d, 1H), 7.06 (t, 1H), 6.92 (d, 1H), 6.66 (d, 1H) ), 6.59 (dd, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.91-5.84 (m, 2H), 4.91 (d, 1H), 4.66 (d, 1H), 4.42-4.27 ( m, 2H), 3.82-3.53 (m, 2H), 2.85 (t, 2H), 2.22-2.05 (m, 1H), 1.85-1.70 (m, 2H), 1.53-1.35 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.9,158.8,156.1,149.0,147.4,142.8,142.5,138.0,132.4,129.1,124.2,123.5,119.5,112.9,108.8,107.7,103.1,101.7,93.8,80.7,58.3,46.0,45.5,45.4,35.2 , 29.8,29.7; MS (ES +) m / z 456 (M + 1).

Example 10.87 1'-[(1-Phenyl-2-ylpiperidin-4-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="211"><img file="JP5118627B2_D0242.tif" /></chemistry> 1'-(Piperidin-4-ylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On hydrogen bromide Acid salt (0.20 g, 0.44 mmol), 2-bromobenzene (0.07 mL, 0.65 mmol), Pd₂(dba)₃A mixture of (0.03 g, 0.03 mmol), BINAP (0.06 g, 0.10 mmol) and NaOBut (0.13 g, 1.30 mmol) was heated in toluene at 100 ° C. for 15 hours under nitrogen. After cooling to ambient temperature, water (30.0 mL) was added. The above mixture was extracted twice with ethyl acetate (50.0 mL) and the combined organic phases were Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography eluting with 30% ethyl acetate in hexanes to give a white solid (0.10 g, 48%). Melting point: 76 ~ 78 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.37-7.16 (m, 4H), 7.12-6.80 (m, 5H), 6.53 (s, 1H), 6.14 (s, 1H), 5.87 (dd, 2H), 4.92 (d, 1H), 4.66 (d, 1H), 3.87-3.55 (m, 4H), 2.72 (t, 2H), 2.12-1.94 (m, 1H), 1.89-1.73 (m, 2H), 1.71-1.45 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.9,156.1,149.0,142.9,142.5,132.4,129.2,129.1,124.2,123.4,119.9,119.5,116.9,108.8,103.1,101.6,93.8,80.8,60.5,58.3,49.8,46.1,34.8,30.1,30.0 ; MS (ES +) m / z 455 (M + 1).

Example 10.88 Synthesis of 1'-(pyridin-2-ylmethyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one hydrochloride

<chemistry num="212"><img file="JP5118627B2_D0243.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with 6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -2- (trifluoromethyl) furan perform noncritical changes to use replace 2- (bromomethyl) pyridine hydrobromide to, 1 '- (pyridin-2-ylmethyl) -6- (trifluoromethyl meth carboxy) spiro [1-benzofuran -3 , 3'-Indole] -2'(1'H) -one was obtained and treated with 4.0 M HCl in dioxane to give the title compound (39%). Melting point: 150-152 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.89-8.78 (m, 1H), 8.62-8.47 (m, 1H), 8.07-7.00 (m, 2H), 7.42-6.70 (m, 7H), 5.52-5.31 (m, 2H), 5.05 (d, 1H), 4.89 (d, 1H);¹³C NMR (75MHz, CD₃OD) δ179.4,163.5,153.1,152.7,148.2,143.8,142.8,133.1,130.6,129.3,127.4,126.8,125.7,125.6,125.4,114.9,110.4,104.9,82.0,58.9,43.0; MS (ES +) m / z 413 (M + 1).

Example 10.89 Synthesis of 1'-(pyridin-3-ylmethyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one hydrochloride

<chemistry num="213"><img file="JP5118627B2_D0244.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with 6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5- (trifluoromethyl) furan Make a non-critical modification using (bromomethyl) pyridine hydrobromide in place of 1'-(pyridine-3-ylmethyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3' -Indole] -2'(1'H) -one was obtained and treated with 4.0 M HCl in dioxane to give the title compound (70%) as a white solid. Melting point: 151 ~ 153 ° C;¹1 H NMR (300MHz, CD₃OD) δ9.07-8.61 (m, 3H), 8.19-8.04 (m, 1H), 7.42-6.71 (m, 7H), 5.28 (s, 2H), 5.05 (d, 1H), 4.86 (d, 1H) );¹³C NMR (75MHz, CD₃OD) δ179.43,163.5,151.8,147.0,142.9,142.4,142.2,133.0,130.6,129.3,128.9,125.5,125.4,125.3,114.9,110.5,104.9,82.0,58.9,42.0; MS (ES +) m / z 413 (M + 1).

Example 10.90 6- (Trifluoromethoxy) -1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one Synthesis of

<chemistry num="214"><img file="JP5118627B2_D0245.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Substituted with a non-critical modification using 6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one to obtain the title compound as a white solid. (82%). Melting point: 78-80 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.33 (td, 1H), 7.21-6.98 (m, 3H), 6.86-6.73 (m, 2H), 6.67 (s, 2H), 6.42 (d, 1H), 5.09 (d, 1H), 5.04 (d, 1H), 4.88 (d, 1H), 4.77 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ176.7,161.7,151.9,150.6,141.5,131.7,129.5,127.5,124.2,124.2,124.0,114.1,112.8,112.8,109.6,109.2,104.3,80.7,57.6,37.1; MS (ES +) m / z 470 ( M + 1).

Example 10.91 Synthesis of 1'-(4-methoxybenzyl) -6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="215"><img file="JP5118627B2_D0246.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with 6- (trifluoromethoxy) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5- (trifluoromethyl) furan A non-critical modification was made using 4-methoxybenzyl chloride in place of the title compound as a white solid (91%). Melting point: 82 ~ 84 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.32-6.80 (m, 9H), 6.68 (s, 2H), 5.06 (d, 1H), 5.03 (d, 1H), 4.80 (d, 1H), 4.77 (d, 1H), 3.80 (s , 3H);¹³C NMR (75MHz, CDCl₃) δ171.1,161.8,159.4,150.5,142.3,132.0,129.2,128.9,127.7,124.1,124.0,123.7,122.2,118.8,114.4,114.1,109.7,104.3,80.9,57.6,55.4,43.9; MS (ES +) m / z 442 (M + 1).

Example 10.92 1'-(Cyclohexylmethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole]-2'(1'H) -On Synthesis

<chemistry num="216"><img file="JP5118627B2_D0247.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replace with Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -on, and 2- (Bromomethyl) -5 A non-critical modification was made using bromomethylcyclohexane in place of-(trifluoromethyl) furan to give the title compound as a white solid (74%). Melting point: 153 ~ 154 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.30 (td, 1H), 7.16 (d, 1H), 7.04 (t, 1H), 6.90 (d, 1H), 6.51 (s, 1H), 6.14 (s, 1H), 5.90-5.84 (m) , 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.72-3.44 (m, 2H), 1.94-1.60 (m, 6H), 1.32-0.99 (m, 5H);¹³C NMR (75MHz, CDCl₃) δ177.8,156.1,148.9,143.0,142.4,132.5,128.9,124.0,123.2,119.7,109.0,103.2,101.6,93.7,80.8,58.3,46.8,36.3,31.1,31.0,26.4,25.9,25.8; MS (ES + ) m / z 378 (M + 1), 400 (M + 23).

Example 10.93 1'-(Methylsulfonyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="217"><img file="JP5118627B2_D0248.tif" /></chemistry> Following the procedure described in Example 10.47, 4'-bromospiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -on Replaced with spiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -one, and 2- (bromomethyl) -5 A non-critical modification was made using methanesulfonyl in place of-(trifluoromethyl) furan to give the title compound as a white solid (51%). Melting point: 215 ~ 217 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.83 (d, 1H), 7.42-7.31 (m, 1H), 7.25-7.17 (m, 2H), 6.52 (s, 1H), 6.20 (s, 1H), 5.93-5.87 (m, 2H) , 4.98 (d, 1H), 4.68 (d, 1H), 3.46 (s, 3H);¹³C NMR (75MHz, CDCl₃) δ176.9,155.8,149.5,142.7,138.1,130.5,129.7,125.9,124.3,118.5,113.8,102.9,101.8,93.8,80.6,58.8,41.8; MS (ES +) m / z 360 (M + 1), 382 (M + 23).

Example 10.94 1'-(2-Piperidin-1-ylethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole]-2'(1'H) -On Hydrochloride Salt synthesis

<chemistry num="218"><img file="JP5118627B2_D0249.tif" /></chemistry> 1'-(2-Aminoethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indol]-2'(1'H) -On (0.20 g, A mixture of 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) and triethylamine (0.17 mL, 1.23 mmol) was refluxed in THF (10.0 mL) for 15 hours and concentrated to dryness under vacuum. The residue was subjected to a flash chromatograph eluting with 10% methanol in ethyl acetate and 1'-(2-piperidin-1-ylethyl) spiro [flo [2,3-f] [1,3] benzodioxole-7. , 3'-Indole] -2'(1'H) -one was obtained and treated with 4.0 M HCl in dioxane to give the title compound (28%). Melting point:&gt; 240 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.40 (t, 1H), 7.27-7.11 (m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71 ( d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H), 3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H);¹³C NMR (75MHz, CD₃OD) δ180.4,157.5,150.5,143.8,142.5,133.9,130.3,125.3,125.1,120.6,110.2,103.9,102.9,94.2,81.4,59.7,55.4,54.9,53.9,36.4,24.2,22.6; MS (ES +) m / z 393 (M + 1).

Example 10.95 1'-[2- (Pyridine-2-ylamino) Ethyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On and 1'-[2- (dipyridine2-ylamino) ethyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1' H)-On synthesis

<chemistry num="219"><img file="JP5118627B2_D0250.tif" /></chemistry> Following the procedure described in Example 10.87, 1'-(piperidine-4-ylmethyl) spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2' Replaced with (1'H) -on 1'-(2-aminoethyl) spiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'-(2- (pyridin-2-ylamino) ethyl) -spiro [fro [ 2,3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one obtained as the first fraction on the chromatograph as a white solid (5%) It was. Melting point: 61 ~ 63 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.05 (d, 1H), 7.50-6.97 (m, 5H), 6.57 (dd, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.03 (s, 1H), 5.85 (s) , 1H), 5.84 (s, 1H), 4.84 (d, 1H), 4.79 (t, 1H), 4.60 (d, 1H), 4.15-3.94 (m, 2H), 3.81-3.64 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.4,158.2,156.0,149.0,148.0,142.4,142.38,137.4,132.3,129.1,124.0,123.5,119.5,113.3,109.0,108.3,103.2,101.6,93.7,80.5,58.3,40.1,39.9; MS (ES + ) m / z 402 (M + 1). 1'-(2- (dipyridine2-ylamino) ethyl) -spiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2'(1'H) -On was obtained from the chromatograph as the second fraction (31%). Melting point: 165 ~ 167 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.31 (dd, 2H), 7.48 (d, 2H), 7.23 (t, 1H), 7.09-6.83 (m, 7H), 6.47 (s, 1H), 5.95 (s, 1H), 5.88-5.81 (m, 2H), 4.73 (d, 1H), 4.67-4.49 (m, 2H), 4.46 (d, 1H), 4.20 (t, 2H);¹³C NMR (75MHz, CDCl₃) δ177.6,157.0,156.0,148.8,148.4,143.1,142.3,137.4,132.3,128.9,123.6,123.1,119.6,117.5,114.5,109.3,103.4,101.6,93.6,80.7,58.2,45.9,39.5; MS (ES + ) m / z 479 (M + 1).

Example 10.96 tert-Butyl 4- [2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) Synthesis of ethyl] piperidine-1-carboxylate

<chemistry num="220"><img file="JP5118627B2_D0251.tif" /></chemistry> Non-using tert-butyl 4-(2-{[(4-methylphenyl) sulfonyl] oxy} ethyl) piperidine-1-carboxylate in place of 4-fluorobenzyl bromide, following the procedure described in Example 10. A critical modification was made to give the title compound in 95% yield. Melting point: 173 ~ 175 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.31 (t, 1H), 7.17 (d, 1H), 7.06 (t, 1H), 6.88 (d, 1H), 6.51 (s, 1H), 6.10 (s, 1H), 5.90-5.84 (m , 2H), 4.90 (d, 1H), 4.65 (d, 1H), 4.0-3.64 (m, 4H), 2.75-2.58 (m, 2H), 1.85-1.09 (m, 16H);¹³C NMR (75MHz, CDCl₃) δ177.5,156.0,155.0,149.0,142.4,142.2,132.6,129.0,124.2,123.4,119.5,108.6,103.0,101.6,93.8,80.5,79.5,58.3,38.0,34.0,33.9,32.1,31.9,28.6; MS (ES +) m / z 515 (M + 23), 393 (M-100).

Example 10.97 1'-(2-Piperidin-4-ylethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Hydrochloride Salt synthesis

<chemistry num="221"><img file="JP5118627B2_D0252.tif" /></chemistry> tert-Butyl 4- [2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) To a solution of ethyl] piperidine-1-carboxylate (0.94 g, 1.91 mmol) in dioxane (5.00 mL) was added 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at ambient temperature for 30 minutes, then anhydrous ether (40.0 mL) was added. The precipitated white solid was filtered, washed with ether and dried to give the title compound (0.75 g, 91%).¹1 H NMR (300MHz, CD₃OD) δ7.37 (t, 1H), 7.20-7.07 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 ( d, 1H), 3.97-3.75 (m, 2H), 3.45-3.33 (m, 2H), 3.01-2.85 (m, 2H), 2.15-2.01 (m, 2H), 1.82-1.37 (m, 5H);¹³C NMR (75MHz, CD₃OD) δ179.8,157.6,150.4,143.7,143.4,133.6,130.3,124.9,124.8,120.8,110.3,103.7,102.9,94.3,81.4,59.8,45.2,38.5,34.4,32.6,29.8,29.7; MS (ES +) m / z 393 (M + 1).

Example 10.98 1'-[2- (1-Cyclopentylpiperidin-4-yl) ethyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1 'H)-Synthesis of on-chloride

<chemistry num="222"><img file="JP5118627B2_D0253.tif" /></chemistry> Cyclopentanone (0.04 mL, 0.45 mmol) and triethylamine (0.12 mL, 0.84 mmol) in a solution of dichloroethane (5.00 mL) in 1'-(2-piperidin-4-ylethyl) spiro [Flo [2,3-f] [ 1,3] Benzodioxol-7,3'-indole] -2'(1'H) -one hydrochloride (0.12 g, 0.28 mmol) and sodium triacetoxybohydride (0.10 g, 0.45 mmol) added. The reaction mixture was stirred for 16 hours and concentrated to dryness under vacuum. The residue was subjected to a flash chromatograph eluting with ethyl acetate / methanol / ammonium hydroxide (15/1 / 0.1) and 1'-[2- (1-cyclopentylpiperidin-4-yl) ethyl] spiro [fro [2, 3-f] [1,3] benzodioxol-7,3'-indole] -2'(1'H) -one is obtained as a white solid, which is treated with 4.0 M HCl in dioxane. , Obtained with the title compound (0.05 g, yield: 32%). Melting point: 153 ~ 155 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.37 (td, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H), 6.11 (s, 1H), 5.88 (s, 1H), 5.87 (s, 1H), 4.83 ( d, 1H), 4.69 (d, 1H), 3.98-3.75 (m, 2H), 3.68-3.38 (m, 3H), 3.01-2.83 (m, 2H), 2.25-2.08 (m, 4H), 1.92- 1.37 (m, 11H);¹³C NMR (75MHz, CD₃OD) δ179.8,157.6,150.4,143.8,143.4,133.6,130.3,124.9,124.8,120.8,110.3,103.7,103.0,94.3,81.4,69.1,59.8,53.2,38.6,34.3,32.5,30.6,30.5,29.4, 24.7; MS (ES +) m / z 461 (M + 1).

Example 10.99 1'-[2- (1-Isopropylpiperidine-4-yl) ethyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1 'H)-Synthesis of on-chloride

<chemistry num="223"><img file="JP5118627B2_D0254.tif" /></chemistry> Following the procedure described in Example 10.98, a non-critical modification was made using acetone in place of cyclopentanone to give the title compound as a white solid (42%). Melting point: 155 ~ 156 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.37 (t, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H), 6.11 (s, 1H), 5.87 (s, 2H), 4.84 (d, 1H), 4.69 ( d, 1H), 3.98-3.75 (m, 2H), 3.58-3.38 (m, 3H), 3.05-2.85 (m, 2H), 2.23-2.09 (m, 2H), 1.82-1.44 (m, 5H), 1.35 (d, 6H);¹³C NMR (75MHz, CD₃OD) δ179.8,157.6,150.5,143.8,143.4,133.6,130.3,125.0,124.8,120.8,110.3,103.7,103.0,94.3,81.4,59.8,59.6,38.6,34.2,32.7,30.6,30.5,24.2,16.9. 15.4; MS (ES +) m / z 435 (M + 1).

Example 10.100 1'-[2- (1-cyclobutylpiperidin-4-yl) ethyl] Spiro [Flo [2,3f] [1,3] Benzodioxole-7,3'-Indole] -2'(1' H)-Synthesis of on-chloride

<chemistry num="224"><img file="JP5118627B2_D0255.tif" /></chemistry> Following the procedure described in Example 10.98, a non-critical modification was made using cyclobutanone in place of cyclopentanone to give the title compound as a white solid (81%). Melting point: 158 ~ 160 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.37 (t, 1H), 7.21-7.05 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 ( d, 1H), 3.98-3.39 (m, 5H), 2.85-2.59 (m, 2H), 2.43-1.42 (m, 13H);¹³C NMR (75MHz, CD₃OD) δ179.8,157.6,150.4,143.7,143.4,133.6,130.3,124.9,124.8,120.8,110.4,103.8,103.0,94.2,81.5,60.5,59.8,50.8,38.6,34.4,32.5,30.1,26.8,14.4; MS (ES +) m / z 447 (M + 1).

Example 10.101 1'-{2- [1- (Tetrahydro-2H-pyran-4-yl) piperidine-4-yl] ethyl} Spiro [Flo [2,3-f] [1,3] benzodioxol-7, 3'-Indole] -2'(1'H)-Synthesis of on hydrochloride

<chemistry num="225"><img file="JP5118627B2_D0256.tif" /></chemistry> Following the procedure described in Example 10.98, a non-critical modification was made using tetrahydro-4H-pyran-4-one in place of cyclopentanone to give the title compound as a white solid (45%). Melting point: 168 ~ 170 ° C;¹1 H NMR (300MHz, CD₃OD) δ7.37 (t, 1H), 7.21-7.06 (m, 3H), 6.52 (s, 1H), 6.11 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 ( d, 1H), 4.12-3.31 (m, 9H), 3.05-2.85 (m, 2H), 2.25-1.45 (m, 11H);¹³C NMR (75MHz, CD₃OD) δ179.8,157.6,150.4,143.7,143.4,133.6,130.3,125.0,124.8,120.8,110.3,103.8,102.9,94.3,81.4,67.2,64.1,59.8,50.7,38.6,34.2,32,7,30.6, 30.5,28.7; MS (ES +) m / z 477 (M + 1).

Example 11 4-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] of benzoic acid Synthetic

<chemistry num="226"><img file="JP5118627B2_D0257.tif" /></chemistry> Following the procedure described in Example 6, methyl 2-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2) Methyl 4-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1' by replacing'H) -yl) methyl] benzoate A non-critical modification using (2'H) -yl) methyl] benzoate gave the title compound (100%).¹1 H NMR (300MHz, CDCl₃) δ12.96 (s, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7.22 (t, 1H), 7.17 (d, 1H), 7.00 (t, 1H), 6.94 (d, 1H) ), 6.68 (s, 1H), 6.21 (s, 1H), 5.90 (s, 2H), 4.98 (s, 2H), 4.76 (ABq, 2H);¹³C NMR (75MHz, CDCl₃) δ177.4,167.5,156.0,148.9,142.6,142.3,141.8,132.1,130.5,130.3,129.3,127.7,124.2,123.7,120.1,109.9,103.5,101.9,93.8,80.4,58.0,43.4.

Example 12 N- (3-Fluorophenyl) -4-[(2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H )-Indole) Methyl] Synthesis of benzamide

<chemistry num="227"><img file="JP5118627B2_D0258.tif" /></chemistry> A.4-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] chloride Preparation of undiluted solution of benzoyl 4-[(2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) methyl] benzoic acid ( Oxalyl chloride (0.95 g, 7.50 mmol) was added to this while stirring a 2.08 g, 5.00 mmol) dry chloroform (50.0 mL) slurry, followed by a drop of DMF. The mixture was stirred at ambient temperature for 2 hours and evaporated to dryness under vacuum. The residue was dissolved in dry dichloromethane (60.0 mL) to give the acid chloride stock solution to be used.

BN- (3-Fluorophenyl) -4-[(2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H )-Indole) Methyl] Synthesis of benzamide To a solution of 3-fluorophenylamine (0.02 mL, 0.24 mmol) in dry dichloromethane (2.00 mL) and triethylamine (0.05 mL, 0.32 mmol), surround the acidified stock solution (2.0 mL, 0.081 M in dichloromethane) obtained above. Added at temperature. The mixture was stirred for 2 hours and washed with 15% HCl solution and water. Separate the organic layer and Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate and the product was precipitated by the addition of hexane. The white solid was filtered and collected to give the title compound (0.06 g) in 70% yield.¹1 H NMR (300MHz, CDCl₃) δ8.30 (s, 1H), 7.83 (d, 2H), 7.58 (ddd, 1H), 7.38 (d, 2H), 7.27-7.23 (m, 2H), 7.21-7.16 (m, 2H), 7.04 (dt, 1H), 6.85-6.78 (m, 1H), 6.74 (d, 1H), 6.46 (s, 1H), 6.10 (s, 1H), 5.77 (d, 1H), 5.68 (d, 1H), 4.97 (ABq, 2H), 4.76 (ABq, 2H); MS (ES +), m / z 509.1 (M + 1).

Example 12.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 12. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="8-1"><img file="JP5118627B2_D0259.tif" /></tables>

<tables num="8-2"><img file="JP5118627B2_D0260.tif" /></tables>

<tables num="8-3"><img file="JP5118627B2_D0261.tif" /></tables>

<tables num="8-4"><img file="JP5118627B2_D0262.tif" /></tables>

<tables num="8-5"><img file="JP5118627B2_D0263.tif" /></tables>

<tables num="8-6"><img file="JP5118627B2_D0264.tif" /></tables>

<tables num="8-7"><img file="JP5118627B2_D0265.tif" /></tables> Example 13 1'-(3-Hydroxypropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="228"><img file="JP5118627B2_D0266.tif" /></chemistry> 1'-[3- (benzyloxy) propyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On ( A suspension of 6.27 g, 14.5 mmol) and 10% Pd / C (0.5 g) in MeOH (150 mL) was hydrogenated overnight under atmospheric pressure of hydrogen and passed through a pad of Celite. The filtrate was concentrated to dryness under vacuum. The residue was crystallized from ether to give the title compound (4.82 g) as a white solid in 98% yield.¹1 H NMR (300MHz, CDCl₃) δ7.38-6.93 (m, 4H), 6.49 (s, 1H), 6.10 (s, 1H), 4.87 (m, 1H), 4.63 (m, 1H), 4.01-3.81 (m, 2H), 3.62 (t, 2H), 2.89 (br, 1H), 1.99-1.91 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.8,156.0,148.9,142.4,142.1,132.3,129.0,128.9,124.1,123.9,119.0,108.6,103.0,101.5,93.6,80.4,58.3,37.8,29.8; MS (ES +) m / z 340.2 (M +) 1).

Example 14 Synthesis of 3- (2'-oxospiro [flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) propanal 1'-(3-Hydroxypropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On (4.82g, 0 in a solution of 14.2 mmol) in dichloromethane (150 mL) with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxole-3 (1H) -one (7.00 g, 16.7 mmol) Added at ° C. The resulting mixture was stirred at 0 ° C for 4 hours, diluted with ethyl acetate and 10% Na.₂S₂O₃Solution, saturated LVDS₃And wash with saline solution in order, anhydrous Na₂SO₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash chromatograph and the product was recrystallized from ethyl acetate / hexane to give the title compound (3.86 g) in 80% yield.¹1 H NMR (300MHz, CDCl₃) δ9.83 (s, 1H), 7.33-6.92 (m, 4H), 6.48 (s, 1H), 6.08 (s, 1H), 4.86 (m, 1H), 4.61 (m, 1H), 4.15-3.98 (m, 2H), 2.97-2.84 (m, 2H); MS (ES +, m / z) 338.1 (M + 1).

Example 15 1'-{3-[(Cyclopropylmethyl) Amino] Propyl} Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H )-On synthesis

<chemistry num="229"><img file="JP5118627B2_D0267.tif" /></chemistry> 3- (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Propanal (0.07 g, To a solution of 0.20 mmol) in THF (5.00 mL) was added (aminomethyl) cyclopropane (0.30 mmol) and MP-triacetoxyborohydride (0.26 g, 0.60 mmol). After shaking overnight, polymer-bound 4-phenyloxybenzaldehyde (0.25 g, 0.18 mmol) was added. After shaking further overnight, the mixture was diluted with ether (10.0 mL) and filtered. The filtrate was concentrated to dryness under vacuum. The residue was recrystallized to give the title compound (0.05 g) as a white solid in a yield of 62%.¹1 H NMR (300MHz, CDCl₃) δ7.32-6.92 (m, 4H), 6.49 (s, 1H), 6.12 (s, 1H), 5.83 (m, 2H), 4.86 (m, 1H), 4.64 (m, 1H), 3.97-3.77 (m, 2H), 2.87-2.80 (m, 2H), 2.66-2.56 (m, 2H), 1.02-0.94 (m, 1H), 0.56-0.47 (m, 2H), 0.25-0.18 (m, 2H) ; MS (ES +) m / z 393.3 (M + 1).

Example 15.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 15. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="9-1"><img file="JP5118627B2_D0268.tif" /></tables>

<tables num="9-2"><img file="JP5118627B2_D0269.tif" /></tables>

<tables num="9-3"><img file="JP5118627B2_D0270.tif" /></tables>

<tables num="9-4"><img file="JP5118627B2_D0271.tif" /></tables>

<tables num="9-5"><img file="JP5118627B2_D0272.tif" /></tables> Example 16 1'-(3-Aminopropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="230"><img file="JP5118627B2_D0273.tif" /></chemistry> 2- [3- (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) propyl]- Hydrazine monohydrate (1.87 g, 37.0 mmol) was added to a solution of 1H-isoindole 1,3 (2H) -dione (3.20 g, 6.80 mmol) in ethanol (70.0 mL). The mixture was stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved again in ethyl acetate. The solution was washed with sodium bicarbonate and aqueous salt solution and deli₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was crystallized from hexane to give the title compound (2.50 g) in 75% yield.¹1 H NMR (300MHz, CDCl₃) δ7.31-7.24 (m, 1H), 7.16-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.94-6.91 (m, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 5.82 (m, 2H), 4.90-4.87 (m, 1H), 4.61 (d, 1H), 3.98-3.71 (m, 2H), 2.77-2.73 (m, 2H), 1.97 (br, 2H) , 1.84-1.81 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ177.8,155.9,148.9,142.3,142.2,132.4,129.0,124.0,123.4,119.4,108.7,103.0,101.5,93.6,80.5,58.2,38.8,37.5,30.6; MS (ES +) m / z 339.3 (M +) 1).

Example 17 3-Chloro-N- [3- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2'H) -yl ) Propyl] Synthesis of thiophene-2-carboxamide

<chemistry num="231"><img file="JP5118627B2_D0274.tif" /></chemistry> 1'-(3-Aminopropyl) Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole]-2'(1'H) -On (0.05g, Triethylamine (0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g, 0.12 mmol) were added to a solution of 0.13 mmol) in dichloromethane (4.00 mL) at 0 ° C. The mixture was stirred for 2 hours and washed with 15% HCl solution and water. EDTA the organic layer₄It was dried in and filtered. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate and the product was precipitated by the addition of hexane. The white solid was collected by filtration and dried in vacuo to give the title compound (0.04 g) in 67% yield.¹1 H NMR (300MHz, CDCl₃) δ7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27-(m, 1H), 7.17 (d, 1H), 7.08-7.03- (m, 1H), 6.93 (t, 1H) , 6.49 (s, 1H), 6.11 (s, 1H), 5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79- (m, 2H), 3.53-3.36- (m, 2H), 2.04-1.93- (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.3,160.6,156.0,149.0,142.4,141.8,132.5,129.4,129.2,129.1,124.2,123.7,123.6,119.2,108.5,102.9,101.6,93.7,80.5,58.3,37.4,36.5,27.3; MS (ES + ) m / z 483 (M + 1).

Example 17.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 17. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="10-1"><img file="JP5118627B2_D0275.tif" /></tables>

<tables num="10-2"><img file="JP5118627B2_D0276.tif" /></tables>

<tables num="10-3"><img file="JP5118627B2_D0277.tif" /></tables>

<tables num="10-4"><img file="JP5118627B2_D0278.tif" /></tables>

<tables num="10-5"><img file="JP5118627B2_D0279.tif" /></tables>

<tables num="10-6"><img file="JP5118627B2_D0280.tif" /></tables>

<tables num="10-7"><img file="JP5118627B2_D0281.tif" /></tables> Example 18 1'-(2-Aminoethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="232"><img file="JP5118627B2_D0282.tif" /></chemistry> 2- [2- (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Ethyl]- Hydrazine (8.00 mL) was added to a suspension of 1H-isoindole 1,3 (2H) -dione (20.0 g, 44.0 mmol) in methanol (400 mL). The mixture was stirred at ambient temperature for 48 hours and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to a flash chromatograph eluting with ethyl acetate / methanol / ammonia (10/1 / 0.2) to give a crude product, which was recrystallized from ethyl acetate to yield the title compound (8.0 g) as a white solid. Obtained at a rate of 56%.¹1 H NMR (300MHz, CDCl₃) δ7.34 (m, 1H), 7.17 (dd, 1H), 7.06 (dd, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 5.89-5.82-( ABq, 2H), 4.93 (d, 1H), 4.66 (d, 1H), 3.95-3.74- (m, 2H), 3.06 (t, 2H), 1.59-1.35-(br, 2H);¹³C NMR (75MHz, CDCl₃) δ178.0,155.9,148.8,142.3,132.4,128.9,124.0,123.4,119.5,108.6,103.1,101.5,93.6,80.5,58.2,43.4,39.8; MS (ES +) m / z 325 (M + 1), 308 (M-16).

Example 19 1- (4-fluorophenyl) -3- [2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -1'(2) 'H) -yl) ethyl] urea synthesis

<chemistry num="233"><img file="JP5118627B2_D0283.tif" /></chemistry> 1'-(2-Aminoethyl) Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2'(1'H) -On (0.15 mmol) And 1-fluoro-4-isocyanatobenzene (0.14 mmol) in anhydrous dichloromethane was added to the mixture of triethylamine (0.01 mmol) at ambient temperature. The mixture is stirred for 16 hours, diluted with dichloromethane (5.00 mL), washed with 10% HCl solution and brine, Na₂SO₄Dry and filter. The filtrate was concentrated to dryness under vacuum to give the title compound (0.05 g) in a yield of 82%.¹1 H NMR (300MHz, DMSO-d₆) δ8.54 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.06-6.91 (m, 3H), 6.67 (s, 1H), 6.52 (t, 1H), 5.94-5.84 (ABq, 2H), 4.74 (d, 1H), 4.61 (d, 1H), 3.91-3.69 (m, 2H), 3.49-3.34 (m, 2H); MS (ES + ) m / z 462 (M + 1), 484 (M + 23).

Example 19.1 The compounds listed in the table below were synthesized using a procedure similar to that described in Example 19. As mentioned above, the compound numbers listed below do not correspond to the compound numbers assigned in the previous general reaction scheme.

<tables num="11-1"><img file="JP5118627B2_D0284.tif" /></tables>

<tables num="11-2"><img file="JP5118627B2_D0285.tif" /></tables>

<tables num="11-3"><img file="JP5118627B2_D0286.tif" /></tables>

<tables num="11-4"><img file="JP5118627B2_D0287.tif" /></tables>

<tables num="11-5"><img file="JP5118627B2_D0288.tif" /></tables>

<tables num="11-6"><img file="JP5118627B2_D0289.tif" /></tables>

<tables num="11-7"><img file="JP5118627B2_D0290.tif" /></tables> Example 20 1'-Pentyl-7H-Spiro [Flo [3,4-f] [1,3] Benzodioxole-5,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="234"><img file="JP5118627B2_D0291.tif" /></chemistry> Following the procedure described in Example 1, 1- (2-cyclopropylethyl) -3- (6-hydroxy-1,3-benzodioxol-5-yl) -3- (hydroxymethyl) -1, Replaced with 3-dihydro-2H-indole-2-one 3-hydroxy-3- [6- (hydroxymethyl) -1,3-benzodioxol-5-yl] -1-pentyl-1,3- A non-critical modification using dihydro-2H-indole-2-one gave the title compound as a colorless solid (45%). Melting point: 113 ~ 115 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.24-7.33 (m, 1H), 7.12 (dd, 1H), 7.01 (t, 1H), 6.87 (d, 1H), 6.74 (s, 1H), 6.15 (s, 1H), 5.92 (dd) , 2H), 5.48 (d, 1H), 5.27 (d, 1H), 3.76-3.56 (m, 2H), 1.71-1.64- (m, 2H), 1.37-1.27- (m, 4H), 0.89-0.84 (m, 3H);¹³C NMR (75MHz, CDCl₃) δ175.9,148.7,148.1,143.6,133.7,132.1,130.3,129.8,125.3,125.0,123.1,113.5,109.1,108.7,101.9,101.7,88.7,74.4,40.0,29.7,29.0,25.3,13.3; MS (ES + ) m / z 352.1 (M + 1).

Example 21 1'-Pentyl Spiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2', 7 (1'H, 6H)-Zeon Synthesis

<chemistry num="235"><img file="JP5118627B2_D0292.tif" /></chemistry> [3- (1,3-Benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro1H-indole-3-yl] in a solution of acetic acid (0.28 g, 0.73 mmol), One drop of DMF and oxalyl chloride (0.32 mL, 3.7 mmol) was added in toluene (10 mL). The mixture was stirred at ambient temperature overnight and concentrated to dryness under vacuum to give a brown oil. This material was dissolved in dichloromethane (15.0 mL), then tin (IV) chloride (0.07 mL, 0.57 mmol) was added at 0 ° C. The mixture was stirred at ambient temperature overnight and quenched with ice water. The mixture was poured into water (100 mL) and the mixture was extracted with dichloromethane (150 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.09 g, 67%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.31 (td, 1H), 7.14 (s, 1H), 7.02 (td, 1H), 6.97-6.92 (m, 2H), 6.22 (s, 1H), 6.03-5.98 (m, 2H), 3.87 -3.63 (m, 2H), 3.17 (d, 1H), 2.85 (d, 1H), 1.79-1.66 (m, 2H), 1.41-1.30 (m, 4H), 0.88 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ201.4,177.5,154.8,151.8,149.6,143.1,132.5,131.6,128.9,123.4,123.2,108.9,103.5,102.6,102.5,53.8,47.7,40.5,29.0,27.1,22.3,14.0; MS (ES +), m / z 386.1 (M + 23), 364.1 (M + 1).

Example 22 1-Pentyl-6'H-Spiro [Indole-3,5'-Naft [2,3-d] [1,3] Dioxol] -2,8'(1H, 7'H)-Zeon Synthesis

<chemistry num="236"><img file="JP5118627B2_D0293.tif" /></chemistry> Following the procedure described in Example 21, [3- (1,3-benzodioxol-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] Replaced with acetic acid and used 3- [3- (1,3-benzodioxole-5-yl) -2-oxo-1-pentyl-2,3-dihydro-1H-indole-3-yl] propanoic acid The title compound was obtained as a white solid (32%).¹1 H NMR (300MHz, CDCl₃) δ7.57 (s, 1H), 7.37-7.28 (m, 1H), 7.08-7.03 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 5.95-5.91 (m, 2H) , 3.73 (t, 2H), 3.37-3.24 (m, 1H), 2.79-2.67 (m, 1H), 2.41-2.32 (m, 2H), 1.76-1.64 (m, 2H), 1.38-1.28 (m, 4H), 0.87 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ195.4,177.4,152.3,148.0,142.7,138.9,133.6,128.8,128.4,124.1,122.9,108.9,106.9,106.6,101.9,51.7,40.2,33.1,32.8,29.0,27.1,22.3,14.0; MS (ES + ) m / z 400.1 (M + 23), 378.1 (M + 1).

Example 23 1'-Pentyl-6,7-Dihydrospiro [Indeno [5,6-d] [1,3] Dioxosol-5,3'-Indole] -2'(1'H) -On synthesis

<chemistry num="237"><img file="JP5118627B2_D0294.tif" /></chemistry> 1'-Pentyl Spiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2', 7 (1'H, 6H) -Dion (0.04g, 0.11 mmol), A mixture of triethylsilane (1.50 mL) and trifluoroacetic acid (2.00 mL, excess) was stirred at ambient temperature overnight. The mixture was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.02 g, 47%) as an oil.¹1 H NMR (300MHz, CDCl₃) δ7.25 (td, 1H), 7.06-6.95 (m, 2H), 6.88 (d, 1H), 6.77 (s, 1H), 6.05 (s, 1H), 5.88-5.82 (m, 2H), 3.81 -3.60 (m, 2H), 3.37-3.24 (m, 1H), 3.13-3.01 (m, 1H), 2.70-2.59 (m, 1H), 2.44-2.32 (m, 1H), 1.76-1.64 (m, 2H), 1.39-1.28 (m, 4H), 0.88 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ179.5,147.9,147.0,142.9,138.2,136.7,134.7,128.1,123.5,122.6,108.3,105.3,103.6,101.2,59.9,40.0,38.3,31.6,29.0,27.1,22.6,14.0; MS (ES +) m / z 372.1 (M + 23), 350.1 (M + 1).

Example 24 1-Pentyl-7', 8'-Dihydro-6'H-Spiro [Indole-3,5'-Naft [2,3-d] [1,3] Dioxol] -2 (1H) -On Synthesis

<chemistry num="238"><img file="JP5118627B2_D0295.tif" /></chemistry> Following the procedure described in Example 23, 1'-Pentyl Spiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2', 7 (1'H, 6H) -Replace with Zeon 1-Pentil-6'H-Spiro [Indole-3,5'-Naft [2,3-d] [1,3] Dioxol] -2,8'(1H, 7'H)- A non-critical modification using dione gave the title compound as an oil (69%).¹1 H NMR (300MHz, CDCl₃) δ7.25 (td, 1H), 7.08-6.94 (m, 2H), 6.90 (d, 1H), 6.60 (s, 1H), 5.89 (s, 1H), 5.81-5.76 (m, 2H), 3.81 -3.66 (m, 2H), 2.96-2.77 (m, 2H), 2.38-2.24 (m, 1H), 2.17-2,06 (m, 1H), 2.02-1.83 (m, 2H), 1.78-1.65 ( m, 2H), 1.42-1.29 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ180.3,146.7,146.1,142.4,137.3,131.6,127.8,127.8,124.1,122.5,109.0,108.3,107.3,100.7,52.0,40.0,34.0,29.4,29.1,27.1,22.4,18.8,14.0; MS (ES + ) m / z 364.1 (M + 1).

Example 25 8', 8'-Difluoro1-Pentyl-7', 8'-Dihydro 6'H-Spiro [Indole-3,5'-Naft [2,3-d] [1,3] Dioxol] -2 (1H )-On synthesis

<chemistry num="239"><img file="JP5118627B2_D0296.tif" /></chemistry> 1-Pentyl-6'H-Spiro [Indol-3,5'-Naft [2,3-d] [1,3] Dioxol] -2,8'(1H, 7'H) -Zeon (0.02 g, A mixture of 0.05 mmol), bis (2-methoxyethyl) aminosulfatrifluoride (0.50 mL) and a drop of ethanol was stirred in a Teflon® bottle at 85 ° C. for 72 hours and water was added slowly. Quenched. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.01 g, 47%) as an oil.¹1 H NMR (300MHz, CDCl₃) δ7.57 (s, 1H), 7.38-7.28 (m, 1H), 7.09-7.01 (m, 2H), 6.95 (d, 1H), 6.03 (s, 1H), 5.96-5.90 (m, 2H) , 3.73 (t, 2H), 3.38-3.24 (m, 1H), 2.79-2.67 (m, 1H), 2.41-2.32 (m, 2H), 1.77-1.63 (m, 2H), 1.39-1.28 (m, 4H), 0.90 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ195.4,177.4,152.3,148.0,142.7,138.9,133.6,128.8,128.4,124.1,122.9,108.9,106.9,106.6,101.9,51.7,40.2,33.1,32.8,29.0,27.1,22.3,14.0; MS (ES + ) m / z 422.2 (M + 23), 380.2 (M + 1).

Example 26 7-Hydroxy-1'-Pentyl-6,7-Dihydrospiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2'(1'H) -On synthesis

<chemistry num="240"><img file="JP5118627B2_D0297.tif" /></chemistry> 1-Pentil-6'H-Spiro [Indole-3,5'-Naft [2,3-d] [1,3] Dioxol] -2,8'(1H, 7'H) -Zeon (0.20g, Sodium borohydride (0.03 g, 0.83 mmol) was added to a solution of 0.55 mmol) in methanol (10.0 mL). The reaction mixture was stirred at ambient temperature for 2 hours, poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.18 g, 90%) as an oil.¹1 H NMR (300MHz, CDCl₃) δ7.36-7.29 (m, 1H), 7.11-6.99 (m, 3H), 6.93 (d, 1H), 5.98 (s, 1H), 5.94-5.87 (m, 2H), 5.16 (d, 1H) , 3.80-3.61 (m, 2H), 2.69 (br, 1H), 2.39 (d, 1H), 1.75-1.62 (m, 2H), 1.38-1.22 (m, 4H), 0.87 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ180.5,148.9,148.5,143.7,140.5,136.9,132.1,128.7,123.7,123.3,108.8,105.7,103.2,101.5,74.8,59.6,40.4,28.9,27.0,22.3,14.0; MS (ES +) m / z 388.4 (M + 23).

Example 27 7-Methoxy-1'-Pentyl-6,7-dihydrospiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2'(1'H) -On synthesis

<chemistry num="241"><img file="JP5118627B2_D0298.tif" /></chemistry> 7-Hydroxy-1'-Pentyl-6,7-Dihydrospiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2'(1'H) -On (0.05) Sodium hydroxide (0.01 mg, 0.21 mmol) was added to a solution of g, 0.14 mmol) in THF (10.0 mL) at 0 ° C. The reaction mixture was stirred for one and a half hours, then iodomethane (0.50 mL) was added. The mixture was stirred at ambient temperature for 2 hours, poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.03 g, 57%) as an oil.¹1 H NMR (300MHz, CDCl₃) δ7.26-7.18 (m, 1H), 6.98-6.82 (m, 4H), 6.10 (s, 1H), 5.88 (s, 2H), 5.26t, 1H), 3.88-3.63 (m, 2H), 3.45 (s, 3H), 2.71-2.54 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.29 (m, 4H), 0.90 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ178.3,148.9,148.4,142.4,136.8,136.6,135.1,128.1,123.1,122.6,108.5,105.0,103.2,101.5,82.7,57.9,55.6,43.4,40.3,29.1,27.2,22.4,14.0:MS (ES +) ) M / z 402.4 (M + 23).

Example 28 1'-Pentyl-6,7-dihydro-5H-Spiro [1,3-dioxolo [4,5-g] Isoquinoline-8,3'-Indole] -2', 5 (1'H) -Dione synthesis

<chemistry num="242"><img file="JP5118627B2_D0299.tif" /></chemistry> 1'-Pentyl Spiro [Indeno [5,6-d] [1,3] Dioxol-5,3'-Indole] -2', 7 (1'H, 6H) -Dione (0.10g, 0.28 mmol), A mixture of sodium azide (0.09 g, 1.40 mmol) and trifluoroacetic acid (2.00 mL) was stirred at 50 ° C. overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to flash column chromatography to give the title compound (0.08 g, 74%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.60 (s, 1H), 7.30 (td, 1H), 7.20 (dd, 1H), 6.98 (td, 1H), 6.93 (d, 1H), 6.32 (br, 1H), 6.21 (s, 1H) ), 5.97-5.92 (m, 2H), 4.02 (dd, 1H), 3.87-3.70 (m, 2H), 3.47 (dd, 1H), 1.80-1.66 (m, 2H), 1.42-4.30 (m, 4H) ), 0.90 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ175.8,165.2,151.6,147.9,141.7,134.3,130.9,129.0,124.5,123.2,122.9,109.0,108.5,105.4,101.9,51.9,48.2,40.4,29.1,27.1,22.3,14.0; MS (ES +) m / z 379.3 (M + 1).

Example 29 2'-oxo-1'-Pentyl-N-Pyridine-2-yl-1', 2'-Dihydrospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'- Indole] -4'-synthesis of carboxamide

<chemistry num="243"><img file="JP5118627B2_D0300.tif" /></chemistry> 4'-Bromo-1'-Pentylspiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indole]-2'(1'H) -On (0.28g, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (0.08 g, 10 mol%), triethylamine (0.33 g, 0.50 mL, 3.25 mmol) and 2-aminopyridine (0.12 g, 1.30 mmol) in N , Exposed to carbon monoxide (40 Psi) in N-dimethylformamide (5.00 mL). The reaction mixture was heated at 80 ° C. for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL), washed with water (3 x 20.0 mL) and brine (2 x 20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography to give the title compound (0.04 g, 14%) as a solid.¹1 H NMR (300MHz, CDCl₃) δ8.52 (d, 1H), 7.87 (br, 1H), 7.69-7.62 (m, 3H), 7.53-7.51 (m, 1H), 7.47-7.38 (m, 3H), 7.04-6.98 (m, 1H), 5.79 (d, 2H), 4.97 (ABq, 2H), 3.84-3.66 (m, 2H), 1.77-1.67 (m, 2H), 1.38-1.33 (m, 4H), 0.90 (t, 3H) ;¹³C NMR (75MHz, CDCl₃) δ177.5,158.2,156.7,149.2,143.5,142.1,132.2,132.0,131.9,131.8,129.6,128.6,128.4,121.8,118.2,110.7,102.0,101.4,93.9,79.5,77.2,58.5,40.6,29.0,27.0 , 22.3,14.0; MS (ES +) m / z 473.2 (M + 2).

Example 29.1 N- (3-Methoxyphenyl) -2'-oxo-1'-Pentyl-1', 2'-dihydrospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3' -Indole] -4'-Synthesis of carboxamide

<chemistry num="244"><img file="JP5118627B2_D0301.tif" /></chemistry> Following the procedure described in Example 29, a non-critical modification was made using 3-methoxyaniline in place of 2-aminopyridine to give the title compound as a colorless solid (20%). Melting point: 173 ~ 175 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.42 (t, 1H), 7.30-7.27 (m, 1H), 7.14 (t, 1H), 7.04-6.97 (m, 2H), 7.23 (s, 1H), 6.74-6.62 (m, 2H) , 6.31 (s, 1H), 6.16 (s, 1H), 5.83 (dd, 2H), 4.87-5.01 (m, 2H), 3.91-3.63 (m, 5H), 1.73-1.78 (m, 2H), 1.37 -1.32 (m, 4H), 0.93-0.86 (m, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,165.1,159.9,149.3,143.6,143.5,142.1,138.1,134.5,129.7,129.5,127.9,122.4,118.3,112.2,110.7,110.5,105.6,101.9,101.6,94.3,79.2,58.3,55.3,40.5 , 28.9,26.9,22.3,13.9; MS (ES +) m / z 501.5 (M + 1).

Example 30 2'-oxo-1'-Pentyl-1', 2'-Dihydrospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -4'-Carbonitrile Synthesis of

<chemistry num="245"><img file="JP5118627B2_D0302.tif" /></chemistry> 4'-Bromo-1'-Pentyl Spiro [Flo [2,3-f] [1,3] Benzodioxol-7,3'-Indol]-2'(1'H) -On (0.10g, 0.23 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.21 g, 0.23 mmol) and 2- (di-tert-butylphosphino) biphenyl (0.07,0.23 mmol), tributyltincyanide (0.07 g, 0.07 g,) A mixture of 0.23 mmol) and potassium cyanide (0.02 g, 0.23 mmol) was purged with nitrogen and anhydrous acetonitrile (10.0 mL) was added. The reaction mixture was refluxed for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL), washed with water (20.0 mL) and brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The brown residue was subjected to column chromatography eluting with ethyl acetate / hexane (65%) to give the title compound (0.03 g, 33%), which was recrystallized from ether to give a colorless solid. Melting point: 128 ~ 129 ° C;¹1 H NMR (300MHz, CDCl₃) δ9.10 (s, 1H), 7.42-7.37 (m, 1H), 7.29-7.27 (m, 1H), 7.09 (d, 1H), 6.53 (s, 1H), 6.03 (s, 1H), 5.87 (dd, 2H), 4.91 (q, 2H), 3.86-3.63 (m, 2H), 1.74-1.62 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.5,157.1,149.5,143.5,142.4,135.4,129.7,128.3,126.4,116.3,114.8,112.3,108.8,102.2,93.7,78.7,58.3,40.6,28.9,26.7,22.2,13.9; MS (ES +) m / z 377.5 (M + 1).

Example 31 1'-Hexyl Spiro [1,3-Dioxolo [4,5-g] Chromen-8,3'-Indole] -2', 6 (1'H, 7H) -Zeon Synthesis

<chemistry num="246"><img file="JP5118627B2_D0303.tif" /></chemistry> THF: H of 2- (1-hexyl-3- (6-hydroxybenzo [d] [1,3] dioxol-5-yl) -2-oxoindoline-3-yl) acetate (0.19 g, 0.43 mmol)₂Lithium hydroxide (0.04 g, 0.86 mmol) was added to the O (2: 1) solution. The mixture was stirred at ambient temperature for 4 hours. The organic solvent was removed under vacuum, the pH of the aqueous residue was adjusted to 2, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum and the residue was subjected to column chromatography eluting with 25% ethyl acetate / hexane to give the title compound (0.09 g, 53%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.33 (dt, 1H), 7.14-7.03 (m, 2H), 6.93 (d, 1H), 6.66 (s, 1H), 6.06 (s, 1H), 5.88 (dd, 2H), 3.76-3.63 (m, 2H), 2.94 (q, 2H), 1.69-1.62 (m, 2H) 1.34-1.22 (m, 6H), 0.83 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ175.9,165.8,148.3,147.2,144.6,142.6,129.9,129.6,123.8,123.4,114.7,109.2,105.1,101.9,99.8,49.6,40.3,37.2,31.2,27.2,26.4,22.4,13.9; MS (ES + ) m / z 394.5 (M + 1).

Example 32 1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole]-2'(1'H) -On Synthesis

<chemistry num="247"><img file="JP5118627B2_D0304.tif" /></chemistry> 6-Bromo-1'-Pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.10 g, 0.27 mmol) and palladium / carbon (0.09 g, 0.01 mmol) The mixture was stirred in methanol / ethyl acetate (1 / 1,4.00 mL) at atmospheric pressure for 16 hours under hydrogen. The solvent was evaporated and the black residue was subjected to a column chromatograph (ethyl acetate / hexane, 1/6) to give the title compound (0.08 g, 97%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.30 (dd, 1H), 7.18 (dd, 1H), 7.20 (d, 1H), 7.02 (dd, 1H), 6.96-6.90 (m, 2H), 6.79 (dd, 1H), 6.69 (d , 1H), 4.93 (d, 1H), 4.67 (d, 1H), 3.89-3.64 (m, 2H), 1.81-1.66 (m, 2H), 1.44-1.31 (m, 4H), 0.92 (t, 3H) );¹³C NMR (75MHz, CDCl₃) δ177.2,160.7,142.5,132.8,129.7,129.0,128.8,123.9,123.3,123.1,121.3,110.4,108.6,58.1,40.4,29.0,27.2,22.3,14.0; MS (ES +) m / z 308.5 (M +) 1).

Example 33 6-Anilino-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="248"><img file="JP5118627B2_D0305.tif" /></chemistry> Aniline (1-benzofuran-3,3'-indole] -2'(1'H) -one (0.08 g, 0.19 mmol) in anhydrous toluene (4.00 mL) solution of 6-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] 0.03 g, 0.29 mmol), xanthophos (0.02 g, 0.03 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.02 g, 0.02 mmol) were added. The reaction mixture was refluxed for 16 hours, cooled to ambient temperature and concentrated to dryness under vacuum. The black residue was subjected to column chromatography (ethyl acetate / hexane, 1/7) to give the title compound (0.05 g, 62%) as a yellow oil.¹1 H NMR (300MHz, CDCl₃) δ7.40-7.25 (m, 6H), 7.18 (d, 1H), 7.12-7.05 (m, 3H), 6.98-6.90 (m, 2H), 6.71 (d, 1H), 6.57 (d, 1H) , 6.48 (dd, 1H), 4.93 (d, 1H), 4.67 (d, 1H), 3.88-3.64 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.30 (m, 4H), 0.92 (t, 3H); MS (ES +) m / z 399.5 (M + 1).

Example 34 6-Morpholine-4-yl-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On (1: 1) Synthesis

<chemistry num="249"><img file="JP5118627B2_D0306.tif" /></chemistry> Following the procedure described in Example 33, a non-critical modification was made using morphine in place of aniline to give the title compound as a brown oil (42%).¹1 H NMR (300MHz, CDCl₃) δ7.32 (d, 1H), 7.15 (d, 1H), 7.05 (dd, 1H), 6.91 (d, 1H), 6.59 (d, 1H), 6.50 (d, 1H), 6.35 (dd, 1H) ), 4.95 (d, 1H), 4.65 (d, 1H), 3.89-3.60 (m, 6H), 3.15-3.05 (m, 4H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H) ), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.5,162.2,153.4,142.6,132.9,128.7,123.9,123.4,123.0,120.1,108.9,108.5,97.9,80.3,66.9,57.7,49.4,40.3,29.0,27.1,22.4,14.0; MS (ES +) m / z 393.5 (M + 1).

Example 35 6-Amino-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="250"><img file="JP5118627B2_D0307.tif" /></chemistry> A.6-[(Diphenylmethylene) Amino] -1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis 6-Bromo-1'-Pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.10 g, 0.26 mmol) in anhydrous toluene (5.00 mL) solution with benzophenone imine (0.09 g, 0.52 mmol), sodium t-butoxide (0.03 g, 0.36 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.01 g, 0.07 mmol) and (±) -2,2'-bis (±) -2,2'-bis ( Diphenylphosphino) -1,1'-binaphthalene (0.12 g, 0.19 mmol) was added. The reaction mixture was refluxed for 16 hours, cooled to ambient temperature, diluted with dichloromethane (50.0 mL) and filtered through a Celite bed. The filtrate was concentrated to dryness under vacuum and the title compound was used in the next step without purification.

B.6-Amino-1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis 6-[(diphenylmethylene) amino] -1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one anhydrous tetrahydrofuran (4.00 mL) solution in 10% aqueous hydrochloric acid solution (2.00 mL) was added. The reaction mixture was stirred for 15 minutes, diluted with aqueous sodium hydrogen carbonate solution (5.00 mL) and extracted with ethyl acetate (3 x 25.0 mL). The combined organic solutions were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/1) to give the title compound (0.02 g, yield: 24%) as a yellow oil.¹1 H NMR (300MHz, CDCl₃) δ7.26 (td, 1H), 7.12 (d, 1H), 6.99 (dd, 1H), 6.89 (d, 1H), 6.43 (d, 1H), 6.23 (d, 1H), 6.08 (dd, 1H) ), 4.86 (d, 1H), 4.60 (d, 1H), 3.86-3.60 (m, 2H), 1.77-1.65 (m, 2H), 1.41-1.30 (m, 4H), 0.89 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ177.8,171.2,162.1,148.7,142.5,133.1,128.6,127.8,123.9,123.7,123.0,118.5,108.5,108.4,97.2,80.2,77.6,77.4,77.2,76.8,64.0,60.4,57.6,40.3,29.7 , 29.0,27.1,22.6,22.4,22.1,19.1,14.2,14.0,13.7; MS (ES +) m / z 323.5 (M + 1).

Example 36 1'-Pentyl-6-Phenoxy Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="251"><img file="JP5118627B2_D0308.tif" /></chemistry> 6-Bromo-1'-Pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.08 g, 0.19 mmol) in anhydrous dioxane (4.00 mL) solution iodide Copper (0.01 g, 0.01 mmol), N, N-dimethylglycine hydrochloride (0.01 g, 0.01 mmol), cesium carbonate (0.17 g, 0.52 mmol) and phenol (0.03 g, 0.32 mmol) were added. The resulting mixture was refluxed under nitrogen for 16 hours, diluted with dichloromethane (50.0 mL) and filtered through a Celite bed. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/6) to give the title compound (0.07 g, 87%) as a colorless oil.¹1 H NMR (300MHz, CDCl₃) δ7.36-7.28 (m, 3H), 7.20-7.00 (m, 4H), 6.92 (d, 1H), 6.62 (dd, 1H), 6.58 (br, 1H), 6.44 (dd, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 3.92-3.64 (m, 2H), 1.70-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); MS (ES + ) m / z 400.5 (M + 1).

Example 37 1'-Pentyl-6-Pyridine-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="252"><img file="JP5118627B2_D0309.tif" /></chemistry> 6-Bromo-1'-Pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.08g, 0.19 mmol), pyridine-3-boronic acid (0.05g, 0.41) N₂Below, it was heated for 16 hours while refluxing. The solvent was evaporated and the black residue was extracted with ethyl acetate (4 x 15.0 mL). The combined organic matter was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 4/1) to give the title compound (0.07 g, yield: 67%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ8.60 (br, 1H), 7.85 (d, 1H), 7.45-7.24 (m, 3H), 7.20-7.10 (m, 2H), 7.12-6.98 (m, 2H), 6.95 (d, 1H) , 6.81 (d, 1H), 5.05 (d, 1H), 4.78 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.9,161.6,149.5,147.3,142.6,139.9,136.4,135.6,133.4,130.1,129.2,124.9,121.7,119.5,110.3,109.7,107.7,80.1,57.8,42.3,28.8,27.1,22.3,14.85; MS (ES +) m / z 385.5 (M + 1).

Example 38 1'-Pentyl-6-Pyridine-4-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="253"><img file="JP5118627B2_D0310.tif" /></chemistry> Following the procedure described in Example 37, a non-critical modification was made using 4-pyridineboronic acid in place of 3-pyridineboronic acid to give the title compound as a white solid (38%). Melting point: 107 ~ 110 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.64-8.58 (m, 2H), 7.45-7.40 (m, 2H), 7.31 (dt, 1H), 7.19-7.13 (m, 2H), 6.93 (d, 1H), 6.79 (d, 1H) , 4.95 (d, 1H), 4.75 (d, 1H), 3.88-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.90 (t, 3H); MS (ES +) m / z 385.5 (M + 1).

Example 39 6- (Methylsulfonyl) -1'-Pentyl Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="254"><img file="JP5118627B2_D0311.tif" /></chemistry> 6-Bromo-1'-Pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.60 g, 1.55 mmol), sodium methanesulfinate (0.19 g, 1.86 mmol) , Copper iodide (0.03 g, 0.16 mmol) and L-proline (0.04 g, 0.31 mmol) in dimethyl sulfoxide (3.00 mL), N₂Below, it was heated at 100 ° C for 2 days. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (4 x 15.0 mL). The combined organic matter was dried over sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 2/3) to give the title compound (0.03 g, 46%) as a pale yellow oil.¹1 H NMR (300MHz, CDCl₃) δ7.46-7.48 (m, 1H), 7.38 (dt, 1H), 7.34 (dt, 1H), 7.13-7.02 (m, 2H), 6.94 (d, 1H), 6.86 (d, 1H), 5.03 (d, 1H), 4.78 (d, 1H), 3.87-3.64 (m, 2H), 3.02 (s, 3H), 1.79-1.68 (m, 2H), 1.41-1.32 (m, 4H), 0.90 (t , 3H);¹³C NMR (75MHz, CDCl₃) δ176.1,161.2,142.6,142.1,135.4,131.5,129.5,124.3,124.0,123.5,120.7,109.5,109.0,80.5,57.7,44.5,40.6,29.0,27.1,22.3,14.0; MS (ES +) m / z 386.5 (M + 1).

Example 40 1'-Pentyl-6- (Phenylsulfonyl) Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="255"><img file="JP5118627B2_D0312.tif" /></chemistry> Following the procedure described in Example 39, a non-critical modification was made using sodium phenylsulfinate in place of sodium methanesulfinate to give the title compound as a yellowish oil (50%).¹1 H NMR (300MHz, CDCl_3,) δ7.94-7.88 (m, 2H), 7.60-7.44 (m, 4H), 7.40 (dd, 1H), 7.31 (dt, 1H), 7.10-6.99 (m, 2H), 6.92 (d, 1H) , 6.78 (d, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.84-3.61 (m, 2H), 1.75-1.65 (m, 2H), 1.39-1.30 (m, 4H), 0.88 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.1,161.2,143.2,142.5,141.2,134.9,133.3,129.4,129.3,127.8,124.1,124.0,123.5,121.1,109.8,108.9,80.5,57.7,40.5,29.0,27.1,22.3,14.0; MS (ES + ) m / z 448.5 (M + 1).

Example 41 1'-Pentyl-5-Phenoxy Spiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="256"><img file="JP5118627B2_D0313.tif" /></chemistry> Following the procedure described in Example 36, 6-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -on was replaced with 5-bromo-1'. A non-critical modification using -pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one gave the title compound as a colorless oil (yield: 10%). ).¹1 H NMR (300MHz, CDCl₃) δ7.32-7.10 (m, 5H), 7.06-6.82 (m, 6H), 6.42 (d, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 3.82-3.62 (m, 2H) , 1.75-1.63 (m, 2H), 1.43-1.34 (m, 4H), 0.85 (t, 3H); MS (ES +) m / z 400.4 (M + 1).

Example 42 1'-(diphenylmethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) spiro [1-benzofuran-3,3'-indole] -2' (1'H)-On synthesis

<chemistry num="257"><img file="JP5118627B2_D0314.tif" /></chemistry> 5-Bromo-1'-(diphenylmethyl) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (3.00 g, 6.22 mmol), bis (pinacolato) diboron (1.80 g) , 7.09 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (0.45 g, 9 mol%) and potassium acetate (5.49 g, 56.0 mmol) in a mixture of anhydrous dimethyl sulfoxide (40.0). In mL), N₂Below, the mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (600 mL). The aqueous mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/6) to give the title compound (1.00 g, 30%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.68 (dd, 1H), 7.40-7.25 (m, 10H), 7.18 (br, 1H), 7.11 (dd, 1H), 7.06-6.91 (m, 4H), 6.50 (d, 1H), 4.99 (d, 1H), 4.74 (d, 1H), 1.27 (d, 12H); MS (ES +) m / z 530.32 (M + 1).

Example 43 Synthesis of 1'-(diphenylmethyl) -5-hydroxyspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="258"><img file="JP5118627B2_D0315.tif" /></chemistry> 1'-(diphenylmethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) spiro [1-benzofuran-3,3'-indole] -2' A mixture of (1'H) -one (4.50 g, 8.50 mmol), hydrogen peroxide (4.86 mL, 30% solution, 42.5 mmol) and sodium hydroxide (16.38 mL, 10% solution, 40.82 mmol) in methanol, The mixture was stirred at 0 ° C for 30 minutes and at an ambient temperature of 16 hours. The reaction mixture was quenched with sodium bisulfite. The pH of the reaction mixture was adjusted to 4 using 14% hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was milled with hexane (20.0 mL) and then ether (15.0 mL) to give the title compound (3.20 g, 90%) as a white solid.¹1 H NMR (300MHz, CDCl₃) δ7.45-7.38 (m, 10H), 7.13 (dd, 1H), 7.07-6.91 (m, 3H), 6.79 (d, 1H), 6.63 (dd, 1H), 6.50 (d, 1H), 6.12 (d, 1H), 4.96 (d, 1H), 4.69 (d, 1H); MS (ES +) m / z 420.23 (M + 1).

Example 44 5-Hydroxyspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="259"><img file="JP5118627B2_D0316.tif" /></chemistry> Following the procedure described in Example 1.28, 1'-(diphenylmethyl) -5'-methylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2 Non-critical using'(1'H) -one to replace 1'-(diphenylmethyl) -5-hydroxyspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one The title compound was obtained as a white solid (48%).¹1 H NMR (300MHz, DMSO-d₆) δ10.58 (s, 1H), 8.85 (s, 1H), 7.21 (dt, 1H), 7.06 (d, 1H), 6.94 (dd, 1H), 6.89 (d, 1H), 6.72 (d, 1H) ), 6.54 (dd, 1H), 6.02 (d, 1H), 4.70 (d, 1H), 4.57 (d, 1H); MS (ES +) m / z 254.2 (M + 1).

Example 45 Synthesis of 2'-oxo-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-yltrifluoromethanesulfonate

<chemistry num="260"><img file="JP5118627B2_D0317.tif" /></chemistry> In a mixture of 5-hydroxyspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.18 g, 0.70 mmol) and trifluoromethanesulfonic anhydride (0.26 g, 0.91 mmol) Triethylamine (0.14 g, 1.93 mmol) was added in dichloromethane (5.00 mL) at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and diluted with dichloromethane (100 mL). After washing with saturated aqueous sodium chloride solution (2 × 20.0 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/2) to give the title compound (0.07 g, 25%) as a pale yellow solid.¹1 H NMR (300MHz, CDCl₃) δ7.92 (br, 1H), 7.29 (dt, 1H), 7.15-7.03 (m, 3H), 7.99-6.94 (m, 2H), 6.69 (d, 1H), 5.03 (d, 1H), 4.76 (d, 1H); MS (ES +) m / z 386.5 (M + 1).

Example 46 2'-oxo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-yltrifluo Synthesis of lomethanesulfonate

<chemistry num="261"><img file="JP5118627B2_D0318.tif" /></chemistry> 2'-oxo-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-yltrifluoromethanesulfonate (0.42 g, 1.10 mmol) and sodium hydroxide (0.07 g, 1.65 mmol) 2- (Bromomethyl) -5- (trifluoromethyl) furan (0.50 g, 2.20 mmol) in N, N-dimethylformamide (5.00 mL) was added to the mixture at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 hours and diluted with ethyl acetate (200 mL). After washing with saturated aqueous sodium chloride solution (2 × 20.0 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate / hexane, 1/3) to give the title compound (0.47 g, 80%) as a clear oil.¹1 H NMR (300MHz, CDCl₃) δ7.34 (t, 1H), 7.18-6.94 (m, 5H), 6.74 (dd, 1H), 6.55 (dd, 1H), 6.40 (d, 1H), 5.09-4.72 (m, 4H); MS (ES +) m / z 534.4 (M + 1).

Example 47 5-Pyridine-3-yl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one Synthesis of hydrochloride

<chemistry num="262"><img file="JP5118627B2_D0319.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) Replaced with -N- (2-fluorophenyl) acetamide 2'-oxo-1'-{[5- (trifluoromethyl) -2-frill] methyl} -1', 2'-dihydrospiro [1-benzofuran Made a non-critical modification using pyridine-3-ylboronic acid in place of -3,3'-indole] -5-yltrifluoromethanesulfonate and pyrimidine-5-boronic acid, 5-pyridine-3-yl -1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one obtained as a white solid (74) %), This was treated with HCl in ether to give the title compound. Melting point: 98 ~ 100 ° C;¹1 H NMR (300MHz, CD₃OD) δ8.96 (br, 1H), 8.74-8.65 (m, 2H), 8.04 (dd, 1H), 7.73 (dd, 1H), 7.37 (dt, 1H), 7.25-7.09 (m, 5H), 6.95 (dd, 1H), 6.67 (d, 1H), 5.20-4.83 (m, 4H);¹³C NMR (75MHz, CD₃OD) δ175.7,161.3,151.1,142.1,140.2,138.6,137.5,137.4,130.0,129.4,128.1,127.5,125.6,125.5,122.3,122.1,120.8,111.4,111.3,109.7,108.1,107.7,78.7,58.3, 34.9; MS (ES +) m / z 463.1 (M + 1).

Example 48 1'-Pentyl-5-Pyridine-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="263"><img file="JP5118627B2_D0320.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide replaced with 5-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and pyrimidine-5 A non-critical modification was made using pyridine-3-ylboronic acid in place of -boronic acid to give the title compound as a white solid (70%).¹1 H NMR (300MHz, CDCl₃) δ8.55 (br, 1H), 7.65 (d, 1H), 7.45-6.98 (m, 7H), 6.92 (d, 1H), 6.85 (d, 1H), 4.98 (d, 1H), 4.72 (d , 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.86 (t, 3H); MS (ES +) m / z 385.5 (M + 1) ).

Example 49 1'-Pentyl-5-Pyrimidine-5-Ilspiro [1-Benzofuran-3,3'-Indole] -2'(1'H) -On Synthesis

<chemistry num="264"><img file="JP5118627B2_D0321.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) Non-critical using -N- (2-fluorophenyl) acetamide with 5-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one Modifications were made to give the title compound as a white solid (40%). Melting point: 115 ~ 117 ° C¹1 H NMR (300MHz, CDCl₃) δ9.08 (s, 1H), 8.74 (s, 1H), 7.41 (dd, 1H), 7.33 (dt, 1H), 7.16 (dd, 1H), 7.11-7.01 (m, 2H), 6.95 (d) , 1H), 6.86 (d, 1H), 5.01 (d, 1H), 4.75 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H) ), 0.88 (t, 3H); MS (ES +) m / z 386.4 (M + 1).

Example 50 1'-Pentyl-5-Pyridine-4-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one synthesis

<chemistry num="265"><img file="JP5118627B2_D0322.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide replaced with 5-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and pyrimidine-5 A non-critical modification was made using pyridine-4-ylboronic acid in place of -boronic acid to give the title compound as a white solid (95%).¹1 H NMR (300MHz, CDCl₃) δ8.55-8.47 (m, 2H), 7.52-7.46 (dd, 1H), 7.35-7.26 (m, 3H), 7.15 (dd, 1H), 7.07-7.00 (m, 2H), 6.97-6.92 ( m, 2H), 4.99 (d, 1H), 4.73 (d, 1H), 3.89-3.67 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); MS (ES +) m / z 385.5 (M + 1).

Example 51 Synthesis of 2'-oxo-1'-pentyl-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-carbonitrile

<chemistry num="266"><img file="JP5118627B2_D0323.tif" /></chemistry> Following the procedure described in Example 30, 4'-bromo-1'-pentylspiro [Flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( Make non-critical changes using 5-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -on to replace 1'H) -on. The title compound was obtained as a white solid (78%).¹1 H NMR (300MHz, CDCl₃) δ7.51 (dt, 1H), 7.34 (dt, 1H), 7.12-6.91 (m, 5H), 5.01 (d, 1H), 4.76 (d, 1H), 3.86-3.63 (m, 2H), 1.80 -1.68 (m, 2H), 1.43-1.32 (m, 4H), 0.92 (t, 3H);¹³C NMR (75MHz, CDCl₃) δ176.2,164.1,142.6,134.8,131.4,130.8,129.6,127.8,123.9,123.5,118.8,111.5,109.1,104.7,80.6,57.3,40.6,29.0,27.1,22.3,14.0; MS (ES +) m / z 333.5 (M + 1).

Example 52 Synthesis of N- (2-fluorophenyl) -2- (2'-oxo-5-pyridin-3-ylspiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) acetamide

<chemistry num="267"><img file="JP5118627B2_D0324.tif" /></chemistry> Following the procedure described in Example 37, 6-bromo-1'-pentylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -on was replaced with 2- (5-bromo). -2'-Oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) made a non-critical modification using acetamide and the title compound Was obtained as a white solid (yield: 55%). Melting point: 98 ~ 100 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.60-8.53 (m, 2H), 8.14 (dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d, 1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ177.9,164.8,160.9,154.2,151.0,147.1,141.7,134.2,131.7,131.5,129.9,129.4,129.1,125.1,124.6,124.5,124.2,124.0,122.5,122.2,115.1,114.8,111.0,109.1,80.0 , 58.1,44.6; MS (ES +) m / z 466.4 (M + 1).

Example 53 1'-[(5-Fluoro-1H-benzimidazol-2-yl) methyl] Spiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -2' (1'H)-On synthesis

<chemistry num="268"><img file="JP5118627B2_D0325.tif" /></chemistry> (2'-Oxospiro [Flo [2,3-f] [1,3] Benzodioxole-7,3'-Indole] -1'(2'H) -Il) Acetic acid (0.50 g, 1.47 mmol) And a mixture of 4-fluorobenzene-1,2-diamine (0.15 g, 1.18 mmol) in anhydrous toluene (20.0 mL), N₂Below, refluxed overnight. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under vacuum. The residue was subjected to column chromatography (ethyl acetate / hexane, 2/1) to give the title compound (0.13 g, 22%). Melting point: 138 ~ 142 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.47-7.39 (m, 1H), 7.32-7.22 (m, 2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H), 5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ179.2 161.3,158.1,156.2,149.2,149.1,142.5,141.2,131.5,129.5,124.4,124.0,118.0,111.6,111.2,109.9,103.1,101.7,93.5,80.5,58.5,38.9; MS (ES +) m / z 430.2 (M + 1).

Example 54 Synthesis of 1'-(diphenylmethyl) -5-pyridin-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="269"><img file="JP5118627B2_D0326.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) -N- (2-fluorophenyl) acetamide replaced with 5-bromo-1'-(diphenylmethyl) spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one, and A non-critical modification was made using pyridine-3-ylboronic acid in place of pyrimidin-5-boronic acid to give the title compound as a white solid (74%). Melting point: 204 ~ 207 ° C¹1 H NMR (300MHz, CDCl₃) δ8.62-8.46 (m, 2H), 7.62 (d, 1H), 7.43-7.26 (m, 11H), 7.16 (dd, 1H), 7.03-6.94 (m, 4H), 6.76 ((d, 1H) ), 6.54 (d, 1H), 5.09 (d, 1H), 4.82 (d, 1H); MS (ES +) m / z 481.5 (M + 1).

Example 55 Synthesis of tert-butyl 3- (2'-oxo-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-yl) piperidine-1-carboxylate

<chemistry num="270"><img file="JP5118627B2_D0327.tif" /></chemistry> A.5-Piperidin-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -on synthesis: Following the procedure described in Example 1.28, 1'-(diphenylmethyl) -5'-methylspiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -2 Use 1'-(diphenylmethyl) -5-pyridin-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -on instead of'(1'H) -on A non-critical modification was made to obtain the title compound, which was used in the next step.

Synthesis of B.tert-butyl 3-(2'-oxo-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5-yl) piperidine-1-carboxylate In a mixture of 5-piperidin-3-ylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one in anhydrous dichloromethane (15.0 mL), triethylamine (0.95 g, 9.36 mmol), Di-tert-butyldicarbonate (1.02 g, 4.68 mmol) was added at 0 ° C. N the reaction mixture at ambient temperature₂Underneath, the mixture was stirred overnight, diluted with dichloromethane (100 mL), and filtered through Celite. The filtrate was concentrated to dryness under vacuum. The brown residue was subjected to column chromatography (ethyl acetate / hexane, 1/1) to give the title compound (0.50 g, 40%) as a white solid. Melting point: 120 ~ 123 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.82 (br, 1H), 7.23-7.21 (m, 2H), 7.14-6.86 (m, 5H), 6.63 (br, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 4.10 -4.00 (m, 2H), 2.70-2.45 (m, 2H), 1.95-1.80 (m, 2H), 1.48-1.38 (m, 11H); MS (ES +) m / z 443.4 (M + 1).

Example 56 tert-Butyl 3- (2'-oxo-1'-{[5- (trifluoromethyl) -2-furyl] methyl} -1', 2'-dihydrospiro [1-benzofuran-3,3'-indole ] -5- Indole) Synthesis of piperidine-1-carboxylate

<chemistry num="271"><img file="JP5118627B2_D0328.tif" /></chemistry> Following the procedure described in Production Example 1A, replace with 4-bromoindole and replace with tert-butyl 3- (2'-oxo-1', 2'-dihydrospiro [1-benzofuran-3,3'-indole] -5. Subcritical changes were made using -yl) piperidine-1-carboxylate and 2- (bromomethyl) -5- (trifluoromethyl) furan in place of 1-bromopentane to give the title compound as a white solid. (10%). Melting point: 59 ~ 61 ° C¹1 H NMR (300MHz, CDCl₃) δ7.34-7.23 (m, 2H), 7.12 (d, 1H), 7.04-6.96 (m, 2H), 6.89 (d, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.41 (s, 1H), 5.10-4.86 (m, 3H), 4.66 (d, 1H), 4.16-3.94 (m, 2H), 2.68-2.38 (m, 2H), 1.90-1.60 (m, 3H), 1.40 (s, 10H), 1.27-1.21 (m, 1H); MS (ES +) m / z 591.2 (M + 23).

Example 57 5-Pyridine-4-yl-1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one Synthesis of hydrochloride

<chemistry num="272"><img file="JP5118627B2_D0329.tif" /></chemistry> Following the procedure described in Example 4.2, 2- (4'-bromo-5,6-difluoro2'-oxospiro [1-benzofuran-3,3'-indole] -1'(2'H) -yl) Replaced with -N- (2-fluorophenyl) acetamide 2'-oxo-1'-{[5- (trifluoromethyl) -2-frill] methyl} -1', 2'-dihydrospiro [1-benzofuran Made a non-critical modification using pyridine-4-ylboronic acid in place of -3,3'-indole] -5-yltrifluoromethanesulfonate and pyrimidine-5-boronic acid, 5-pyridine-4-yl -1'-{[5- (trifluoromethyl) -2-furyl] methyl} spiro [1-benzofuran-3,3'-indole] -2'(1'H) -one was obtained as a white solid, which Was treated with HCl in ethanol to give the title compound (54%). Melting point: 108 ~ 110 ° C;¹1 H NMR (300MHz, CDCl₃) δ8.57-8.47 (m, 2H), 7.52 (dd, 1H), 7.37-7.29 (m, 3H), 7.18 (dd, 1H), 7.12-7.00 (m, 3H), 6.92 (d, 1H) , 6.75 (dd, 1H), 6.43 (d, 1H), 5.114.83 (m, 3H), 4.75 (d, 1H);¹³C NMR (75MHz, CDCl₃) δ176.2,164.3,156.7,151.5,141.5,140.8,131.5,131.1,130.7,129.8,127.7,124.3,124.1,123.4,123.1,112.9,112.2,110.0,109.4,80.9 57.5,37.3 MS (ES +) m / z 466.4 (M + 1).

Example 58 Synthesis of 5-methoxy-1'-methylspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one

<chemistry num="273"><img file="JP5118627B2_D0330.tif" /></chemistry> 5-Hydroxyspiro [1-benzofuran-3,3'-indole] -2'(1'H) -one (0.10 g, 0.39 mmol), triphenylphosphine (0.20 g, 0.76 mmol) and methanol (0.05 g, To a mixture of 1.6 mmol) was added diethylazodicarboxylate (0.14 g, 0.80 mmol) in anhydrous tetrahydrofuran at 0 ° C. N the reaction mixture₂The mixture was stirred at the lower ambient temperature for 16 hours and concentrated to dryness under vacuum. The brown residue was subjected to column chromatography (ethyl acetate / hexane, 1/1) to give the title compound (0.02 g, yield: 14%) as a yellowish solid. Melting point: 159 ~ 161 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.32 (dt, 1H), 7.14 (d, 1H), 7.05 (t, 1H), 6.93-6.83 (m, 2H), 6.74 (dd, 1H), 6.25 (d, 1H), 4.89 (d , 1H), 4.63 (d, 1H), 3.63 (s, 3H), 3.28 (s, 3H); MS (ES +) 282.3 (M + 1).

Example 59 N- [2- (2'-oxospiro [Flo [2,3-f] [1,3] benzodioxole-7,3'-indole] -1'(2'H) -yl) ethyl]- Synthesis of 2- (trifluoromethoxy) benzamide

<chemistry num="274"><img file="JP5118627B2_D0331.tif" /></chemistry> Following the procedure described in Example 17, 1'-(3-aminopropyl) spiro [flo [2,3-f] [1,3] benzodioxol-7,3'-indole] -2'( 1'H)-Replace with on 1'-(2-aminoethyl) spiro [Flo [2,3-f] [1,3] Benzoyl chloride-7,3'-Indole] -2'(1 A non-critical modification was made using'H) -one and 2- (trifluoromethoxy) benzoyl chloride in place of 3-chlorothiophene-2-carbonyl chloride to give the title compound as a colorless solid (91%). ). Melting point: 183 ~ 184 ° C;¹1 H NMR (300MHz, CDCl₃) δ7.86-7.83 (m, 1H), 7.50-7.45 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.11 (m, 2H), 7.07-7.02 (m, 1H), 6.84 ( t, 1H), 6.47 (s, 1H), 6.10 (s, 1H), 5.82 (dd, 2H), 4.87 (d, 1H), 4.64 (d, 1H), 4.10-3.94 (m, 2H), 3.90 -3.68 (m, 2H);¹³C NMR (75MHz, CDCl₃) δ178.2,165.0,155.9,148.8,145.9,142.3,141.9,132.4,132.1,131.3,129.2,127.6,127.3,124.0,123.6,121.2,121.1,119.2,108.7,103.0,101.4,93.6,80.4,58.2,39.5 , 38.2; MS (ES +) m / z 513.4 (M + 1).

Biological assay Various techniques for testing the activity of the compounds of the present invention are known in the art. To fully understand the inventions described herein, the following biological assays are described. It should be understood that these examples are for illustration purposes only and do not construe the present invention as limiting in any way.

Biological Example 1 Guanidine influx assay (in vitro assay) This example describes an in vitro assay for testing test agents and profiling test reagents for human or rat sodium channels that are stably expressed in cells of endogenous or recombinant origin. The assay is also useful for measuring the sodium channel blocking compound IC-50. The assay is based on the guanidine influx assay described in Reddy, NL et al., J Med Chem (1998), 41 (17): 3298-302.

The granidine influx assay is a radiotracer flux assay used to measure the ion flux activity of sodium channels in a highly treated microplate format. The assay is combined with various known sodium channel modulators to assay the potential of the test reagents.¹⁴Use C-guanidine hydrochloride. Potential is measured by IC-50 calculation. Selectivity is measured by comparing the potential of a compound in a channel of interest to that potential with respect to other sodium channels (also referred to as "selective profiling").

Each test reagent is assayed against cells expressing the channel of interest. Potential-opening sodium channels are TTX-sensitive or insensitive. This property is useful for assessing the activity of channels of interest when remaining in a mixed group with other sodium channels. Table 1 below summarizes cell lines useful in screening for certain channel activity in the presence or absence of TTX.

<tables num="12"><img file="JP5118627B2_D0332.tif" /></tables> It is also possible to use recombinant cells that express these sodium channels. Cloning and proliferation of recombinant cells are known to those of skill in the art (eg, Klugbauer, N, et al., EMBO J. (1995), 14 (6): 1084-90; and Lossin, C. et al., Neuron (2002). ), 34, p877-884).

Cells expressing the channel of interest are grown by the supplier or, in the case of recombinant cells, in the presence of selective growth medium such as G418 (Gibco / Invitrogen). Cells are separated from culture dishes containing enzymatic solution (1X) Trypsin / EDTA (Gibco / Invitrogen) and analyzed for density and viability using a hemocytometer (Neubawell). The isolated cells were washed, resuspended in their culture, and then placed in Scintiplates (Beckman Carter) (approximately 100,000 cells / well) at 37 ° C / 5% CO.₂Incubate for 20 to 24 hours. Thoroughly wash with low sodium HEPES buffered saline (LNHBSS) (150 mM choline chloride, 20 nM HEPES (Sigma), 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose) and then with LNHBSS. Add diluted agent to each well. (Various concentrations of test reagents may be used.) Activation / radioactive label mixtures include aconitine (Sigma) and¹⁴Contains C-guanidine hydrochloride (ARC).

After loading the cells with the test reagent and the activated / radioactive label mixture, the Scintiplates are cultured at ambient temperature. After culturing, the Scint plates are thoroughly washed with guanidine-added LNHBSS (Sigma). Scintiplates are dried and then counted using Wallac MicroBeta TriLux (Perkin-Elmer Life Sciences). The ability of test reagents to block sodium channel activity resides within cells expressing different sodium channels.¹⁴Judgment by comparing the amount of C-guanidine. Based on this data, a wide variety of calculations, such as those described elsewhere herein, may be used to determine if the test reagents are selective for a particular sodium channel.

The IC-50 value of the test reagent for a particular sodium channel may be measured using the general method described above. IC-50s are performed 2 or 3 times using a 3, 8, 10, 12 or 16 point curve, starting at a concentration of 1, 5 or 10 μM, continuously diluting, sub-nanomol, nanomol and low micro. Measurements may be made so that the concentration reaches the range of the meter. Usually, the median concentration of the test reagent is set to 1 μM and continuous concentrations greater than or less than half the dilution are employed (eg 0.5 μM; 5 μM and 0.25 μM; 10 μM and 0.125 μM; 20 μM). Calculate IC-50 curve using 4-parameter logistic model or S-shaped capacitance-response model formula: (fit = (A + ((BA) / (1+ ((C / x) ^ D))))) To do.

Double selectivity, selectivity factor or multiple of selectivity, IC-50 value of test sodium channel control sodium channel, eg Na_VCalculated by dividing by a value of 1.5.

Biological Example 2 Electrophysiological assay (in vitro assay) Cells expressing the channel of interest were in DMEM growth medium (Gibco) with 0.5 mg / mL G418, +/- 1% PSG and 10% heat-inactivated fetal bovine serum at 37 C ° and 5% CO₂Incubated in. Cells were placed in a 10 mm dish for electrophysiological recording.

Whole cell recordings were examined by an established whole cell voltage clamping method (Bean et al., Supra) using an Axopatch 200B amplifier and Clampex software (Axon Instruments, Union City, CA). All experiments were performed at ambient temperature. The electrodes were tip-thermally machined against a voltage error resistance of 2-4 megaohms and capacitance artifacts were minimized by series resistance compensation and capacitance compensation, respectively. Data were acquired at 40 kHz and filtered at 5 kHz. External (bath) solutions are NaCl (140mM), KCl (5mM), CaCl₂(2mM), MgCl₂It is composed of (1 mM) and HEPES (10 mM) and has a pH of 7.4. Internal (pipette) solution is (mM unit) NaCl (5), CaCl₂(0.1), MgCl₂It is composed of (2), CsCl (10), CsF (120), HEPES (10) and EGTA (10) and has a pH of 7.2.

Steady-state affinity of the compound for rest and inactive state of the channel (K respectively)_rAnd K_i) Was used to plot a current-voltage relationship (IV curve) using 12.5 ms test pulses for a depolarizing voltage of -60 to + 90 mV from a holding potential of -110 mV. A voltage close to the peak of the IV curve (-30 to 0 mV) was used as the test pulse throughout the remaining time of the experiment. The steady-state inactivation (availability) curve is then drawn by measuring the activated current during the 8.75 ms test pulse after a 1-second conditioning pulse for potentials in the range -110 to -10 mV. did. To monitor the channel in steady state, create a signal "diary" protocol with a holding potential of -110 mV, dormant current (10 ms test pulse), rapid inactivation (-80 to -50 mV 5 ms prepulse followed by 10 ms The current after the test pulse) and the current between the various holding potentials (35 ms tilted to the test pulse level) were recorded. Compounds were applied during the "diary" protocol and blocks were monitored at 15 second intervals.

After the compound reached equilibrium, the voltage dependence of steady-state inactivation in the presence of the compound was measured. Compounds that block channel dormancy reduce the induced current during the test pulse from the total holding potential, while compounds that primarily block the inactive state during the test pulse at a more polarized potential. , Reduced the induced current. Hibernate current (I_rest) And the current between the inactive state (I)_inactivated) Was used to measure the steady-state affinity of the compound. Based on the Michaelis-Menten model of suppression, I_restOr I_inactivatedAs the concentration of compound required to cause 50% suppression of_rAnd K_iWas calculated.

<maths num="1"><img file="JP5118627B2_D0333.tif" /></maths> V_maxIs the rate of inhibition, h is the Hill coefficient (with respect to the interaction site), K_mIs the Michaelis-Menten constant and [drug] is the concentration of the test compound. I_restOr I_inactivated50% suppression (1 / 2V_max), The drug concentration is numerically K_mWill be the same as, each K_rAnd K_iApproximate to.

Biological Example 3 Painless sensation induced by sodium channel blockers Heat-induced tail flick latency test In this study, the analgesic effect produced by administration of the compounds of the invention was observed in mice via heat-induced tail flicks. The test includes a heat source consisting of a projection bulb with a light beam focused on a point above the tail of the mouse being tested. Tail flick latency is 40, 80, 120, which determines the response time before drug treatment and in response to adverse thermal stimuli, i.e., from the application of radiant heat on the back of the tail to the occurrence of tail flicks. And measured and recorded at 160 minutes.

The first part of this study evaluated the baseline tail flick latency for 65 animals once daily for two consecutive days. These animals were then randomly assigned to one of 11 different treatment groups, including vehicle control, morpholine control, and 9 compounds at 30 mg / kg were administered intramuscularly. After drug administration, animals were carefully monitored for signs of toxicity, including shaking or seizures, hyperactivity, shallow, rapid or suppressed breathing and grooming failure. The optimum culture time of the nuclear compound was measured by regression analysis. The analgesic activity of the test compound was expressed as a percentage of the highest possible effect (% MPE) and calculated using the formula below.

<maths num="2"><img file="JP5118627B2_D0334.tif" /></maths>During the ceremony Latent time after drug administration = Waiting time for individual animals to move (flick) their tail from the heat source after inoculation with the drug Latent time before drug administration = Wait time required for flicking the tail from the heat source before inoculating the drug for individual animals Cutoff time (10 seconds) = maximum irradiation to heat source.

Acute pain (formalin test) The formalin test is used as an animal model of acute pain. In the formalin test, animals were briefly conditioned in the Plexiglas laboratory for 20 minutes a day prior to the test day. On the day of the test, animals were randomly injected with the substance under test. Thirty minutes after drug administration, 50 μL of 10% formalin was subcutaneously injected into the sole of the left hind paw of the rat. Video data was taken immediately after formalin administration and lasted for 90 minutes.

Take the image using Actimetrix Limelight software,^*Save to a file with a .llii extension and then convert to MPEG-4 code. The video is then analyzed using the behavior analysis software "The Observer 5.1" (version 5.0, Nordus Information Technology, Wageningen, The Netherlands). Video analysis was performed by observing animal behavior, scoring each by type, and defining the length of behavior (Dubuisson and Dennis, 1977). Scored behaviors include (1) normal behaviors (2) no weight on the feet (3) raising the feet (4) licking / biting or scratching the feet. Raising, covering, or over-licking, chewing, and scratching the injected foot suggest a pain response. A painless response or compound protection is suggested if both feet are resting on the floor without apparently covering, over-licking, chewing or scratching the injected foot.

Analysis of formalin test data is performed according to two factors: (1) percent maximal potential inhibitory effect (% MPIE) and (2) pain score. % MPIE was calculated by a series of steps, first summing the lengths of abnormal behaviors (behaviors 1, 2, 3) of each animal. Single values in the vehicle group were obtained by averaging all scores within the vehicle treatment group. Obtain the MPIE value for each animal by the following calculation. MPIE (%) = 100-[(total treatment / average vehicle value) x 100%] The pain score is calculated from the surveyed scale as described above. To calculate the pain rate for each animal, multiply the duration and severity of the behavior (percentage of response severity) and divide the duration of the behavior by the overall length of the observation. The calculation is expressed by the following formula. Pain rate = [0 (To) + 1 (T1) + 2 (T2) + 3 (T3)] / (To + T1 + T2 + T3) The compounds of the present invention were shown to be effective in the range of 30 mg / kg and 0.1 mg / kg.

CFA-induced chronic inflammatory pain In this study, calibrated von Flyfilament was used to assess contact allodynia. After a full week of adaptation to the animal facility, a 0.5 mg / mL emulsion with CFA suspended in 150 μL of Complete Freud Adjuvant (CFA) emulsion (oil / saline (1: 1)). ) Was subcutaneously injected into the sole of the left hind paw of the rat under shallow isoflurane anesthesia. Animals were left awake from anesthesia and baseline thermal and mechanical nociception thresholds for all animals were evaluated 1 week after CFA administration. All animals were conditioned to the laboratory for 20 minutes a day before the start of the experiment. The test and control substances were administered to animals, the nociception threshold was measured at defined time points after drug administration, and the analgesic response was measured for each of the six possible treatments. The time points used were predetermined to show the highest analgesic response for each test compound.

Animal thermal nociception thresholds were assessed using the Hargreaves test. The animals were placed in a plexiglass enclosure placed on an ascending glass platform equipped with a heating unit. The glass platform is temperature regulated at a temperature of approximately 30 ° C for all preliminary tests. The animals were allowed to acclimatize for 20 minutes after being placed in the enclosure until there was no exploratory activity. Model 226 Sole / Tail Stimulation Painless Meter (IITC, Woodland Hills, CA) was used to irradiate a radiant heat beam from under the glass platform to the back of the hind paw. During all preliminary tests, the idle and active intensity of the heat source was set to 1 and 45, respectively, and a 20 second cutoff time was used to prevent tissue damage.

After the Hargreaves test, the threshold of action on the tactile sensation of animals was measured using a Model 2290 electric phone fly tactile meter (IITC Life Sciences, Woodland Hills, CA). The animals were placed in an ascending plexiglass enclosure placed on the surface of Myamesh. After 10 minutes of containment, pre-calibrated von Fry hair was applied perpendicularly to the sole surface of both feet of the animal with sufficient force to cause slight curling of the hair against the paw, starting with 0.1 g of hair. Raised in order. The test is continued until the hair measures the lowest force that induces quick flicker on the foot, or until the cutoff force reaches about 20 g. This cut-off force represents about 10% of the animal's body weight and was used because the use of stiffer hair helped prevent the entire leg from rising, which changes the nature of the stimulus. The compounds of the present invention were shown to be effective in the range of 30 mg / Kg and 0.1 mg / Kg.

Postoperative model of hyperalgesia In this model, hyperalgesia caused by an internal planar incision in the paw is measured by applying increased sensory stimuli to the paw until the animal removes the paw from the applied stimulus. Using a No. 10 scalpel while anesthetizing the animal under 3.5% isofloran fed through a nose cone, on the flat part of the left hind leg, through the skin and fascia, the proximal end of the heel A 1 cm longitudinal incision was made starting from 0.5 cm and extending towards the toes. After the incision, the skin was sewn using sterile silk sutures # 2, 3-0. The injured area was covered with polysporin and betadyne. Animals were returned to their home gauge overnight for recovery.

Retraction thresholds for sensory stimuli in animals for both operated (ipsilateral) and unoperated (contralateral) feet using a Model 2290 Electric Phone Fly Tactile Meter (IITC Life Sciences, Woodland Hills, CA). Can be measured. The animals were placed in an ascending plexiglass enclosure placed on the surface of Myamesh. At least 10 minutes after acclimatization, pre-calibrated von Fry hair was applied perpendicularly to the sole surface of both feet of the animal with sufficient force to cause slight curling of the hair against the paw, 0.1 g of hair. I started from and raised them in order. The test was continued until the hair measured the lowest force that induced quick flicker on the foot, or until the cutoff force reached about 20 g. This cut-off force represents about 10% of the animal's body weight and was used because the use of stiffer hair helped prevent the entire leg from rising, which changes the nature of the stimulus.

The compounds of the present invention have been shown to be effective in the range of 30 mg / Kg and 0.1 mg / Kg.

Neuropathic Pain Model; Chronic Atrophy Briefly, a scalpel No. 10 was used to make an incision of approximately 3 cm through the skin and fascia at the central level of the thigh of the animal's left hind leg. The left sciatic nerve was exposed through the blunt disection and through the biceps femoris, taking care to minimize bleeding. Four loose ligatures were tied along the sciatic nerve with # 0 non-degradable sterilized silk sutures at intervals of 1-2 mm. When viewed under an anatomical microscope at 4x magnification, the tension of the loose ligature was tightened enough to induce a slight stenosis of the sciatic nerve. In sham-surgery animals, the left sciatic nerve was exposed without further manipulation. An antibacterial ointment was applied directly to the wound and the muscles were closed using sterile sutures. Betadine was applied to and around the muscle and the skin was closed with a surgical clip.

The threshold of action on the tactile sensation of animals was measured using a Model 2290 electric phone fly tactile meter (IITC Life Sciences, Woodland Hills, CA). The animals were placed in an ascending plexiglass enclosure placed on the surface of Myamesh. After 10 minutes of containment, pre-calibrated von Fry hair was applied perpendicularly to the sole surface of both feet of the animal with sufficient force to cause slight curling of the hair against the paw, starting with 0.1 g of hair. Raised in order. The test is continued until the hair measures the lowest force that induces quick flicker on the foot, or until the cutoff force reaches about 20 g. This cut-off force represents about 10% of the animal's body weight and was used because the use of stiffer hair helped prevent the entire leg from rising, which changes the nature of the stimulus. The compounds of the present invention have been shown to be effective in the range of 30 mg / kg and 0.1 mg / Kg.

The thermal nociception threshold of animals was evaluated using the Hargreaves test. After the tactile threshold measurement, the animals were placed in a plexiglass enclosure placed on an ascending glass platform equipped with a heating unit. The glass platform is temperature regulated at a temperature of approximately 24-26 ° C for all preliminary tests. The animals were allowed to acclimatize for 10 minutes after being placed in the enclosure until there was no exploratory activity. Model 226 Sole / Tail Stimulation Painless Meter (IITC, Woodland Hills, CA) was used to irradiate the back of the foot from under the glass platform with a radiant heat beam. During all preliminary tests, the idle and active intensity of the heat source was set to 1 and 55, respectively, and a 20 second cutoff time was used to prevent tissue damage.

Biological Example 4 Aconitine-induced arrhythmia test The antiarrhythmic activity of the compounds of the present invention will be demonstrated by the following tests. Arrhythmias were induced by intravenous administration of aconitine (2.00 μg / Kg) dissolved in physiological saline. The test compound of the present invention was intravenously administered 5 minutes after the administration of aconitine. Antiarrhythmic activity was evaluated by measuring the time from aconitine administration to the onset of extrasystoles (ES) and the time from aconitine administration to the onset of ventricular tachycardia (VT).

In rats under isoflurane anesthesia (1/4 to 1/3 of 2%), first make an incision in the neck area, cut off the trachea, and then make a 2 mm incision, with the tube opening just above the mouth. A tracheostomy was performed by inserting a tracheal tube 2 cm into the trachea so that it was located. The tube was secured with suture and joined to the ventilator during the experiment.

An incision (2.5 cm) was then made in the femoral region and a blunt dissection probe was used to dissect the femoral vessels. Cannulas were inserted into both femoral veins, one for maintenance of pentobarbital anesthesia (0.02-0.05 mL) and the other for intravenous injection and injection of drugs and vehicles. The femoral artery was cannulated with a transmitter blood pressure gel catheter.

ECG reeds were attached to the chest muscles in the lead II position (upper right / above the heart-white lead and lower left / below the heart-red lead). The reed was fixed with suture.

All surgical areas were covered with gauze moistened with 0.9% saline. After surgery, saline (1-1.5 mL 0.9% solution) was supplied to moisten the area. Animal ECG and aeration were equilibrated for at least 30 minutes.

Intravenous aconitine injection of 2 μg / Kg / min was performed for 5 minutes to induce arrhythmia. During this time, ECG was recorded and continuously monitored. Intravenous bolus injection (10, 30 or 100 μg / kg) of the test compound of the present invention resulted in a complete return to normal baseline ECG.

Therefore, the compounds of the present invention demonstrated antiarrhythmic activity when tested in this model.

Biological Example 5 Ischemia-induced arrhythmia test The rodent model of ventricular arrhythmias in the severe cardioversion and prevention paradigm is being used to test potential treatments for atrial and ventricular arrhythmias in humans. Cardiac ischemia, which causes myocardial infarction, is a common cause of illness and death. The ability of compounds to prevent ischemia-induced acute ventricular tachycardia and fibrillation is acceptable for measuring the efficacy of compounds in the medical setting for acute atrial and ventricular tachycardia and fibrillation. It is a possible model.

Sensory paralysis is first induced by pentobarbital (ip) and maintained by intravenous iv bolus. Male SD rats have a trachea with a cannula for mechanical ventilation in the room air, with a single heartbeat of 10 ml / Kg and 60 strokes / minute. The right femoral artery and vein are cannulated with PE50 tubes for mean blood pressure (MAP) recording and intravenous administration of the compound, respectively.

There is an opening between the 4th and 5th ribs, with a 1.5cm opening to allow the heart to be seen. Each rat is placed on a notched platform and a metal restraint is hooked onto the thoracic cavity, which widens the thoracic cavity. A suture needle was used to penetrate the atrium just below the lifted atrium and exit the ventricles downward diagonally to obtain a&gt; 30% to &lt;50% occlusion area (OZ). The drain point is ~ 0.5 cm below where the aorta contacts the left ventricle. The suture was taut so that a loose loop (occluder) formed around the branch of the artery. The chest was then closed with one end of an obstructor accessible to the outside of the chest.

The electrodes were placed at the lead II position (tip of the right atrium) for ECG measurement as follows. One electrode was inserted into the right forelimb and the other into the left hind limb.

Body temperature, MAP, ECG and heart rate were constantly recorded throughout the experiment. Once the important parameters were stabilized, a 1-2 minute record was taken to establish baseline values. Once the baseline value was established, intravenous injection of the compounds or control substances of the invention was initiated. After 5 minutes of intravenous infusion of the compound or control, the suture was removed and tightly tied to the LCA, creating ischemia in the left ventricle. Important parameters were recorded continuously for 20 minutes after tying, unless the MAP reached a critical level of 20-30 mmHg for at least 3 minutes. In such cases, the animal was sentenced to death and stopped recording and then disposed of. The ability of the compounds of the invention to prevent arrhythmias and maintain near-normal MAP and HR was evaluated and compared to controls.

The compounds of the present invention demonstrated their ability to prevent ischemia-induced ventricular tachycardia and fibrillation when tested in this model.

All U.S. patents, U.S. patent application gazettes, U.S. applications, foreign patents, foreign patent applications and non-patent documents cited herein and / or cited in the application datasheet are hereby incorporated by reference in their entirety. Incorporate into the specification.

As described above, the present specification has described specific embodiments of the present invention for the sake of explanation, but various modifications may be made as long as they do not deviate from the spirit and scope of the present invention. Will be accepted. Therefore, the present invention is not limited to the scope of the appended claims.